Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Genetics - Health Professional Information [NCI]

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 PDQ summary on von Hippel-Lindau Disease 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. Treatment of MTC consists of surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection. In addition, risk-reducing thyroidectomy has been shown to reduce the subsequent incidence of persistent or recurrent disease in MEN2 patients who had thyroidectomy earlier in life. The timing of risk-reducing thyroidectomy is guided by the risks associated with specific RET variants, although basal calcitonin levels may be used to determine the optimal timing of the procedure. MEN2-related parathyroid disease may also be treated surgically or with medical therapy in high-risk surgical patients.

  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

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.

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.

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, particularly for differences that exist in the germline. 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 disease. 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 disease are discussed in the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and von Hippel-Lindau Disease.

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 was further stratified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family: MEN2A, familial medullary thyroid cancer (FMTC), and MEN2B (which is sometimes referred to as MEN3). FMTC is now considered a subtype of MEN2A.[1] 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.[2] 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.[3,4,5] 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.[6,7,8] 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. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.
2. Inherited tumour syndromes. In: Lloyd RV, Osamura RY, Klöppel G, et al.: WHO Classification of Tumours of Endocrine Organs. 4th ed. International Agency for Research on Cancer, 2017, pp. 262–66.
3. 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.
4. 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.
5. 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.
6. Stoffer SS, Van Dyke DL, Bach JV, et al.: Familial papillary carcinoma of the thyroid. Am J Med Genet 25 (4): 775-82, 1986.
7. Mazeh H, Sippel RS: Familial nonmedullary thyroid carcinoma. Thyroid 23 (9): 1049-56, 2013.
8. Lupoli G, Vitale G, Caraglia M, et al.: Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet 353 (9153): 637-9, 1999.

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:

• Parathyroid tumors and primary hyperparathyroidism (PHPT).
• Duodenopancreatic neuroendocrine tumors (NETs).
• Pituitary tumors.

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.[2,3,4]

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.[10,11,12]

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.[13,14,15] (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 type	Estimated Penetrance	Symptoms
MEN1 = multiple endocrine neoplasia type 1.
Gastrinoma	≤70%[7,18]	Peptic ulcer disease and esophagitis
		Diarrhea
		Abdominal pain
		Weight loss
Nonfunctioning	20%–55%[7,19]	Local compressive symptoms: abdominal pain, jaundice, anorexia, weight loss
Insulinoma	10%[7]	Whipple's triad: symptomatic hypoglycemia reversed by glucose administration with associated elevation of insulin, C-peptide, and proinsulin levels
Vasoactive intestinal peptide	1%[7,20]	Watery diarrhea
		Hypokalemia
		Achlorhydria
Glucagonoma	1%[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 carriers of MEN1 pathogenic variants undergoing prospective endoscopic ultrasonography of the pancreas.[19,23] These tumors can be metastatic. One study of 108 carriers of MEN1 pathogenic 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 MEN1gene 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 type	Estimated Penetrance	Symptoms
MEN1 = multiple endocrine neoplasia type 1.
Prolactinoma	20%[7]	Galactorrhea
		Amenorrhea/infertility
		Hypogonadism
Somatotropinoma	10%[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),[27] including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[28,29,30] The following manifestations have also been reported:[31,32,33]

• 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.[34] 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.[5,29] 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).[34] 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.[35] 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.[36] 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.[36] 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.[37,38] Figure 1 illustrates some of the challenges in identifying MEN1 in a family.

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.[39,40] In individuals with apparently isolated PHPT or pituitary adenomas, the pathogenic variant prevalence is lower, on the order of 2% to 5%,[25,41,42] 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:[7,43,44]

• 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.[3,45,46] Over 1,300 pathogenic variants have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[47,48] 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.[7,49,50] One large study demonstrated the highest rates of heritability for pituitary, adrenal, and thymic NETs.[51]

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%.[49,52] 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.[53] 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). 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.[54,55] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[56] 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.[57,58,59] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 pathogenic variants.[58,60,61] 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.[62] 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.[63] 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

Condition	Gene(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.
MEN1	MEN1	PHPT, pituitary adenomas, duodenopancreatic NETs[7,9,64]
FIHP	MEN1,HRPT2	PHPT[57,58,59,60,61]
HPT-JT	HRPT2	PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma[54,55,56]
FHH	CaSR	Hyperparathyroidism (not primary)[62,65]

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 MEN1^a

Biochemical Test or Procedure	Condition Screened For	Age 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.
a Adapted from Brandi et al.[4]and Thakker et al.[7]
b The 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.[19,66]
c The age to initiate screening and the screening frequency for pituitary tumors may be debatable because the clinical significance of small, nonfunctional tumors is unclear;[67]further study may be warranted.
Serum prolactin and/or insulin-like growth factor 1	Pituitary tumors	5	Every 1 y
Fasting total serum calcium and/or ionized calcium and PTH	Parathyroid tumors and PHPT	8	Every 1 y
Fasting serum gastrin	Duodenopancreatic gastrinoma	20	Every 1 y
Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptide	Duodenopancreatic NETs	<10	Every 1 y
Fasting glucose and insulin	Insulinoma	5	Every 1 y
Brain MRIc	Pituitary tumors	5	Every 3–5 y based on biochemical results
Abdominal CT or MRIb[4]	Duodenopancreatic NETs	20	Every 3–5 y based on biochemical results
Abdominal CT, MRI, or endoscopic ultrasonographyb[7]	Duodenopancreatic NETs	<10	Every 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.[38] 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.[63] 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.[63] 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.[68] Insufficient resection renders a patient to need reoperation.[13,14,15,63] 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).[69,70] 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.[69]

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). Surgical enucleation has been associated with higher recurrence compared with distal pancreatectomy, and a decreased rate of endocrine insufficiency compared with a Whipple procedure.[71] 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.[72,73] Unfortunately, there is no specific tumor marker or combination of tumor markers that are predictive of disease-specific mortality.[74] Long-acting somatostatin analogs may have a role in early-stage MEN1 duodenopancreatic NETs.[75] 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.[75] 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.[73,76,77,78] 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.[79] Tumor size does seem to influence patient survival, with patients with smaller tumors having increased survival after resection.[80] While more-extensive surgical approaches (e.g., pancreatoduodenectomy) have been associated with higher cure rates and improved overall survival,[81,82,83] they also have higher rates of postoperative complications and long-term morbidity.[84] 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.[85]

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.[86,87] 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.[88,89] 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.[88,89,90,91]

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.[92]

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.[93]

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,[94,95,96] and have a higher rate of metastasis than sporadic insulinoma.[93] Surgery can range from enucleation of single or multiple large tumors to partial pancreatic resection, or both,[95] to subtotal or total pancreatectomy.[94,95] More-extensive surgical approaches are associated with a lower rate of recurrence [81,82,95,97] 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.[98] Intraoperative monitoring of insulin/glucose can help determine whether insulin-secreting tumors have been successfully excised.[89,99]

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).[100] The multifocal nature makes complete surgical resection difficult. It is critical to manage symptoms before considering any type of surgical intervention.[101] 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);[102] 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.[103] 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.[7,83]

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.[88,104] 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.[88,104,105]

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.[24,73] Tumors smaller than 1.5 cm are not likely to have lymph node metastases,[106] 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.[107] 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.[7,108]

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108. Pieterman CR, Vriens MR, Dreijerink KM, et al.: Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer 10 (1): 157-71, 2011.

Multiple Endocrine Neoplasia Type 2

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH) (referred to as C-cell neoplasia or C-cell carcinoma in situ in more recent publications)[1]; pheochromocytoma (PHEO); and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH clonal C-cell proliferation. In contrast, sporadic MTC is typically unilateral and/or unifocal. Because approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[2] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[3,4] Metastatic PHEOs in MEN2 have not been reported.[5] Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes on the basis of the presence or absence of certain endocrine tumors in the individual or family:

1. MEN2A.
2. Familial medullary thyroid cancer (FMTC).
3. MEN2B (sometimes referred to as MEN3).

Current stratification has moved away from a solely phenotype -based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype.[6] Current classification now includes two MEN2 syndromes: MEN2A and MEN2B. The MEN2A syndrome is further classified on the basis of the presence of associated conditions. For example, classical MEN2A includes those with MTC, PHEO, and/or hyperparathyroidism. Additional categories include MEN2A with cutaneous lichen amyloidosis, MEN2A with Hirschsprung disease (HSCR), and FMTC (presence of a RETgermline pathogenic variant and MTC but no family history of PHEO or hyperparathyroidism).[1] Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals.[7] The vast majority of MEN2 cases are MEN2A.

MTC and CCH

MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is a controversial diagnosis, but most pathologists agree that it is defined as more than seven C-cells per cluster, complete follicles surrounded by C-cells, and C-cells in a distribution beyond normal anatomical location.[1,8,9,10] Individuals with RET pathogenic variants and CCH are at substantially increased risk of progressing to MTC. MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.

A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test.[11] CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family.[12,13,14]

MTC accounts for 1% to 2% of new cases of thyroid cancer diagnosed annually in the United States.[15] Approximately 75% of thyroid cancer cases diagnosed in the United States are sporadic (i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN2). The peak incidence of the sporadic form is in the fifth and sixth decades of life.[3,16] A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.[17]

In the absence of a positive family history, MEN2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET pathogenic variants,[18,19] larger series indicate a prevalence range of 1% to 7%.[20,21] On the basis of these data, testing for pathogenic variants in the RETgene is widely recommended for all cases of MTC.[1,22]

Level of evidence (Screening): 3

Natural history of MTC

Thyroid cancer represents approximately 2.3% of new malignancies occurring annually in the United States, with an estimated 43,800 cancer diagnoses and 2,230 cancer deaths per year.[23] Of these cancer diagnoses, 1% to 2% are MTC.[15]

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by CCH, although CCH is a relatively common abnormality in middle-aged adults.[8,9]

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 86%–89% 5-year survival for MTC compared with 94%–98% 5-year survival for papillary and follicular thyroid cancer).[15,24] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis.[25,26,27]

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, and diagnosis by biochemical or genetic screening (i.e., screening for calcitonin elevation, RET variants) versus symptoms.[26,28,29,30]

A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases.[28]

Hereditary MTC

While most MTC cases are sporadic, approximately 20% to 25% are hereditary because of pathogenic variants in the RET proto-oncogene.[31] Pathogenic variants in the RET gene cause MEN2, an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the MEN1 section of this summary for more information.)

MEN2-Related PHEO

PHEOs arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are relatively rare tumors and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[32,33,34,35,36,37] When biochemical screening in an individual who has or is at risk of MEN2 suggests PHEO, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[38] Confirmation of the diagnosis can be made using iodine I 131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[13,38,39,40]

For individuals with PHEO, a diagnosis of MEN2 is often considered in individuals with bilateral disease, those with an early age of onset (age <35 y), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to PHEO. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[41] and the hereditary paraganglioma syndromes.[42] (Refer to the Familial PHEO and PGL Syndrome section of this summary for more information about hereditary PHEO and the PDQ summary on von Hippel-Lindau Disease for more information about VHL.)

Primary Hyperparathyroidism (PHPT)

PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the result of a single adenoma.[43] PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:

• MEN1.
• Hyperparathyroidism–jaw tumor syndrome.
• Familial isolated hyperparathyroidism.
• MEN2.[44,45,46]

Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.

Clinical Diagnosis of MEN2 Subtypes

The diagnosis of the two MEN2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene.

MEN2A

Classical MEN2A

MEN2A is diagnosed clinically by the occurrence of two specific endocrine tumors in addition to MTC: PHEO and/or parathyroid adenoma and/or hyperplasia in a single individual or in close relatives.[1]

The classical MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[47] Since genetic testing for RET pathogenic variants has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC.[13,48,49,50]

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[13,49] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 years and 25 years (mean, 15 y).[13] If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain between the ages of about age 5 years and 20 years. More than 50% of such patients have cervical lymph node metastases.[3] Diarrhea, the most frequent systemic symptom, occurs in patients with a markedly elevated plasma calcitonin level or bulky disease and/or hepatic metastases and implies a poor prognosis.[1,3,51,52] Up to 30% of patients with MTC present with diarrhea and advanced disease.[53]

MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[54,55,56] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[54,57] MEN2-associated PHEOs usually present after MTC, typically with intractable hypertension.[58]

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[53,59] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[59] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[60,61,62] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid cancer in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, 4 double adenomas, and 25 hyperplastic glands.

MEN2A with cutaneous lichen amyloidosis

A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[63,64]

MEN2A with Hirschsprung disease (HSCR)

HSCR, a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, occurs in a small number of individuals with MEN2A-associated RET pathogenic variants.[65] Pathogenic variants at specific cysteine residues in exon 10 (i.e., codons 609, 618, and 620) are most commonly associated with HSCR, although individuals with pathogenic variants in other exons can still be affected.[66] HSCR can occur outside of a diagnosis of MEN2A and infants with HSCR may benefit from their own genetic evaluation regardless of the likelihood of MEN2A because HSCR can present as part of other syndromes. Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline pathogenic variants in the RET proto-oncogene.[67,68] Certain loss-of-function RET variants have been associated with isolated HSCR,[69] indicating that not all individuals with HSCR and a germline RET variant necessarily have MEN2A.

Figure 2 depicts some of the classic manifestations of MEN2A in a family.

Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a RET pathogenic variant across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. Age at onset can vary widely, even within families. MEN2A families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages.

Familial medullary thyroid cancer (FMTC)

Up to 50% of MEN2A cases are of the FMTC subtype, and are defined as families or single individuals with germline RET pathogenic variants and MTC alone in the absence of PHEO or parathyroid adenoma/hyperplasia.[1] This definition replaces previous classification of FMTC as a stand-alone diagnosis.[1] Previously, misclassification of families as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) could result in overlooking the risk of PHEO, a disease with significant morbidity and mortality. For this reason, FMTC is now considered a subtype of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome.[70] Current management guidelines [1] recommend that patients thought to have pure FMTC also be screened for PHEO and hyperparathyroidism.

MEN2B

MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[71,72,73,74] In cases of de novo pathogenic variants, the diagnosis of MEN2B is often delayed, after the development of MTC. The MTC is often fatal, particularly in the presence of metastatic disease, which is common at the time of diagnosis. It is important, therefore, for pediatricians to recognize the endocrine and nonendocrine clinical manifestations of the syndrome as an earlier diagnosis may result in lifesaving treatment of MTC, before metastatic spread.[75]

The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[76] MEN2B is characterized by the early development of an aggressive form of MTC in all patients.[71] Patients with MEN2B who do not undergo thyroidectomy at an early age (at approximately age 1 y) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN2B was 21 years. PHEOs occur in about 50% of MEN2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon.[48,71] Patients with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.

Patients with MEN2B may have diffuse ganglioneuromatosis of the gastrointestinal tract with associated symptoms that include abdominal distension, megacolon, constipation, and diarrhea.[77] A review of the literature reported the presence of constipation as a common symptom in 72.7% of patients with MEN2B. Additionally, gastrointestinal symptoms occurred during the first year of life in 52.3% of patients with MEN2B. Intestinal biopsy led to the diagnosis of ganglioneuromatosis in 27.3% of patients.[78]

About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[73,74]

A retrospective review of the clinical presentation of 35 cases of MEN2B with de novo pathogenic variants treated at a single institution found that 22 cases were diagnosed because of endocrine manifestations of the syndrome.[75] The diagnosis of PHEO, a neck mass, and/or skeletal abnormalities led to the identification of MTC. The remaining 13 patients presented with a nonendocrine manifestation, including oral neuromas, corneal nerve abnormalities, persistent diarrhea, failure to thrive, or skeletal abnormalities with frequent falls. Of the entire cohort, 21 patients had one or more physician referrals for the evaluation of an MEN2B-related feature, an average of 5 years before the diagnosis of MEN2B.

It is critical for pediatricians to maintain a high index of suspicion when evaluating patients with any of the clinical manifestations associated with MEN2B. In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[79] Some authors have recommended referral to genetic counseling for an individual with MTC or any of the following features:[71,79]

• Benign oral and submucosal neuromas.
• Elongated face and large lips.
• Ganglioneuromatosis.
• Inability to cry tears (biologic mechanism unknown).

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited pathogenic variants in the RET gene, located on chromosome region 10q11.2.[80,81,82] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[83,84]

RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed.[31,85,86] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin, also interact with one of four coreceptors in the GDNF-family receptor–alpha family.[85] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules.

Genetic testing

MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement.[87] At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN2. Testing allows the identification of people with asymptomatic MEN2 who can be offered risk-reducing thyroidectomy and biochemical screening as preventive measures. A negative pathogenic variant analysis in at-risk relatives, however, is informative only after a disease-causing variant has been identified in an affected relative. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[88,89] (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)

Germline DNA testing for RET pathogenic variants is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[90,91] Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline RET pathogenic variant.[92] Between 1% and 10% of individuals with apparently sporadic MTC will carry a germline RET pathogenic variant, underscoring the importance of testing all individuals diagnosed with MTC.[93,94,95]

There is no evidence for the involvement of other genetic loci, and all pathogenic variant–negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable pathogenic variant, clinical recommendations can be based on the clinical features in the affected individual and in the family.

There is considerable diversity in the techniques used and the approach to RET pathogenic variant testing among the various laboratories that perform this procedure. Methods used to detect variants in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing.[92,96] Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for variants in the exons that are most commonly found to carry variants (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed.

These differences in variant detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about clinical validity.)

Genotype-Phenotype Correlations and Risk Stratification

Genotype-phenotype correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed pathogenic variant–stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[1,90,97] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy.[90] This stratification has been revised by the American Thyroid Association (ATA).[1,98,99] The specific pathogenic variants and their ATA classification are summarized in Table 5 below.

ATA-Highest Risk (HST) (previously labeled ATA-D) pathogenic variants are the most aggressive and carry the highest risk of developing MTC.[1] This category includes those with MEN2B and RET codon M918T pathogenic variants and is associated with the youngest age at disease onset and the highest risk of mortality. ATA-High Risk (H) (previously called ATA-C) pathogenic variants, at codons 634 and A883F, are associated with a slightly lower risk, yet the MTC in patients with these pathogenic variants is still quite aggressive and may present at an early age.[100] Former ATA-levels A and B pathogenic variants are now combined into a single group called Moderate Risk (MOD) and are associated with a lower risk of aggressive MTC relative to the risk seen in carriers of ATA-HST and ATA-H pathogenic variants.[99] Results from a study of 387 RET pathogenic variant carriers with MTC have suggested that ATA-MOD variants may be associated with MTC as aggressive as seen in individuals with ATA-H variants but present at a later age.[101] The risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[1] Patients with early stage I and stage II disease can achieve 100% survival rates regardless of the ATA risk category.[101] Common pathogenic variants in the ATA-MOD category are shown in Table 5.

Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[100,102,103,104,105,106] Approximately 95% of individuals with MEN2B will have the M918T pathogenic variant.[102,103,104,107] As discussed above, 50% of individuals with MEN2B will develop PHEO but PHPT is rare. A retrospective review of all published cases of A883F variant carriers (N = 13) found that the MTC disease course was more indolent than what was observed in M918T carriers. A883F carriers had later disease onset (50% penetrance for MTC at age 19 y), 5- and 10-year survival rates of 88%, and 63% of patients achieved biochemical cure for MTC.[100] In addition to variants at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline variants.[108,109,110,111,112] It is likely that as testing for RET becomes more common in clinical practice, additional double variant phenotypes will be described.

Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R pathogenic variant, 26.0% carried the C634Y pathogenic variant, and 9.1% had the C634G pathogenic variant.[48] In general, pathogenic variants at codon 634 are associated with PHEOs and PHPT.[48,113] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with pathogenic variants at codon 634.[48,50,114] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 pathogenic variant.[115] Codon 634 pathogenic variants have also been described in FMTC but are almost exclusively C634Y.[48]

In summary, ATA-HST and ATA-H (previously levels D and C, respectively) pathogenic variants confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of PHEO (up to 50%).[48,116] Individuals with codon 634 pathogenic variants (but not codon 883 or 918 variants) also have an increased risk of PHPT.[48]

Moderate-risk variants located in exon 10 of the RET gene include variants at codons 609, 611, 618, 620, and 630. These variants involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[20,48,97,117,118,119,120,121] The risk of MTC in individuals with these pathogenic variants is approximately 95% to 100%; the risk of PHEO and hyperparathyroidism is lower than that seen in individuals with high-risk pathogenic variants.

Individuals with pathogenic variants previously classified as ATA-level A (now classified with ATA-level B as ATA-MOD, i.e., codons 321, 515, 533, 600, 603, 606, 531/9 base pair duplication, and 532 duplication) have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these pathogenic variants tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with these pathogenic variants who developed MTC before age 20 years.[48,122,123,124,125,126] Although PHEO and PHPT are not commonly associated with these pathogenic variants, they have been described.[126]

Table 5. Genotype-Phenotype Correlations in Multiple Endocrine Neoplasia Type 2^a

RETPathogenic variant	Exon	Risk of Aggressive MTC	Approximate Incidence of PHEO	Approximate Incidence of HPTH	Presence of CLA	Presence of HSCR
CLA = cutaneous lichen amyloidosis; HSCR = Hirschsprung disease; HPTH = hyperparathyroidism; MTC = medullary thyroid cancer; PHEO = pheochromocytoma.
a Adapted from Wells et al.[1]
G533C	8	Moderate	10%	-	N	N
C609F/G/R/S/Y	10	Moderate	10%–30%	10%	N	Y
C611F/G/S/Y/W	10	Moderate	10%–30%	10%	N	Y
C618F/R/S	10	Moderate	10%–30%	10%	N	Y
C620F/R/S	10	Moderate	10%–30%	10%	N	Y
C630R/Y	11	Moderate	10%–30%	10%	N	N
D631Y	11	Moderate	50%	-	N	N
C634F/G/R/S/W/Y	11	High	50%	20%–30%	Y	N
K666E	11	Moderate	10%	-	N	N
E768D	13	Moderate	-	-	N	N
L790F	13	Moderate	10%	-	N	N
V804L	14	Moderate	10%	10%	N	N
V804M	14	Moderate	10%	10%	Y	N
A883F	15	High	50%	-	N	N
S891A	15	Moderate	10%	10%	N	N
R912P	16	Moderate	-	-	N	N
M918T	16	Highest	50%	-	N	N

In addition to the pathogenic variants categorized in Table 5, a number of rare or novel RET variants have been described. Some of these represent pathogenic variants that lead to MEN2A phenotypes. Others may represent low-penetrance alleles or modifying alleles that confer only a modest risk of developing MTC.[127] A multicenter study identified eight families with a RET K666N variant. Of the 16 screened family members identified as having a pathogenic variant, only one had MTC.[127] Still others may be benign polymorphisms of no clinical significance. For example, some studies demonstrate compelling evidence that RET variants Y791F (p.Tyr791Phe) and S649L (p.Ser649Leu) are likely benign polymorphisms, on the basis of equal frequencies among cases and healthy controls and co-occurrence with other disease-causing variants that cosegregate with disease in the family.[128,129] A long-term follow-up study of Danish Y791F carriers (n = 20) showed no sign of MEN2A (MTC, PHPT, PHEO, cutaneous lichen amyloidosis, or HSCR) among the cohort, with a median age of 49.5 years (range, 7–87 y).[130] Therefore, carriers of these variants are not treated as having MEN2 syndrome and asymptomatic family members are generally not tested for these variants. Comprehensive testing of all hotspot variants in exons 8 and 10–16 may be performed to rule out any other RET pathogenic variants, and more extensive testing of other disease-related genes may be warranted because of a diagnosis of PHEO. (Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section of this summary for more information.)

Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A. The presence of certain RET polymorphisms or haplotypes is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, HSCR, and age at onset of metastatic involvement with MTC.[131,132,133,134] A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available RET variant online database repository was developed and includes a complete list of variants and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[135]

Surveillance

Screening at-risk individuals for PHEO

The presence of a functioning PHEO can be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN2A or MEN2B. However, childhood PHEOs are rare in MEN2.[1] The ATA recommends that annual screening for PHEO be considered by age 11 years in patients with ATA-HST or ATA-H RET pathogenic variants.[1] The ATA recommends that patients with ATA-MOD RET pathologic variants have periodic screening for PHEO beginning by age 16 years.[1] MRI or other imaging tests may be ordered only if the biochemical results are abnormal.[26,136] Studies of individuals with sporadic or hereditary PHEO (including, but not limited to, individuals with MEN2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic nature of catecholamine excretion.[32,33,34,35,36,37,38,137] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of PHEO.[38,138] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized PHEO. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery.

Level of evidence: 5

Screening at-risk individuals for hyperparathyroidism

MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, left untreated, may become symptomatic.[59] Childhood hyperparathyroidism is rare in MEN2. Three studies found the median age at diagnosis was about 38 years.[59,139,140] The ATA provides recommendations for annual screening for hyperparathyroidism,[1] with screening beginning by age 11 years in carriers of ATA-HST and ATA-H pathogenic variants and by age 16 years for carriers of ATA-MOD RET pathogenic variants.[1] Testing typically includes albumin-corrected calcium or ionized serum calcium with or without intact parathyroid hormone (PTH) measurement.

Level of evidence: 5

Screening at-risk individuals in kindreds without an identifiableRETpathogenic variant

Risk-reducing thyroidectomy is not routinely offered to at-risk individuals unless MEN2A is confirmed. The screening protocol for MTC in patients with MEN2A is annual calcitonin stimulation test; however, caution must be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[12,13,141] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[13] Screening for PHEO and parathyroid disease is the same as described above.

For patients at risk of FMTC, annual screening for MTC is the same as for patients with MEN2A.

Level of evidence: 5

Interventions

Treatment for MTC

Risk-reducing thyroidectomy

Risk-reducing thyroidectomy is the oncologic treatment of choice for patients with MEN2. Children with the M918T RET pathogenic variant may benefit from a thyroidectomy in the first year of life, perhaps in the first months of life.[1] Likewise, children with ATA-H category RET pathogenic variants may undergo prophylactic thyroidectomy at age 5 years or earlier, on the basis of serum calcitonin levels. The ATA recommends that children in the ATA-MOD category have a physical examination, ultrasonography of the neck, and measurement of the serum calcitonin beginning around age 5 years as these tumors may have later onset but are similarly aggressive once this is taken into account.[1,99] The absence of an abnormal calcitonin level may prompt continued measurement every 6 to 12 months.

A multidisciplinary team caring for the patient, including the pediatrician, pediatric endocrinologist, and surgeon should determine the timing of surgery in conjunction with the child's parents on the basis of the trend in serum calcitonin levels, ultrasonographic findings, preference of the family, and experience of the treating physicians.[1]

In children with some ATA-H or ATA-MOD RET pathogenic variants, some studies have suggested that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[142,143,144,145] These findings suggest that surgery may be safely delayed in carriers of an RET pathogenic variant until basal or stimulated calcitonin levels increase on routine testing. The benefits of this approach are particularly noteworthy in the younger population of pathogenic variant carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. A large study of 2,740 children aged 16 years and under has provided data on age-specific reference ranges for calcitonin levels in younger children that may assist in decision making.[146] Because some calcitonin assays may be more sensitive than others,[144] attention to the type of testing, as well as calcitonin levels will need to be considered. However, normal preoperative basal calcitonin does not exclude the possibility of the patient having MTC.[147]

For patients with RET germline variants, older age at prophylactic thyroidectomy has been significantly associated with a higher risk of postoperative persistent or recurrent disease.[148] Consistent with this, a study of young, clinically asymptomatic individuals with MEN2A showed there was a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (defined as younger than age 8 y) and who had no evidence of lymph node metastases.[149] Several studies have shown that there is a significantly lower rate of invasive or metastatic MTC among those who undergo surgery at an earlier age than among those who undergo surgery at a later age.[150] For patients with the most aggressive M918T RET variant, cure is exceptional if surgery is performed after age 4 years.[142,151] Together, these findings are consistent with more favorable outcomes for patients undergoing early risk-reducing surgery.[150,152,153]

Although thyroidectomy before biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, a selective strategy for postoperative and lifelong surveillance might depend on the final pathologic determination of whether a carcinoma was present and whether it was micromedullary or macromedullary.[1,154] One study found that 10% of patients with MEN2A undergoing thyroidectomy developed recurrent disease, on the basis of initially undetectable basal and stimulated calcitonin levels (<2 pg/mL) that became positive 5 to 10 years after surgery.[149] Only 2% of patients had residual disease after prophylactic surgery as assessed by a persistently elevated basal or stimulated calcitonin.[149]

Questions remain concerning the natural history of MEN2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. Earliest reports of MTC in MEN2B before age 3 years, and before age 6 years in MEN2A cases with ATA-H or ATA-MOD RET variants have been documented.[142,149,151,155] Conversely, another case report documented onset of cancer in midlife or later in some families with the FMTC subtype of MEN2A and in elderly relatives who carry the RET variant genotype but have not developed cancer.[156] Subsequent data have suggested that some ATA-MOD RET variants, which were previously thought of as more indolent may be as aggressive as ATA-H variants, but are associated with delayed onset of disease.[99,101] Emerging data pertaining to the timing of disease onset and local metastases by risk category are evolving.[101] These clinical observations suggest that the natural history of the MEN2 syndromes is variable and could be subject to modifying effects related to specific RET pathogenic variants, other genes, behavioral factors, or environmental exposures.

Level of evidence: 4b

Therapeutic thyroidectomy

The standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule and central lymph node dissection.[1] A therapeutic central neck dissection is typically performed if there is radiographic evidence of metastatic lymph node involvement or if the serum calcitonin level is higher than 40 pg/mL.[1] The decision to perform a prophylactic central neck dissection is generally made on the basis of multiple factors such as patient age, pathogenic variant, presence of concomitant PHPT, and the vascularity of the parathyroid glands.[1] Selective autotransplantation of parathyroid glands that were devascularized during a prophylactic thyroidectomy and/or central neck clearance is recommended. A selective approach also significantly reduces the detrimental outcome of hypoparathyroidism.[157]

The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life [151] and is considered the most aggressive MEN2 phenotype. In patients with MEN2A, the ATA-H high-risk codon 634 pathogenic variant is much more likely to be associated with invasive or metastatic MTC and development of persistent or recurrent disease than pathogenic variants in codons 804, 618, or 620.[150] One series of 503 at-risk individuals with ATA-MOD category pathogenic variants (including codons 533, 609, 611, 618, 620, 791, and 804) reported cumulative penetrance rates, median time to MTC, and positive predictive value of preoperative calcitonin.[143] The risk of developing MTC by age 50 years ranged from 18% to 95%, depending on the codon, with codon 620 having the highest penetrance. Most patients with MTC had node-negative disease, confirming the more indolent disease course that had been previously reported with these pathogenic variants. Although an elevated preoperative calcitonin level strongly predicted the presence of MTC, relatively high false-negative rates (low normal calcitonin levels with MTC) were noted for many of the codons. This information is useful when counseling carriers of pathogenic variants regarding the extent of surgical resection.

The ATA recommends compartment-directed lymph node dissection for local or regional disease (no evidence of distant metastases) in the following situations:[1]

• If there is no evidence of neck nodal metastases by ultrasonography in biopsy-proven thyroid disease, prophylactic central neck dissection should be performed concomitant with initial thyroidectomy.
• If nodal disease is present in either the central or lateral neck, a compartment-oriented lateral neck dissection of the ipsilateral side should be performed.
• If nodal disease is present and basal calcitonin levels are greater than 200 pg/mL, then consider contralateral lateral neck dissection.

Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases.[158] In one study of 224 patients from a single institution, preoperative basal calcitonin levels greater than 500 pg/mL predicted failure to achieve biochemical remission.[158] The authors of this study found that nodal metastases started appearing at basal calcitonin levels of 40 pg/mL (normal, <10 pg/mL). In node-positive patients, distant metastases emerged at basal calcitonin levels of 150 pg/mL to 400 pg/mL. Another study of 308 RET pathogenic variant carriers found that a normal basal preoperative calcitonin excluded the presence of lymph node metastases (negative predictive value, 100%).[145] Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.

With regard to prognosis, structural and metastatic disease recurrence is common in germline RET pathogenic variant carriers and can happen up to 20 years after initial treatment. Despite this, overall survival (OS) is generally favorable, with one study citing an OS rate of 92% at 10 years.[159]

Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent, and treatment may be initiated on the basis of ideal body weight. For healthy adults aged 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 µg/kg to 1.8 µg/kg given once daily.[160] Older patients may require 20% to 30% less thyroid hormone.[161] Children metabolize T4 more rapidly than adults and consequently require relatively higher replacement by body weight. Depending on the age of the child, replacement is typically between 2 µg/kg to 6 µg/kg.[162] It is important to note, however, that replacement is preferred over suppressive therapy. Since C-cell tumors are not thyroid-stimulating hormone (TSH)–dependent for growth, the T4 therapy for patients with MTC therefore may be adjusted to maintain a TSH within the normal reference range. Thyroglobulin measurement may also be useful for adjusting and maintaining TSH levels within a normal reference range to prevent additional regrowth of remnant thyroid tissue.[163]

Level of evidence (central neck dissection): 5

Level of evidence (hormone replacement therapy): 3c

Level of evidence (therapeutic thyroidectomy): 4

Adjuvant therapy

Chemotherapy and radiation therapy are generally not effective against MTC.[4,164,165] Hence, targeted molecular therapies are being explored to manage MTC. RET inhibitors and multikinase inhibitors are being used to block RET activity.

There are two U.S. Food and Drug Administration–approved RET inhibitors (pralsetinib and selpercatinib) that are now available for patients with MTC who have a RETpoint mutation. These RET inhibitors are also available for patients who have differentiated thyroid cancers with a RET fusion. A multicenter, phase I/II trial (ARROW) was conducted to evaluate the efficacy of pralsetinib in patients with RET-mutant MTC with or without prior treatment with vandetanib or cabozantinib. Among 55 patients who were previously treated with a multikinase inhibitor, the overall response rate was 60% (95% confidence interval [CI], 46%–73%) and 1-year progression-free survival (PFS) rate was 75% (95% CI, 63%–86%). Among 21 treatment-naïve patients, the overall response rate was 71% (95% CI, 48%–89%) and the 1-year PFS rate was 81% (95% CI, 63%–98%).[166] A similar phase I/II trial (LIBRETTO) examined the efficacy of selpercatinib in patients with RET-mutant MTC with or without prior treatment with vandetanib or cabozantinib. Among 55 patients who were previously treated with a multikinase inhibitor, 69% had an objective response (95% CI, 55%–81%); the 1-year PFS rate was 82% (95% CI, 69%–90%). Among 88 treatment-naïve patients, the objective response rate was 73% (95% CI, 62%–82%) and the 1-year PFS rate was 92% (95% CI, 82%–97%).[167]

The use of vandetanib and cabozantinib is approved by the U.S. Food and Drug Administration for adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that progression-free survival (PFS) was longer in adults who received vandetanib than in those who received placebo.[168] A phase I/phase II study of children with MEN2B found an objective partial response rate of 47% with vandetanib.[169] Subsequent follow-up analysis of this cohort revealed that a partial response was seen in 10 of 17 patients; stable disease was seen in an additional 6 individuals. Median PFS was 6.7 years.[170] A double-blind phase III trial that compared cabozantinib with placebo in 330 patients with progressive MTC showed an improvement in median PFS across all subgroups.[171,172] In this trial, patients who had pathogenic variants, including RET or RAS, were more likely to have a prolonged PFS compared with patients lacking both pathogenic variants.[173] Prospective studies may further clarify whether particular pathogenic variants can be used to guide therapy. Neither cabozantinib nor vandetanib has demonstrated improved OS.[168,171,172] Importantly, these agents are not effective at inhibiting some MEN2 RET variants, specifically those at codon 804,[174] making genotype an important consideration for treatment with RET inhibitors. Further, a 2018 study has demonstrated the development of resistance to these agents through somatic acquisition of a V804M mutation in RET.[175] Finally, multikinase inhibitors are associated with significant toxicities, possibly due to their off-target effects on other kinases.[176] Other multikinase inhibitors for targeting RET are being studied in clinical trials; however, they may only provide limited advantages over vandetanib and cabozantinib. For these reasons, ongoing studies are focusing on the development of selective RET inhibitors with fewer off-target effects that are able to block the activity of all RET variant forms and the use of combination therapy in MTC. Future studies will likely focus on the development of new targeted therapies and the use of combination therapy in MTC.[177,178]

Level of evidence (pralsetinib): 4

Level of evidence (selpercatinib): 3dii

Level of evidence (vandetanib): 2

Level of evidence (cabozantinib): 1

(Refer to the PDQ summary on Thyroid Cancer Treatment [Adult] for more information about the treatment of thyroid cancer.)

Treatment for MEN2-related PHEO

PHEO may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy (anterior or posterior) is the recommended approach after appropriate preoperative medical blockade for the treatment of unilateral PHEO.[1,90,98,179] The risks, benefits, and potential of life-threatening adrenal insufficiency should be considered at the time of the initial operative planning. If disease appears unilateral, the contralateral gland may develop metachronous disease in 17% to 72% of patients.[5,180] In one series, 23 patients with a unilateral PHEO and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[181] A PHEO developed within the retained gland in 12 (52%) of these patients, occurring a mean of 11.9 years after initial surgery. During follow-up, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed PHEO. In contrast, 10 of 43 patients (23%) treated with bilateral adrenalectomy experienced at least one episode of acute adrenal insufficiency. Thus, unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral PHEO in patients with MEN2.[1,182,183] Many experts suggest consideration of a cortical-sparing technique, even at the initial operation for seemingly unilateral disease.[1,184] (Refer to the Interventions section in the Familial PHEO and Paraganglioma Syndrome section of this summary for more information.) Because of the risk of contralateral gland disease, periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland is recommended.[1]

Regarding the operative approach, several studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found it to be safe and effective, with very low mortality and a low rate of minor complications, and conversion to open surgery required rarely.[180,185,186,187,188,189,190,191]

Level of evidence: 4

Treatment for hyperparathyroidism

Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally in the preoperative planning or at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic PHPT.[90] In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism.[1]

Treatment of hyperparathyroidism typically employs some extent of surgical removal of the involved glands. Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients;[59] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm (4 of 11 patients [36%] developed postoperative hypoparathyroidism), subtotal parathyroidectomy (6 of 12 patients [50%] developed hypoparathyroidism), and resection only of glands that were macroscopically enlarged (3 of 29 patients [10%] developed hypoparathyroidism). These data indicate that excision of only those parathyroid glands that are enlarged appears to be sufficient therapy in most cases.

Some investigators have suggested using the MEN2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in situ in the neck. For adult patients with MEN2A, in whom the glands have been inadvertently devascularized during primary surgical treatment for MTC, it is suggested that the glands needing reimplantation be implanted in the nondominant forearm. This approach minimizes the need for further surgical intervention in the neck should hyperparathyroidism develop or recur.[1,157,192,193] For children, the risk/benefit ratio must be carefully weighed to avoid overtreatment and subsequent aparathyroidism.[194] It is important to confirm that the remnant or autotransplanted parathyroid tissue is functional.[1,98,195,196]

Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating PTH levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with PHPT.[197] In patients who are high-risk surgical candidates, those with recurrent hyperparathyroidism, or those in whom life expectancy is limited, medical therapy may be a viable alternative to a surgical approach.[1] Consequences of long-term therapy with cinacalcet are unknown.

Level of evidence: 5

Genetic Counseling

Mode of inheritance

All of the MEN2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN2, the risk of inheriting the MEN2 pathogenic variant is 50%. Some individuals with MEN2, however, carry a de novo pathogenic variant; that is, they carry a new pathogenic variant that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN2 who have an affected parent varies by subtype.

MEN2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo pathogenic variants or incomplete penetrance of the mutant allele is possible.[198]

FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.

MEN2B: About 50% of affected individuals have de novo RET gene pathogenic variants, and 50% have inherited the pathogenic variant from a parent.[199,200] The majority of de novo pathogenic variants are paternal in origin, but cases of maternal origin have been reported.[201]

Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo pathogenic variants, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.

Attitudes toward preimplantation genetic testing

One study explored the attitudes of individuals with MEN1 and MEN2 toward preimplantation genetic testing (PGT).[202] Ninety-one clinic-based patients from a single U.S. institution who had MEN1 and an MEN1 pathogenic variant or MEN2 and a RET pathogenic variant were surveyed. The study found that 30% (10 of 33) of those with MEN1 and 37% (21 of 57) of those with MEN2 were aware of PGT; 82% (27 of 33) of those with MEN1 and 61% (34 of 56) of those with MEN2 thought PGT should be offered; and 61% (19 of 31) of those with MEN1 and 43% (23 of 54) of those with MEN2 would consider PGT.

Psychosocial issues

The psychosocial impact of genetic testing for pathogenic variants in RET has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a pathogenic variant may affect self-esteem, family relationships, and quality of life.[203] In addition, misconceptions about genetic disease may result in familial blame and guilt.[204,205] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[206,207,208,209] The medical value of early screening and risk-reducing treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family.

One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety.[210] Pathogenic variant–positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.[211]

A small qualitative study (N = 21) evaluated how patients with MEN2A and family members conceptualized participation in lifelong high-risk surveillance.[212] Ongoing surveillance was viewed as a reminder of a health threat. Acceptance and incorporation of lifelong surveillance into routine health care was essential for coping with the implications of this condition. Concern about genetic predisposition to cancer was peripheral to concerns about surveillance. Supportive interventions, such as Internet discussion forums, can serve as an ongoing means of addressing informational and support needs of patients with MTC undergoing lifelong surveillance.[213]

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193. Scholten A, Schreinemakers JM, Pieterman CR, et al.: Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract 17 (1): 7-15, 2011 Jan-Feb.
194. Machens A, Dralle H: Advances in risk-oriented surgery for multiple endocrine neoplasia type 2. Endocr Relat Cancer 25 (2): T41-T52, 2018.
195. Khan MI, Waguespack SG, Hu MI: Medical management of postsurgical hypoparathyroidism. Endocr Pract 17 (Suppl 1): 18-25, 2011 Mar-Apr.
196. Stålberg P, Carling T: Familial parathyroid tumors: diagnosis and management. World J Surg 33 (11): 2234-43, 2009.
197. Peacock M, Bilezikian JP, Klassen PS, et al.: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90 (1): 135-41, 2005.
198. Schuffenecker I, Ginet N, Goldgar D, et al.: Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am J Hum Genet 60 (1): 233-7, 1997.
199. Norum RA, Lafreniere RG, O'Neal LW, et al.: Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8 (2): 313-7, 1990.
200. Carlson KM, Bracamontes J, Jackson CE, et al.: Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55 (6): 1076-82, 1994.
201. Kitamura Y, Scavarda N, Wells SA, et al.: Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet 4 (10): 1987-8, 1995.
202. Rich TA, Liu M, Etzel CJ, et al.: Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer 13 (2): 291-9, 2014.
203. Freyer G, Ligneau B, Schlumberger M, et al.: Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: trends for future evaluations. Ann Oncol 12 (10): 1461-5, 2001.
204. Freyer G, Dazord A, Schlumberger M, et al.: Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation. Ann Oncol 10 (1): 87-95, 1999.
205. Grosfeld FJ, Lips CJ, Ten Kroode HF, et al.: Psychosocial consequences of DNA analysis for MEN type 2. Oncology (Huntingt) 10 (2): 141-6; discussion 146, 152, 157, 1996.
206. Johnston LB, Chew SL, Trainer PJ, et al.: Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 52 (2): 127-36, 2000.
207. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000.
208. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Psychological risks of genetically testing children for a hereditary cancer syndrome. Patient Educ Couns 32 (1-2): 63-7, 1997 Sep-Oct.
209. Giarelli E: Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research. Psychooncology 11 (1): 59-73, 2002 Jan-Feb.
210. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2. Am J Med Genet 91 (1): 1-7, 2000.
211. Grosfeld FJ, Beemer FA, Lips CJ, et al.: Parents' responses to disclosure of genetic test results of their children. Am J Med Genet 94 (4): 316-23, 2000.
212. Giarelli E: Bringing threat to the fore: participating in lifelong surveillance for genetic risk of cancer. Oncol Nurs Forum 30 (6): 945-55, 2003 Nov-Dec.
213. Schultz PN: Providing information to patients with a rare cancer: using Internet discussion forums to address the needs of patients with medullary thyroid carcinoma. Clin J Oncol Nurs 6 (4): 219-22, 2002 Jul-Aug.

Multiple Endocrine Neoplasia Type 4

Introduction

Multiple endocrine neoplasia type 4 (MEN4) is a novel, rare syndrome with clinical features that overlap with the other MEN syndromes. The most common phenotype of the 19 established cases of MEN4 that have been described to date is primary hyperparathyroidism (PHPT), followed by pituitary adenomas. MEN4 is caused by germline pathogenic variants in the tumor suppressor gene CDKN1B (12p13.1).[1] This syndrome was discovered initially in rats (MENX) [2] and later in humans (MEN4). The syndrome has the phenotype of being multiple endocrine neoplasia type 1 (MEN1)-like. The incidence of CDKN1B variants in patients with an MEN1-related phenotype is difficult to estimate, but it is likely to be in the range of 1.5% to 3.7%.[3,4,5]Pathogenic variants leading to the MEN4 phenotype are transmitted in an autosomal dominant fashion.

Clinical Diagnosis

PHPT due to parathyroid neoplasia affects approximately 80% of the reported cases of MEN4. PHPT occurs at a later age in MEN4 than in MEN1 (mean age ~56 y vs. ~25 y, respectively), with a female predominance.[6] There have been no reports of PHPT recurrence after surgical resection, which might indicate that PHPT in MEN4 represents an overall milder disease spectrum than in MEN1. Pituitary involvement in MEN4 is the second most common manifestation of the disease, affecting approximately 37% of the reported cases. Pituitary adenomas in MEN4 vary and include nonfunctional, somatotropinoma, prolactinoma, or corticotropinoma types. The age at diagnosis for these lesions also varies widely, from 30 years to 79 years. The youngest patient reported to have MEN4 presented at age 30 years with acromegaly.[2] Pancreatic neuroendocrine tumors (NETs) have been rare, with only a few cases reported. These include duodenopancreatic or gastrointestinal NETs that could be nonfunctioning or hormonally active and may secrete several substances, including gastrin, insulin, adrenocorticotropic hormone, or vasoactive intestinal polypeptide. Although adrenal neoplasia is a frequent finding in MEN1, only one case of nonfunctional bilateral adrenal nodules has been reported in MEN4.[5] Skin manifestations that are commonly reported in MEN1, such as lipomas, angiofibromas, and collagenomas, have not been reported in MEN4. There is no known genotype -phenotype correlation.

Genetics, Inheritance, and Genetic Testing

The CDKN1B variant codes for p27Kip1 (commonly referred to as p27 or KIP1), a putative tumor suppressor gene that regulates cell cycle progression. Alterations in this gene lead to a decrease in expression of p27 protein, triggering uncontrolled cell cycle progression. Although the loss of one allele of p27 is a frequent event in many human cancers, the remaining allele is rarely mutated or lost by loss of heterozygosity in human cancers.[7]Somatic mutations or germline pathogenic variants in CDKN1B have also been identified in patients with sporadic PHPT, small intestinal NETs, lymphoma, and breast cancer. These findings demonstrate a novel role for CDKN1B as a tumor susceptibility gene in other neoplasms.[8,9,10]

To date, only 19 cases having CDKN1B germline variants have been reported in the medical literature.[8] Thirteen pathogenic germline variants that have been frameshift, nonsense, or missense variants have been described.[11,12]

Index cases or individuals with MEN1-like features and negative results of MEN1 genetic testing are offered genetic counseling and testing for MEN4. Confirmation of an MEN4 diagnosis is only made with genetic testing for CDKN1B variants. In clinical practice, patients with asymptomatic or symptomatic PHPT who are also young (typically <30 y) and have multigland disease, parathyroid carcinoma, or atypical adenoma, or those with a family history or evidence of syndromic disease and negative for MEN1 or RET, are candidates for genetic testing for CDKN1B using accredited laboratories.[8] For those with proven disease, screening is also offered to a first-degree relative with or without MEN1 features. The identification of a germline CDKN1B variant should prompt periodic clinical biochemical screening for MEN4.

Surveillance

Surveillance of CDKN1B pathogenic variant carriers should be performed, though guidelines have yet to be established.[8,13] Currently, surveillance is primarily clinical and concentrates on evidence of growth hormone excess, with annual biochemical evaluation for insulin-like growth factor-1 and annual blood work for PHPT.[13] For known carriers, surveillance begins at adolescence. The role of imaging has not been established.

Interventions

For parathyroid and pituitary disease, the treatment is surgical, in accordance with treatment for other familial syndromes. (Refer to the MEN1 section of this summary for more information.)

Outcomes

A study of 293 MEN1 pathogenic variant–positive cases and 30 MEN1 pathogenic variant–negative cases, all with the MEN1 phenotype, showed that the pathogenic variant–negative cohort developed disease manifestations later in life, with improved life expectancy.[14] One of the limitations in applying this finding to MEN4 is that only 1 of these 30 MEN1-negative patients was CDKN1B positive.

References:

1. Marinoni I, Pellegata NS: p27kip1: a new multiple endocrine neoplasia gene? Neuroendocrinology 93 (1): 19-28, 2011.
2. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al.: Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 103 (42): 15558-63, 2006.
3. Georgitsi M, Raitila A, Karhu A, et al.: Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 92 (8): 3321-5, 2007.
4. Agarwal SK, Mateo CM, Marx SJ: Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 94 (5): 1826-34, 2009.
5. Molatore S, Marinoni I, Lee M, et al.: A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat 31 (11): E1825-35, 2010.
6. Lee M, Pellegata NS: Multiple endocrine neoplasia type 4. Front Horm Res 41: 63-78, 2013.
7. Philipp-Staheli J, Payne SR, Kemp CJ: p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res 264 (1): 148-68, 2001.
8. Alrezk R, Hannah-Shmouni F, Stratakis CA: MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr Relat Cancer 24 (10): T195-T208, 2017.
9. Malanga D, De Gisi S, Riccardi M, et al.: Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype. Eur J Endocrinol 166 (3): 551-60, 2012.
10. Occhi G, Regazzo D, Trivellin G, et al.: A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet 9 (3): e1003350, 2013.
11. Georgitsi M: MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. Best Pract Res Clin Endocrinol Metab 24 (3): 425-37, 2010.
12. Lee M, Pellegata NS: Multiple endocrine neoplasia syndromes associated with mutation of p27. J Endocrinol Invest 36 (9): 781-7, 2013.
13. Wasserman JD, Tomlinson GE, Druker H, et al.: Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res 23 (13): e123-e132, 2017.
14. de Laat JM, van der Luijt RB, Pieterman CR, et al.: MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med 14 (1): 182, 2016.

Familial Pheochromocytoma and Paraganglioma Syndrome

Introduction

Paragangliomas (PGLs) and pheochromocytomas (PHEOs) are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. Individuals may present with secondary hypertension. In 2004, the World Health Organization characterized adrenal gland tumors as PHEOs.[1] The term paraganglioma is reserved for non-adrenal (or extra-adrenal) neoplasms and may arise in various sites from the paraganglia along the parasympathetic nerves or the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. Only those arising from sympathetic neural chains have secretory capacity. PGLs found in the skull base or head and neck region typically arise in the glomus cells, near the carotid body, along the vagal nerve or jugular fosse, and are usually from parasympathetic paraganglia and therefore rarely secrete catecholamines.[2,3] The most recognizable tumors are found at the carotid body. PGLs below the neck are most commonly located in the upper mediastinum or the urinary bladder.[3] The reported incidence of these tumors in the general population is variable because they may be asymptomatic but ranges from 1 in 30,000 to 1 in 100,000 individuals.[3] One autopsy study found a much greater incidence of 1 in 2,000 individuals, suggesting a high frequency of occult tumors.[4] PGLs have an equal sex distribution and can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PGLs and PHEOs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/PHEO syndromes.

PGLs and PHEOs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. A minority of these tumors are malignant and present with an aggressive clinical course. PGL and PHEO malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Common sites of metastases include the bone, liver, and lungs.[1,7,8]

There are a lack of reliable molecular, immunohistochemical, and genetic predictors that distinguish between benign and malignant tumors.[9] However, in some studies, multivariate analysis indicates that certain factors lead to a higher malignancy rate (up to 70% in one study [10]). These factors include the following: an SDHB pathogenic variant,[11,12] young patient age,[10,12] extra-adrenal tumors,[12] and large tumors.[13] Some experts view local invasion into surrounding tissue as an additional marker of malignancy, whether the tumor is resectable or unresectable.[8,14,15] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[16,17,18,19,20] Consequently, it is difficult to estimate the rate of malignancy in patients with PGLs. Studies have reported malignancy rates that range from 5% to 20%; certain gene-specific estimates of malignancy are also available.[21]

Clinical Diagnosis of PGL and PHEO

A PGL may cause a variety of symptoms depending on the location of the tumor and whether the tumor has secretory capacity. PGLs of the head and neck are rarely associated with elevated catecholamines. Secretory PGLs and PHEOs may cause hypertension, headache, tachycardia, sweating, and flushing. Typically, nonsecretory tumors are painless, coming to attention only when growth of the lesion into surrounding structures causes a mass effect. Patients with a head or neck PGL may present with an enlarging lateral neck mass, hoarseness, Horner syndrome, pulsatile tinnitus, dizziness, facial droop, or blurred vision.[22]

Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[23] This evaluation is best performed by measuring urine and/or plasma fractionated metanephrines (normetanephrine and metanephrine), which yields a higher sensitivity and specificity than directly measuring catecholamines (norepinephrine, dopamine, and epinephrine).[24] For patients whose plasma metanephrines levels are measured, blood is collected after an intravenous catheter has been inserted and the patient has been in a supine position for 15 to 20 minutes.[25] Additionally, the patient should not have food or caffeinated beverages, smoke cigarettes, or engage in strenuous physical activity in the 8 to 12 hours before the blood draw.[25]

Imaging of PGLs is the mainstay of diagnosis; the initial evaluation includes computed tomography (CT) of the neck and chest. Magnetic resonance imaging (MRI) also has utility for the head and neck.[24] PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. MRI may also be used to distinguish the tumor from adjacent vascular and skeletal structures. On T2-weighted images, a tumor that is larger than 2 cm is likely to display a classic "salt and pepper" appearance, a reflection of scattered areas of signal void mingled with areas of high signal intensity from increased vascularity.[26]

Nuclear imaging, particularly somatostatin receptor scintigraphy (SRS) in combination with anatomic imaging, may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits).[27] Benign tumors are reported to be more sensitive to SRS than iodine I 123-metaiodobenzylguanidine (123I-MIBG) imaging. Sensitivity is highest for the head and neck region compared with abdomen PGLs or PHEOs (91% vs. 40% and 42%, respectively).[28] SRS has been reported to be superior to MIBG in detecting metastatic tumors (95% vs. 23%, respectively).[28] 123I-MIBG, however, is highly sensitive for PHEO [28] and positron emission tomography–computed tomography (PET-CT) is very specific for PGLs. Functional imaging for PGLs and/or PHEOs with fluorine F 18-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or PET-CT may be particularly helpful in localizing head and neck tumors. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient's genetic status, on the basis of the metabolic activity of the various tumors.[11] It has been suggested that patients with SDHx and VHLpathogenic variants are more likely to have higher 18F-fludeoxyglucose activity, which is related to gene activation in response to hypoxia.[11,29] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx pathogenic variants may have false-negative results with such scans. Gallium Ga 68-DOTATATE PET-CT is a newer, highly sensitive imaging modality for determining the extent of disease in patients with metastatic involvement.[8,30,31] Tumors with VHL pathogenic variants may likewise be missed with MIBG scans.[11]

Imaging of PHEOs usually consists of a dedicated CT of the adrenal gland. When biochemical screening in an individual who has or is at risk of multiple endocrine neoplasia type 2 (MEN2) suggests PHEO, localization studies, such as MRI or CT, can be performed.[32] Confirmation of the diagnosis can be made using iodine I 131-MIBG scintigraphy or PET imaging.[32,33,34]

Genetics, Inheritance, and Genetic Testing

A significant proportion of individuals presenting with apparently sporadic PHEO or PGL are carriers of germline pathogenic variants. Up to 33% of patients with apparently sporadic PHEO, and up to 40% of patients with apparently sporadic PGLs, actually have a recognizable germline pathogenic variant in one of the classical PGL/PHEO susceptibility genes.[18,35,36,37,38,39,40] One study found that in individuals with a single tumor and a negative family history, the likelihood of an inherited pathogenic variant was 11.6%,[18] whereas other groups detected pathogenic variants in 41% of such patients.[39,41] On the basis of one large population study, up to 85% of patients younger than 21 years with PGL/PHEO have a pathogenic variant, with over 50% of these patients having an SDHB pathogenic variant.[10,42] (Refer to the PDQ summary on Childhood Pheochromocytoma and Paraganglioma Treatment for more information about PGL/PHEO in children.) Even among carriers of SDHB pathogenic variants there can be reduced penetrance and delayed onset of disease, which may further obscure the hereditary nature of the disease.[43] As such, all patients with PHEO or PGL, even those with apparently sporadic tumors, may be considered for genetic testing because of the high frequency of pathogenic variants associated with these conditions.[24]

PGLs and PHEOs can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau disease (VHL), MEN2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by pathogenic variants in one of the following four genes: SDHA, SDHB, SDHC, and SDHD (collectively referred to as SDHx). The SDHx proteins form part of the succinate dehydrogenase (SDH) complex, which is located on the inner mitochondrial membrane and plays a critical role in cellular energy metabolism.[44] Pathogenic variants in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. Pathogenic variants in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL/PHEO,[45,46,47,48] but these variants are less common. The mechanism of tumor formation has remained elusive. One study suggests that SDHx-associated tumors display a hypermethylator phenotype that is associated with downregulation of important genes involved in the differentiation of neuroendocrine tissues.[49]

The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with pathogenic variants in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. FPGL/PHEO syndromes are among the rare inherited diseases in which genomic imprinting contributes to the risk of disease. For example, the SDHD pathogenic variant is normally not activated when inherited from the mother, and the risk of FPGL/PHEO syndromes is not increased. There are reports of disease in individuals with maternally inherited SDHD pathogenic variants,[50,51,52,53] although the apparent risk is still unknown but appears to be quite low. However, when a pathogenic variant is inherited from the father, the risk for FPGL/PHEO is greatly increased.[54,55] In other words, while the pathogenic variant can be passed down from mother or father, tumors are almost exclusively seen in individuals with paternally inherited pathogenic variants.[54,55] Potential mechanism(s) of tumorigenesis in individuals with maternally inherited pathogenic variants have been described.[53,56] In cases of FPGL not caused by SDHD or SDHAF2 pathogenic variants, first-degree relatives (FDRs) of an affected individual have a 50% chance of carrying the pathogenic variant and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance pathogenic variants, it is important to offer genetic testing to all unaffected FDRs once the pathogenic variant in the family has been identified.

Genetic testing for hereditary PHEO and PGL syndromes has until recently been largely based on published algorithms,[24] whereby testing is performed stepwise on the basis of factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[18,57,58] This approach allowed for cost-effective, targeted testing on the basis of clinical features. Within the last several years, however, next-generation sequencing (NGS) technology has led to a dramatic decrease in the cost and increase in the efficiency of genetic testing, and interrogation of pathogenic variants in 10 to 30 genes for the same cost of testing two or three genes is now possible.[59] These tests are particularly effective for individuals and families who have an atypical presentation or overlapping clinical features where the "best fit" candidate gene is not obvious.[60] Screening through a multigene panel moderately increases the detection rate. In a small series of 87 patients with PHEO, 25.3% of individuals (22 of 87) were found to have germline pathogenic variants on a screening panel that included ten PGL/PHEO-associated genes; 11.7% had germline pathogenic variants in VHL, 6.8% in RET, 2.3% in SDHD, 2.3% in MAX, 1.1% in SDHB, and 1.1% in TMEM127.[61] Apparently sporadic tumors were present in 74.7% of patients (65 of 87).

Genotype-Phenotype Correlations

In FPGL/PHEO, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the genetic variant. While these correlations can help guide genetic testing and screening decisions, caution must be used given the high degree of variability seen in these conditions.

SDHD pathogenic variants are mainly associated with an increased risk of parasympathetic PGLs. These are more commonly multifocal and located in the head and neck, with a low rate of malignancy.[10,21,62,63] Multiple series showed a risk of 71% for a head and neck tumor in SDHD carriers.[20,64] The lifetime risk for any PGL in any location in SDHD carriers was estimated to be as high as 77% by age 50 years in one series [64] and 90% by age 70 years in a second series.[63] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[65] In another study of 160 probands and nonprobands with SDHD pathogenic variants, the risk to age 60 years for all PGL/PHEO was 79%, but the risk for nonprobands only to age 60 years was 50%. In this same study, there was a statistically significant higher penetrance for symptomatic tumors associated with SDHD pathogenic variants compared with SDHB.[62]

The SDHD pathogenic variant p.Pro81Leu (P81L) is common, especially among individuals of European ancestry, and has been previously described as having a distinct phenotype with a low risk for PHEO and sympathetic PGL, and almost exclusive presentation of head and neck PGL.[63] In a 2018 study, the risk to age 60 years for PHEO and sympathetic PGL was lower than 5% among probands and nonprobands with P81L and higher than 25% among those with other SDHD pathogenic variants (P = .01).[62]

Pathogenic variants in the SDHB gene are associated with sympathetic PGLs, although PHEO and parasympathetic PGLs also have been described. SDHB PGLs are more commonly located in the abdomen and mediastinum than in the head and neck. While older studies reported a high age-related penetrance,[65] newer data suggest that the penetrance ranges from 9% to 35% by age 50 years.[43,66,67,68,69] There is some evidence that the penetrance in SDHB carriers may be lower in females than in males.[62,70]

Symptoms of hormonal hypersecretion in those with pediatric-onset PGL/PHEO were common in one series of pediatric carriers of SDHB germline pathogenic variants; hypertension was seen in 76%, followed by headache in 68%, sweating/diaphoresis in 51%, palpitations in 40%, nausea and/or vomiting in 31%, and flushing in 25%.[10] The rate of malignancy is higher with SDHB than with the other SDH genes, with up to one-third of patients having malignant tumors in most series.[63,64] However, in one study among nonprobands only, the rate of malignant disease to age 60 was only 4.2 %.[62] One single-center study of pediatric SDHB carriers found that 70% of childhood-onset PGL/PHEO patients developed metastatic disease, with a median interval between diagnoses of primary tumors of 4 years (range, 0–26 y).[10] Pathogenic variants in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), pituitary tumors, renal cell carcinoma, and papillary thyroid cancer.[62,63,64]

SDHC pathogenic variants are rare, accounting for an estimated 0.5% of all PGLs.[65] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, 3 (2%) had an SDHC pathogenic variant.[36] Another series of 121 index cases from a head and neck PGL registry showed a pathogenic variant rate of 4% (5 of 121), [71] and another series identified 26 SDHC variants among 391 probands with PGL/PHEO (6.6%).[62]SDHC pathogenic variants most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[18,62,72] Given small populations sizes, lifetime risk estimates for PGL/PHEO associated with pathogenic SDHC variants are limited, but one study of 43 probands and nonprobands found a lifetime risk for all PGL/PHEO to age 60 years of approximately 75%; among nonprobands only, the risk was 25% (95% confidence interval, 0%–57%).[62] Pathogenic variants in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the classic dyad of PGLs and GISTs but can also include pituitary and thyroid tumors.[62,73]

Pathogenic variants in SDHA, SDHAF2, MAX, and TMEM127 have also been described; collectively, they account for up to 6% of cases without pathogenic variants in the classical PGL/PHEO genes, with about one-half of these in SDHA.[60]

Although biallelic pathogenic variants in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[74] it was not until recently that monoallelic pathogenic variants were linked to an increased risk of developing PGL. One series showed a 7.6% incidence of SDHA pathogenic variants in a cohort of 393 patients with PGL in the Netherlands.[75] Tumors most commonly develop in the head and neck, followed by the adrenal glands and abdomen (extra-adrenal).[76,77] In the same series from the Netherlands,[75] the estimated penetrance for non-index pathogenic variant carriers was 10% by age 70 years.

Initially, pathogenic variants in SDHAF2 were described only in head and neck PGLs.[48]

The MAX gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[45] Three different germline pathogenic variants were identified, and a follow-up series of 59 cases by the same group identified an additional five variants. The MAX protein plays a key role in the development and progression of neural crest cell tumors.[78]

The TMEM127 gene is located on chromosome 2q11.2 and encodes a transmembrane protein known to be a negative regulator of mTOR, which regulates multiple cellular processes. A review of 23 patients with TMEM127 pathogenic variants showed that 96% (22 of 23) had a PHEO, and 9% (2 of 23) had a PGL.[65]

A study of an additional 58 patients from the European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group more than doubled the number of previously reported carriers of the rare predisposition genes SDHA (n = 29), SDHAF2 (n = 1), MAX (n = 8), and TMEM127 (n = 20).[60] The study identified malignant disease in 12% of SDHA pathogenic variant carriers and 10% of TMEM127 carriers, which is significantly higher than previous estimates. Extra-adrenal tumors were common in the cohort (48%), particularly in SDHA carriers (79%) who had an overrepresentation of head and neck tumors (44%). However, no GIST tumors were identified in SDHA carriers in this cohort, compared with frequent reports in previously identified cohorts. SDHA-related tumors occurred in patients as young as 8 years. Tumors associated with MAX pathogenic variants were almost all in the adrenal glands, and frequently bilateral. Overall, penetrance of developing a PGL/PHEO by age 40 years was estimated to be 73% for MAX pathogenic variant carriers, 41% for TMEM127 carriers, and 39% for SDHA carriers. Penetrance was also calculated for pathogenic variant–positive relatives and was significantly lower for these individuals (13%) compared with index patients for SDHA carriers, but not significantly different for MAX or TMEM127 probands and nonprobands. It is important to remember that these relatively small studies are prone to selection and ascertainment biases, as mentioned above. For example, only 22% of family members from this cohort had cascade screening, which affects penetrance calculations. Additionally, the high rates of metastatic disease could represent ascertainment bias of a tertiary care center, and the lack of GIST tumors could be because this was a PGL/PHEO-specific registry, and therefore might not capture the full spectrum of related tumors.[79]

Surveillance

Patients with an identified germline pathogenic variant in one of the SDH genes are at a significantly increased risk of developing PGLs, PHEOs, renal tumors, and GISTs. PHEOs and PGLs typically have a slow growth pattern, but unchecked growth can lead to mass effect and, ultimately, neurologic compromise. Further, although most of these tumors are benign, some may undergo malignant transformation. As such, periodic screening for interval development of a tumor is of critical importance because early detection and removal can minimize risk to the patient.[12] Although limited studies have been performed to delineate the ideal protocol, total-body MRI has been proposed as a reasonable method for screening because of its high sensitivity and minimal radiation exposure.[24,80] In one study, 37 carriers of SDHx pathogenic variants underwent annual biochemical testing and annual or biennial whole-body MRI beginning at age 10 years.[81] This screening protocol identified six tumors in five patients. The sensitivity of MRI was 87.5%, and the specificity was 94.7%. The sensitivity of biochemical testing was significantly lower at 37.5%, with a specificity similar to MRI at 94.9%.[81] A retrospective study of 157 patients evaluated a rapid contrast-enhanced angio-MRI protocol for the detection of head and neck paragangliomas in carriers of SDH pathogenic variants.[82] This protocol had a high sensitivity and specificity of 88.7% and 93.7%, respectively. Another group, analyzing their experience with a cohort of 157 patients, proposed an algorithm of sequential queries into tumor characteristics to identify those at greatest risk for malignant tumors, and therefore more rigorous surveillance. The presence of any one of the following features including extra-adrenal location, positive family history, positive genetic testing, or tumor size greater than 4 cm was associated with a 100% sensitivity and a 42.5% specificity for the identification of malignancy. The authors further suggested that long-term surveillance may be de-escalated for those patients with small adrenal tumors (4 cm or smaller), as none developed a malignancy in their cohort after a mean follow-up of 7.3 years.[12] Prospective validation of these findings at another institution would be valuable.

Although the optimal imaging protocol for surveillance in carriers of SDH pathogenic variants remains unclear, annual biochemical testing and clinical surveillance may be considered. Biochemical testing can be performed by measuring plasma-free metanephrines/catecholamines or 24-hour urinary excretion of fractionated catecholamines (including methoxytyramine, a dopamine metabolite, if available). Clinical surveillance may include physical examination and blood pressure measurement. Clinical surveillance and biochemical testing may begin between ages 5 years and 10 years, or 10 years earlier than the earliest age at diagnosis in the family.[83,84] One highly specialized center has recommended beginning surveillance at age 6 years for SDHB carriers.[10]

Level of evidence: 4

Interventions

Preoperative management

Medical management is the bridge to surgical resection of PGLs/PHEOs. Preoperative medical therapy is not essential for patients without evidence of catecholamine hypersecretion, although some advocate its use regardless of the results of hormonal testing.[25] The aim of pharmacologic therapy is to control hypertension for at least 10 to 14 days before surgery.[85] Management is aimed at preventing catecholamine-induced complications, even in patients who may not present with preoperative hypertension, to avoid intraoperative hypertensive crisis, cardiac arrhythmias, pulmonary edema, and cardiac ischemia. Failure to adequately block the catecholamine excess can dramatically increase the risk of perioperative mortality from hypertensive crisis and lethal arrhythmias and cause hypotensive crisis after tumor removal.[86,87]

In the absence of a randomized controlled trial comparing the various regimens, there is no universally recommended approach. The alpha-adrenoreceptor blocker phenoxybenzamine (Dibenzyline) is most frequently used to control blood pressure and expand the blood volume.[25] Other alpha-blocking drugs have also been used with success, including prazosin, terazosin, or doxazosin; these drugs are more specific alpha-1 adrenergic competitive antagonists and have a shorter half-life than phenoxybenzamine.[88,89] The noncompetitive binding of phenoxybenzamine to the alpha receptors, coupled with its longer half-life, may result in a sustained effect of the drug, with some patients experiencing postoperative hypotension.[25,90] One study found that patients treated with sustained-release doxazosin had more stable perioperative hemodynamic changes and a shorter time interval to preoperative blood pressure control than did patients who received phenoxybenzamine.[90]

A high-volume tertiary care center proposed deviating from the general recommendation for perioperative alpha-receptor blockade. In a closed-case series that compared patients with and without blockade, there was no significant difference in maximal intraoperative systolic arterial pressure or hypertensive episodes.[91] Further study is warranted.

Once the alpha blockade is initiated, expansion of the blood volume is often necessary, as these patients are typically volume contracted.[92,93] In addition to the vasodilatory effects from alpha blockade, volume expansion may be achieved by consuming a high-sodium diet and high fluid intake or a preoperative saline infusion. A clinical manifestation of adequate blockade is the symptom of nasal stuffiness or lightheadedness.

Calcium channel blockers such as nicardipine or nifedipine also have been employed to control the hypertension preoperatively.[94] A calcium channel blocker may be used in conjunction with alpha and beta blockade for refractory hypertension or used alone as a second-line agent for patients with intolerable side effects from alpha blockade.[25]

Consideration of preoperative imaging is warranted if a pathogenic variant has been identified, as it may alter the surgical plan and approach.[42] (Refer to the Clinical Diagnosis of PGL and PHEO section of this summary for more information about imaging modalities.)

Surgery

Surgical resection is the treatment of choice for PGL and PHEO. Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[83,95] Open resection is commonly recommended for large tumors (>6 cm–7 cm) because of the increased risk of technical difficulty within the confined space of laparoscopy. Means of exposure and approach are based on the anatomic location of the tumor. Direct access to the adrenal and para-aortic region can be achieved with the posterior approach. It is direct, safe, and efficient.[96] Adequate exposure of the complete tumor is important for complete removal. Robotic assistance can be utilized in select cases because it offers a three-dimensional, magnified view of the anatomy.[97] The efficacy and safety of posterior retroperitoneoscopic adrenalectomy is established, but ongoing studies are examining the relevance of this approach in familial syndromes (refer to NCT02618694).

PGLs are commonly located in the para-aortic retroperitoneal sympathetic chain above the aortic bifurcation, below the takeoff of the inferior mesenteric artery (organ of Zuckerkandl), or near the dome of the bladder.[98,99] Malignant PGLs have a dense fibrous capsule that may adhere to surrounding vascularity, which can make complete resection difficult or unfeasible.[8,99] Regional lymph nodes may be involved with malignant tumors, and if suspected preoperatively or noted intraoperatively, a regional lymphadenectomy may be performed.

Genetic testing is best performed before the initial surgery to inform the risk of recurrent or contralateral disease and to guide the extent of resection (e.g., whether to preserve the cortex) because synchronous or metachronous bilateral disease is quite common in hereditary PHEO. Preoperative knowledge of a germline pathogenic variant significantly affects variables associated with a cortical-sparing adrenalectomy. Preserving the cortex is important in patients with a known pathogenic variant because they are at risk of developing a contralateral tumor. Cortical sparing reduces the possibility of future adrenal insufficiency with contralateral adrenalectomy. This consideration must be weighed against the high risk of malignancy in SDHB carriers. In one study cohort of 108 patients, 33% of patients with a germline pathogenic variant did not have a family history of an inherited syndrome, and 36% of the patients with SDHB germline pathogenic variants had no family history and no previous history of PGL/PHEO on presentation.[100] In one retrospective series that spanned nearly 50 years, 15 of the 49 patients (30%) who presented with a unilateral PHEO and underwent unilateral total adrenalectomy developed PHEO in the contralateral gland at a median of 8.2 years (range, 1–20 y) after initial diagnosis.[101] Of the 15 patients who developed PHEO in the contralateral gland, 8 had MEN2A, 2 had MEN2B, 2 had VHL, and 1 had familial PHEO. The risk of developing a contralateral tumor increased over time, with 25% of patients developing tumors after a median of 6 years and 43% after a median of 32 years. Cortical-sparing surgery is an attractive option because it minimizes the risk of adrenal insufficiency and the need for lifelong steroid supplementation. In large series of patients, cortical-sparing surgery has a 3% to 7% recurrence rate after cortical preservation versus a 2% to 3% recurrence rate after total resection (recurrence in the adrenal bed).[101,102] The frequency of steroid dependence in both studies was lower in patients who underwent cortical-sparing techniques than in patients who did not (57% compared with 86%). One of 39 patients (3%) developed adrenal insufficiency after a cortical-sparing procedure; 5 of 25 patients (20%) developed adrenal insufficiency after total adrenalectomy.[101] These study authors recommend cortical-sparing surgery as a viable option for patients with hereditary PHEO, including patients who initially present with seemingly unilateral disease.

Level of evidence: 5

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98. Ober WB: Emil Zuckerkandl and his delightful little organ. Pathol Annu 18 Pt 1: 103-19, 1983.
99. Mundschenk J, Lehnert H: Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 106 (5): 373-6, 1998.
100. Nockel P, El Lakis M, Gaitanidis A, et al.: Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery. Surgery 163 (1): 191-196, 2018.
101. Grubbs EG, Rich TA, Ng C, et al.: Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg 216 (2): 280-9, 2013.
102. Castinetti F, Qi XP, Walz MK, et al.: Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 15 (6): 648-55, 2014.

Carney-Stratakis Syndrome

Clinical Description

Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. Although similarly named, this syndrome is distinctly different from Carney complex and Carney triad (refer to Table 6). CSS is characterized by an autosomal dominant germline pathogenic variant in the succinate dehydrogenase (SDH) subunit B, C, or D (SDHx) genes that demonstrates incomplete penetrance. Affected individuals develop multifocal, locally aggressive gastrointestinal stromal tumors (GISTs) and multiple neck, intrathoracic, and intra-abdominal paragangliomas (PGLs) at relatively early ages.[1,2,3] CSS-associated GISTs and PGLs display phenotypes that differ from their sporadically occurring, more-common counterparts; as a result, it is important to understand the unique features of imaging, treatment, and surveillance in patients with CSS.

Table 6. Comparison of Carney-Stratakis Syndrome, Carney Triad, and Carney Complex

Syndrome	Inheritance Pattern	Mean Age at Onset (y)	Affected Sex	Associated Lesions	Pathogenic Variants	Tumor Behavior
AD = autosomal dominant; GIST = gastrointestinal stromal tumor; F = female; M = male.
Carney-Stratakis syndrome[1,3,4]	AD	23	M, F	Paraganglioma, stomach epithelioid GIST	GermlineSDHxpathogenic variants common; noKITorPDGFRApathogenic variants	GIST metastasis but protracted course; paraganglioma aggressive
Carney triad[4,5,6]	None	<30	>95% F	Lung chondroma, paraganglioma, stomach epithelioid GIST	NoKITorPDGFRApathogenic variants; rarely,SDHxpathogenic variants (9.5% in one series)[7]	GIST metastasis but protracted course
Carney complex[8,9]	AD	20	M, F	Lentigines, myxomas, schwannoma, thyroid follicular adenomas or carcinoma, primary pigmented nodular adrenocortical disease, pituitary adenomas	GermlinePRKAR1Apathogenic variants	N/A

Genetics, Inheritance, and Genetic Testing

The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function mutation in the KIT or PDGFRA gene, as is seen in the vast majority of GISTs.[10] SDH deficiency is also a characteristic finding of pediatric-type GISTs; CSS-associated GISTs display clinical findings similar to these tumors, including young age at onset (median age, 19 y), specificity to the stomach, multifocality, and resistance to imatinib.[3,11,12,13] Furthermore, tumor size and mitotic rate do not accurately predict metastatic potential or survival, as SDH-deficient GISTs frequently metastasize to regional lymph nodes, the peritoneal cavity, and the liver; however, long-term survival is common.[6,14]

Refer to the Genetics, Inheritance, and Genetic Testing section in the Familial Pheochromocytoma and PGL Syndrome section of this summary for more information about genetic testing for the genes involved in CSS.

Surveillance

Although the natural history of CSS is poorly understood, experts recommend that ongoing surveillance include the following: close patient follow-up with annual history that focuses on symptoms of anemia and catecholamine excess, physical exam, biochemical analysis with plasma metanephrine level and chromogranin A to detect recurrent PGLs, and cross-sectional imaging. Although many PGLs do not secrete catecholamines, chromogranin A has been found to be elevated in PGLs and may be a useful marker for tumor recurrence. The appropriate screening imaging modality is unknown at this time, but fluorine F 18-fludeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) is highly sensitive at identifying extra-adrenal PGLs and GISTs. Because of the risks of ionizing radiation exposure from CT, some suggest using MRI for annual surveillance.[15,16]

Level of evidence: 4

Interventions

Because multiple primary GISTs and PGLs are common with CSS, preoperative imaging is paramount to accurately identify the extent of disease before surgical planning. Most patients will present having already undergone imaging with CT or magnetic resonance imaging (MRI). Both methods have excellent sensitivity for identifying PGLs, but additional functional imaging is recommended because of the diffuse nature of these tumors. 18F-FDG PET-CT is superior to iodine I 123-metaiodobenzylguanidine at identifying SDHx-associated PGLs and, because of the high metabolic activity of GISTs, has excellent sensitivity in identifying them.[15,17] Thus, in patients with SDHx pathogenic variants, including those with CSS, 18F-FDG PET-CT is the preferred functional imaging modality to optimally detect and stage all GISTs and PGLs.[16] Some evidence suggests that 18F-fluoro-L-dihydroxyphenylalanine (18F-FDOPA) PET-CT is superior at identifying the primary PGL, while 18F-FDG PET-CT is superior at identifying metastases.

There are no prospective treatment studies involving patients with CSS; therefore, recommendations are based on limited clinical experience, single case series, and extrapolations from genetically-similar tumors with similar clinical behavior. 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. Surgical resection can be accomplished with laparoscopic or open techniques. For PGLs, vascular reconstruction is uncommon. Although PGLs are commonly present in the paraaortic region, the need for major vascular reconstruction is uncommon. GIST tumors can be resected with wedge resection and primary closure and re-anastomosis. Ensuring negative margins is important, as patients for whom a complete resection is accomplished experience the longest survival.[18] In the rare setting of synchronous disease, combined resection is appropriate if tolerable by the patient. More commonly, tumors develop metachronously, with GISTs arising first; individual resection occurs at the time of diagnosis of each tumor.

A thorough preoperative endoscopy and complete surgical exploration of the stomach are essential, as multiple separate GISTs are frequently encountered. The high frequency of multifocality and the likelihood of tumor recurrence do not justify a prophylactic total gastrectomy because of its substantial associated morbidity. Furthermore, a total gastrectomy is generally only performed when the current disease burden precludes a lesser resection. To this end, gastric wedge resection with gross negative margins is the surgical goal.[19] Sampling of any suspicious nodes at the time of resection is commonly performed. Evidence suggests that locally advanced CSS-associated GISTs demonstrate a rather indolent course;[20] thus, the concern for nodal involvement based on preoperative imaging or abdominal exploration need not deter resection of the primary tumor. While a role for neoadjuvant imatinib in locally advanced adult-type GISTs has been widely described to improve resectability or reduce the burden of resection, it is unlikely to have any effect in locally advanced SDH-deficient GISTs.[21] Evidence suggests that for these tumors, the second-line targeted agents, including sorafenib, sunitinib, dasatinib, and nilotinib, may be beneficial in the adjuvant setting.[22,23] No data support using these agents in the neoadjuvant setting at this time.

Regarding treatment of CSS-associated PGLs, patients are commonly initiated on alpha-blockade preoperatively to minimize perioperative cardiac morbidity and mortality. PGLs typically occur in the para-aortic chain from the urinary bladder and the aortic bifurcation to the superior mediastinum and head and neck. As in the treatment of GISTs, the operative goal is resection of all known disease. Preoperative imaging and intra-operative exploration are essential to achieving this goal. Multiple tumors are common; when disease is present in the bilateral adrenal glands, the surgeon faces the possibility of rendering a patient steroid dependent with a lifelong risk of a fatal Addisonian crisis. In this setting, a surgeon proficient in performing a cortical-sparing adrenalectomy may be consulted.

Level of evidence: 5

References:

1. 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.
2. 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.
3. 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.
4. Gaal J, Stratakis CA, Carney JA, et al.: SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 24 (1): 147-51, 2011.
5. Agaimy A, Pelz AF, Corless CL, et al.: Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep 18 (1): 9-15, 2007.
6. Zhang L, Smyrk TC, Young WF, et al.: Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 34 (1): 53-64, 2010.
7. Boikos SA, Xekouki P, Fumagalli E, et al.: Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet 24 (4): 569-73, 2016.
8. Boikos SA, Stratakis CA: Carney complex: pathology and molecular genetics. Neuroendocrinology 83 (3-4): 189-99, 2006.
9. Correa R, Salpea P, Stratakis CA: Carney complex: an update. Eur J Endocrinol 173 (4): M85-97, 2015.
10. Hensen EF, Bayley JP: Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer 10 (2): 355-63, 2011.
11. Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008.
12. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35 (11): 1712-21, 2011.
13. Sawhney SA, Chapman AD, Carney JA, et al.: Incomplete Carney triad--a review of two cases. QJM 102 (9): 649-53, 2009.
14. Rege TA, Wagner AJ, Corless CL, et al.: "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol 35 (4): 495-504, 2011.
15. Ayala-Ramirez M, Callender GG, Kupferman ME, et al.: Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome. Nat Rev Endocrinol 6 (2): 110-5, 2010.
16. Timmers HJ, Kozupa A, Chen CC, et al.: Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 25 (16): 2262-9, 2007.
17. Timmers HJ, Chen CC, Carrasquillo JA, et al.: Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 94 (12): 4757-67, 2009.
18. Abadin SS, Ayala-Ramirez M, Jimenez C, et al.: Impact of surgical resection for subdiaphragmatic paragangliomas. World J Surg 38 (3): 733-41, 2014.
19. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007.
20. Maki RG, Blay JY, Demetri GD, et al.: Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion. Oncologist 20 (7): 823-30, 2015.
21. Ganjoo KN, Villalobos VM, Kamaya A, et al.: A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 25 (1): 236-40, 2014.
22. Gill AJ, Chou A, Vilain R, et al.: Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol 34 (5): 636-44, 2010.
23. Janeway KA, Albritton KH, Van Den Abbeele AD, et al.: Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer 52 (7): 767-71, 2009.

Familial Nonmedullary Thyroid Cancer

Clinical Description

Papillary and follicular cancers, along with their various histologic subtypes, arise from the follicular cells of the thyroid and are collectively referred to as differentiated thyroid cancer or nonmedullary thyroid cancer (NMTC). Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, comprising over 85% of all cases, and is rapidly increasing in incidence worldwide.[1]

Radiation exposure, particularly during childhood, has been extensively studied as a causative factor in the development of thyroid cancer; however, it accounts for only a small minority of cases.[2,3] One of the strongest risk factors for the development of thyroid cancer is a family history of the disease, in which cases are termed familial nonmedullary thyroid cancer (FNMTC). The exact incidence of FNMTC is difficult to determine because the criteria used to qualify as a heritable condition varies among studies. Criteria that have yet to be universally defined include the number of affected relatives and their relationship (i.e., first-degree relatives, second-degree relatives, etc.), pattern of inheritance, and the presence of coexisting thyroid conditions.

Further confounding the distinction between inherited and sporadic disease is the high prevalence of incidental microcarcinomas, which may be found in 10% to 15% of surgeries or autopsies.[4] Because there are, as of yet, no known gene variants responsible for FNMTC in the majority of families, this high background prevalence of disease poses a challenge in assessing the risk of a thyroid malignancy in other family members. This uncertainty may be especially problematic in equivocal cases of inherited disease; for example, two second-degree relatives with thyroid cancer.

FNMTC may be part of a larger syndrome associated with tumors involving other organs or may represent a stand-alone condition. Table 7 outlines the various hereditary syndromes associated with NMTC.

Genetics, Inheritance, and Genetic Testing

The genetics of familial medullary thyroid cancer (FMTC) in the context of multiple endocrine neoplasia type 2 are well established. Genetic factors also clearly contribute to NMTC, as it has one of the highest heritabilities of any cancer site, with a relative risk of fivefold to tenfold for relatives of patients, especially (female) siblings.[5,6,7,8] FNMTC, which includes follicular subtypes, primarily papillary, is thought to account for 5% to 10% of all NMTC cases.[5,9,10] Notably, when there are only two individuals affected in a family, there is a 40% to 60% chance that the disease is actually sporadic, whereas when three or more family members are affected there is a 96% chance the disease has an inherited component.[11] With the exception of a few rare genetic syndromes with NMTC as a minor component, the majority of FNMTC is nonsyndromic and the underlying genetic predisposition is unclear. Still, the term familial cancer is somewhat misleading as FNMTC pedigrees demonstrate a definitive mendelian pattern of inheritance which is autosomal dominant with incomplete penetrance and variable expressivity.[5,12,13,14,15] However, unlike FMTC, FNMTC is a polygenic disease with no single locus responsible for the majority of cases or easily identifiable phenotype and it is likely modified by multiple low-penetrance alleles and environmental factors.[16]

Ruling out syndromic FNMTC

As there is no clinical genetic testing for nonsyndromic FNMTC, identification of at-risk families must rely on astute clinicians obtaining a thorough clinical examination and detailed personal and family history of any patient presenting with thyroid cancer or disease. Aspects of a history that suggest FNMTC include multiple generations affected, early-onset bilateral/multifocal thyroid tumors (especially in males) with a more aggressive clinical course, and association with benign thyroid pathologies.[17] Detailed work-up is critical in FNMTC as it is ultimately a diagnosis of exclusion in the sense that other familial cancer predisposition syndromes associated with NMTC must first be ruled out, such as Cowden syndrome or familial adenomatous polyposis. These differential diagnoses for FNMTC are outlined in Table 7. Notably, the association of NMTC with McCune-Albright, Peutz-Jeghers, ataxia-telangiectasia, and multiple endocrine neoplasia type 1 syndromes is less established.

Table 7. Hereditary Syndromes Associated With Nonmedullary Thyroid Cancer^a

Syndrome	Gene	Inheritance	Incidence of Thyroid Cancer (%)	Type of Thyroid Cancer	Extrathyroidal Clinical Features
FAP = familial adenomatous polyposis; FTC = follicular thyroid cancer; MNG = multinodular goiter; PTC = papillary thyroid cancer.
a Adapted from Nose,[18]Sturgeon et al.,[19]and Vriens et al.[17]
FAP/Gardner syndrome	APC	Autosomal dominant	2	PTC (cribriform morular variant)	Gastrointestinal adenomatous polyps; Gardner syndrome also includes desmoid tumors, supernumerary teeth, fibrous dysplasia of skull, osteomas, epidermoid cysts, hypertrophy of retinal epithelium
Cowden syndrome (PTENhamartoma syndrome)	PTEN(rarelySDHx,KLLN,AKT1,PIK3CA)	Autosomal dominant	10–35	FTC, PTC	Malignant tumors and hamartomas of breast, endometrium, thyroid, kidney, gastrointestinal tract, brain, skin
Carney complex	PRKAR1α	Autosomal dominant	11–15	FTC, PTC	Myxomas of soft tissues, skin and mucosal pigmentation (blue nevi), schwannomas, tumors of adrenal, pituitary and testicle
Werner syndrome	WRN	Autosomal recessive	18	FTC, anaplastic PTC	Premature aging (adult progeria), scleroderma-like skin changes, cataracts, subcutaneous calcifications, muscular atrophy, diabetes
DICER1syndrome	DICER1	Autosomal dominant	Unknown	PTC (and MNG)	Familial pleuropulmonary blastoma; cystic nephroma; ovarian Sertoli-Leydig cell tumors
McCune-Albright syndrome	GNAS	Mosaicsomatic mutations	Unknown	FTC	Polyostotic fibrous dysplasia, café-au-lait spots, endocrine hyperfunction of pituitary, adrenal, gonadal tissues
Peutz-Jeghers syndrome	STK11 (LKB1)	Autosomal dominant	Unknown	Primarily PTC	Hamartomas of small intestine, mucocutaneous hyperpigmentation, Sertoli cell testicular tumors
Ataxia-telangiectasia	ATM	Autosomal recessive	Unknown	Primarily PTC	Cerebellar ataxia and nystagmus, oculocutaneous telangiectasia, immunodeficiency, lymphoreticular cancers
Multiple endocrine neoplasia type 1 (MEN1)	MEN1	Autosomal dominant	Unknown	Primarily PTC	Tumors of parathyroid glands, endocrine gastroenteropancreatic tract, anterior pituitary gland

Identifying genes and inherited variants associated with nonsyndromic FNMTC

Various methods have been employed to uncover the landscape of genetic variation associated with FNMTC, mainly genome-wide linkage analysis using microsatellite markers evenly distributed across the genome and informative large pedigrees with multiple affected family members. More than 15 genetic loci have been linked to FNMTC, which are summarized in Table 8. The loci that are italicized represent those where the susceptibility gene has been identified; the causal genes at the other loci remain unknown. The first four loci were identified by microsatellite linkage analysis. The remaining loci have been identified by increasingly dense single nucleotide variant (SNV) arrays as well as microRNA arrays and, most recently, next-generation sequencing. (Refer to the PDQ Cancer Genetics Overview summary for more information about linkage analysis and next-generation sequencing.) Most of these studies have been done on groups of families with pedigrees consistent with FNMTC; however, two of the loci were identified through large, population level SNV array analysis. It is important to note that several studies have excluded the genes that are most commonly somatically altered in association with sporadic NMTC as having a role in FNMTC, namely BRAF, RET, RET/PTC, MET, MEK1, MEK2, RAS, and NTRK.[20]

Table 8. Nonsyndromic Familial Nonmedullary Thyroid Cancer Susceptibility Loci

Locus	Location	Tumor Type	Sample Sizea		Study Type	Original Cohort Country of Origin	Year	References
FTC = follicular thyroid cancer; MNG = multinodular goiter; miRNA = microRNA; NMTC = nonmedullary thyroid cancer; PRN = papillary renal neoplasia; PTC = papillary thyroid cancer; SNV = single nucleotide variant; WES =whole-exome sequencing.
a Combined across studies.
MNG1	14q31	MNG with PTC	1kindred		Microsatellite linkage	Canada	1997	[21]
			18 MNG
			2 PTC
TCO	19p13.2	PTC with oxyphilia	1 kindred		Microsatellite linkage	France	1998	[22,23,24,25]
			20 families
			6 MNG
			3 PTC
			49 NMTC
fPTC/PRN	1q21	PTC with PRN	1 kindred		Microsatellite linkage	United States	2000	[26]
			5 PTC
			2 PRN
NMTC1	2q21	PTC (follicular variant)	1 kindred, 80 pedigrees		Microsatellite linkage	Tasmania	2001	[24,25,27]
			19 families
			49 NMTC
FTEN	8p23.1-p22	PTC (classic)	1 kindred		10K SNV array	Portugal	2008	[28]
			11 benign
			5 NMTC
Unknown	8q24	PTC with melanoma	26 families		50K SNV array	United States	2009	[29]
FOXE1	9q22.33	PTC/FTC	60 families		300K SNV array	Iceland/Spain/United States	2009	[30]
			197 PTC/FTC
NKX2-1/TITF-1	14q13.3	PTC and MNG	60 families		300K SNV array	Iceland/United States/Spain	2009	[30]
			197 PTC/FTC
Unknown	6q22	PTC/FTC (classic)	38 families		50K SNV array	United States/Italy	2009	[31]
			49 PTC
miR-886-3p	5q31.2	PTC	21 PTC		3K miRNA array	United States	2011	[32]
			7 FNMTC
			10 normal thyroid tissue
miR-20a	13q31.3	PTC	21 PTC		3K miRNA array	United States	2011	[32]
			7 FNMTC
			10 normal thyroid tissue
Telomere-telomerase complex (TERT, TRF1, TFR2, RAP1, TIN2, TPP1, POT1)	5p15.3 (TERT), etc.	PTC	47 PTC				2008	[33]
SRGAP1	12q14	PTC	38 families		250K SNV array	United States/Poland	2013	[34]
HAPB2	10q25-26	PTC, follicular adenoma	1 kindred		WES	United States	2015	[35]
			7 PTC
RTFC (c14orf93)	14q11.2	PTC	15 families		WES	China	2017	[36]

Susceptibility loci identified through linkage analyses

MNG1, TCO, fPTC/PRN and NMTC1 are proposed FNMTC susceptibility loci identified in families with multiple affected individuals and are summarized in Table 8. Conflicting evidence exists regarding the linkage to the loci described above. MNG1 has shown strong evidence of linkage in only one Canadian kindred with multiple multinodular goiters (MNGs) and linkage analyses in 124 additional families failed to find an association between MNG1 and FNMTC. Therefore, the locus may be important for MNG alone but not for FNMTC.[21,22,26,37,38,39] TCO accounts for a minority of FNMTC cases, but specifically those associated with tumor cell oxyphilia, which is a rare morphology that does not apply to the majority of FNMTC cases ascertained.[22,23,24,25] fPTC/PRN is also a rare subtype of FNMTC in which PTC is associated with papillary renal neoplasia, but other than the original family reported, no additional families sharing this phenotype have been identified.[22,26,39] NMTC1 seems to predispose to the follicular variant of PTC, another rare subtype. Classic PTC and oxyphilic tumors are also associated with this locus, though to a lesser extent.[24,24,27] In 2001, a comprehensive mutation and linkage analysis of 22 international FNMTC families revealed that only one family had significant linkage to any known susceptibility locus (TCO in this case), including the ones described above.[22] This cumulative evidence suggests that these FNMTC loci account for disease in a small subset of families, which is consistent with the concept that FNMTC exhibits genetic and locus heterogeneity.

Susceptibility loci identified through genome-wide SNV arrays

Five FNMTC loci have been identified through increasingly dense SNV arrays, also listed in Table 8. The first FNMTC study done by SNV array along with microsatellite analysis was in 2008 in a Portuguese family.[28] This family had five members with PTC (4 classic and 1 follicular variant) and 11 members with benign thyroid diseases. The susceptibility locus was identified at 8p23.1-p22 and designated FTEN (familial thyroid epithelial neoplasia). The 8q24 locus was first identified from a linkage analysis study using SNV arrays of 26 FNMTC families (with PTC). One family had three generations of PTC and melanoma (and MNG); but melanoma was not reported in the other 25 families. Sequencing of genes in the 8q24 region did not reveal any candidate pathogenic variants, but gene expression analysis indicated AK023948 (PTSCC1), a noncoding RNA gene that is downregulated in PTC, could be involved.[29]

In 2009, a population-level study was done in Iceland on 197 cases of PTC or FTC and compared with genotypes of 37,196 Icelandic controls.[30] Two loci had high statistical significance, 9q22.33 and 14q13.3, which are near the genes FOXE1 and NKX2-1, respectively. Two SNVs in particular were associated with increased risk of PTC and FTC: rs944289 (near NKX2-1) and rs965513 (near FOXE1). These results were replicated in two additional large cohorts from the United States (726 individuals tested) and Spain (1,433 individuals tested), as well as other cohorts that also found additional SNVs of interest, particularly in FOXE1.[30,40,41]FOXE1 remains a gene of interest in FNMTC because it produces a thyroid transcription factor with a key role in thyroid gland formation, differentiation, and function.[42] The NKX2.1/TITF-1 gene also encodes a thyroid transcription factor. A germline variant, A339V, has been reported in two FNMTC families affected with MNG or PTC/MNG;[43] however, this association could not be replicated in subsequent studies of other families.[44] Lastly, a large United States and Italian cohort (110 individuals, 49 affected, from 28 FNMTC families) was studied using a 50K SNV array. The majority of these families had classic PTC. The pooled analysis showed linkage to previously identified 1q21 locus (PRN) and a new locus at 6q22.[31]

MicroRNA (miRNA) susceptibility loci

miRNAs are small noncoding RNAs that regulate gene expression. Whole-genome miRNA microarrays were used to evaluate 21 sporadic and seven familial NMTC cases, as well as ten normal thyroid tissue samples.[32] Two miRNAs, miR-20a (13q31.3) and miR-886-3p (5q31.2), were differentially expressed between sporadic and familial NMTC, as confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Both were also downregulated in NMTC compared with normal thyroid tissues by fourfold. Cell-line transfection studies using miR-886-3p confirmed that it plays a critical role in cell proliferation and migration and it regulates genes involved in DNA replication and focal adhesion pathways.[32] Furthermore, a polymorphism in pre-miR-146a (rs2910164) has been shown to affect miRNA expression and was identified in a significant proportion of the tumors of 608 PTC patients, suggesting it could contribute to genetic predisposition to PTC and play a role in the tumorigenesis through somatic changes.[45] The role of gene regulatory mechanisms and their effect on gene expression and FNMTC tumorigenesis warrants further exploration.

Telomere-telomerase complex

Telomeres are noncoding chromosomal ends consisting of tandem repeats that are important in maintaining chromosomal stability. Telomere length is maintained by a telomerase complex that includes telomerase reverse transcriptase (TERT), along with six other proteins: TRF1, TFR2, RAP1, TIN2, TPP1, and POT1.[46] Shortened telomere length is associated with chromosomal instability that can play a role in cancer development. The telomere-telomerase complex has become a focus of investigation as another possible genetic mechanism for predisposition to FNMTC. In 2008, a cohort of patients with FNMTC was studied using qualitative PCR and fluorescence in situ hybridization to evaluate relative telomere length.[33] They found that telomere length was significantly shorter in familial PTC patients compared with unaffected family members and sporadic PTC. The same group also found that the telomeres in FNMTC cancers were relatively fragile and had a high rate of fragment formation.[47] A second study of telomere length in FNMTC also showed shorter telomere lengths in 13 affected patients compared with 31 unaffected family members.[48] However, the same study showed that relative telomere length was not associated with altered copy number or expression of telomere complex genes hTERT, TRF1, TFR2, RAP1, TIN2, TPP1, or POT1. Other studies have failed to show any significant differences in telomere length between FNMTC and sporadic PTC cases.[49] The role and mechanism of the telomere-telomerase complex in predisposition to FNMTC remains to be elucidated.

Other recently identified FNMTC susceptibility genes and variants

SRGAP1 is a gene that was identified in 2013 through genome-wide linkage analysis of 38 FNMTC families with PTC from the United States and Poland.[34] Four germline missense variants were identified but two variants, Q149H and A275T, were most notable because they segregated in two separate families but not in 800 sporadic cases. SRGAP1 regulates the small G-protein CDC42 in neurons and affects cell mobility.[50] Functional assays demonstrated that Q149H and R617C variants in SRGAP1 could lead to loss-of-function changes that impair ability to inactivate CDC42, which could lead to tumorigenesis.[34] Further studies are needed to validate the association of this gene in other FNMTC cohorts.

HAPB2 was identified in 2015 through whole-exome sequencing (WES) in seven affected members of an FNMTC kindred with PTC and follicular adenoma, using unaffected spouses as controls.[35] One specific germline variant, G534E, was found in the heterozygous state in all affected cases. The group also detected this variant through next-generation sequencing in 4.7% of NMTC cases from the Cancer Genome Atlas. This variant was associated with increased HAPB2 protein expression in the thyroid neoplasms of affected family members. This was not seen in normal thyroid tissue or in individuals with sporadic PTC. Functional G534E studies showed that this variant increased colony formation and cellular migration, suggesting a loss of tumor suppression function. Notably, the authors used a criterion of general population frequency of 1% or less to filter variants identified in this kindred using the 1000 Genomes Project (phase III) and HapMap3. However, subsequent correspondences commented on higher reported frequencies of G534E variants from public databases including that of the Exome Aggregation Consortium (ExAC) (2.22% in the total population, 3.29% in non-Finnish European individuals) and the National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity Exome Sequencing Project database (5.5% in the total population, 3.88% in American individuals of European descent).[51,52,53] Many additional studies were conducted to ascertain the frequency of HAPB2 G534E in FNMTC with variable results. While the G534E variant was not identified in 12 Chinese FNMTC families with PTC (nor in 217 patients with sporadic PTC) [53] or in 11 Middle Eastern FNMTC family members,[54] it was shown to segregate in several independent FNMTC kindreds with PTC from a United States study.[55] Several other studies showed that the G534E variant was found in controls and sporadic cases just as often, or more often, than it was found in familial cases of PTC (if the variant was identified in familial PTC cohorts at all). In some cases, the G534E variant did not segregate with disease in familial PTC cohorts.[54,56,57,58] Therefore, it seems that the HAPB2 G534E variant frequency differs among ancestries and populations; this variant was present in low-to-moderate levels in individuals of European ancestry and in low levels, or completely absent, in individuals of Asian and Middle Eastern ancestries. Larger validation studies are required to determine its role and association with FNMTC.

Lastly, RTFC (c14orf93) was identified through WES of FNMTC families in China.[36] Three genes were identified as candidate genes for FNMTC (RTFC, PYGL, and BMP4) but the RTFC gene was the only one shown to have oncogenic function in promoting thyroid cancer cell survival under starving conditions and promoting cell migration and colony-forming capacity. Specifically, the V205M (c.613G>C) variant in RTFC was important because it was identified in FNMTC patients but absent in unaffected controls. Two additional oncogenic mutations of RTFC were identified (R115Q and G209D) in patients with sporadic NMTC. Collectively, the ExAC frequencies of these variants in East Asian populations are higher than the ExAC frequencies in the total population, which may indicate that this gene is most relevant in East Asian families with FNMTC. Larger validation studies of this gene and these variants need to be conducted.

In summary, although multiple susceptibility loci have been identified in FNMTC families, no single locus accounts for the majority of nonsyndromic FNMTC and no gene identified shows strong enough associations to warrant clinical genetic testing. Newer sequencing techniques, including WES, will allow for new genes to be discovered and evaluated. Identifying susceptibility genes will allow for screening and early diagnosis, which in turn would lead to improved outcomes for patients and families.

Surveillance

Differentiated thyroid cancer, whether inherited or sporadic, may be associated with a high rate of recurrence, depending on the clinicopathologic features of the disease. Disease recurrence may occur as late as 40 years after initial diagnosis.[59]Surveillance for recurrent disease therefore plays an important role in the long-term management of patients with these tumors. The optimal follow-up strategy is dependent upon both the initial tumor characteristics and the patient's response to therapy.[60] Fortunately, for most patients, the disease is associated with a low risk of recurrence, and surveillance is accordingly less intensive. In these cases, postoperative evaluation is centered on sonographic examination of the neck and measurement of serum thyroglobulin.[60]

Thyroglobulin, a protein produced by both benign and malignant thyroid follicular cells, is used as a tumor marker for patients with differentiated thyroid cancer. Thyroglobulin measurement is most sensitive after a total thyroidectomy, so detection of thyroglobulin—particularly an increasing trend in the serum concentration—is often an early indicator of recurrent or progressive disease.[61] However, it is important to recognize several caveats about the use of this tumor marker. It is imperative to assess serum thyroid-stimulating hormone (TSH) and thyroglobulin antibody levels concomitantly at each measurement. Thyroglobulin rises with increasing TSH values; therefore, an elevating thyroglobulin level could indicate progressive disease or simply a rising TSH level. Furthermore, the presence of thyroglobulin antibodies can interfere with the accurate measurement of thyroglobulin, with most cases resulting in a spurious lowering of the tumor marker.[62] In such cases, the antibody titer may be used as a surrogate marker of disease status.[60] The final caveat about the use of thyroglobulin as a tumor marker is that the test must be performed in the same laboratory at each measurement to accurately assess the trend in levels; each assay can render a different value of thyroglobulin on the same serum sample.[60] Measurement of serum thyroglobulin to assess for recurrent or persistent disease may be performed 3 to 6 months after therapy is completed and monitored periodically thereafter, depending on the concern for persistent or recurrent disease.[60] Stimulated thyroglobulin testing (after withdrawal of thyroid hormone reaches a minimum TSH level of 30 mIU/L or after recombinant TSH injection) may be useful in select patients, particularly in patients with follicular thyroid cancer or in whom there is high clinical suspicion of recurrent or residual disease.

Whether a patient has received radioactive iodine or only surgery, careful ultrasonography of all compartments in the anterior neck is an important tool to determine if there is recurrent or residual disease because most disease is localized in this region. The initial ultrasonography is typically performed 6 to 12 months after surgery.[60] Ultrasonography may be performed sooner if there is concern about residual disease, but it is important for the sonographer to recognize the potential for false-positive findings due to postoperative swelling. The timing and need for subsequent sonographic evaluation of the neck is dependent upon the patient's risk for recurrence and the serum thyroglobulin status.[60]

Ultrasonography combined with a serum thyroglobulin test has a very high sensitivity for identifying nodal disease, far superior to the radioiodine diagnostic whole-body scans that were historically the mainstay of surveillance.[61]

Interventions

Once a thyroid nodule is detected, further work-up includes complete ultrasonography of the thyroid, as well as a comprehensive neck ultrasonography to evaluate the central and lateral neck lymph nodes. Comprehensive preoperative neck ultrasonography not only provides the opportunity for fine-needle aspiration (FNA) biopsy of any suspicious nodes before surgery but also allows the surgeon to plan the appropriate surgery and counsel the patient regarding a surgical procedure and its associated risks.[63]

FNA is indicated for cytologic evaluation of suspicious nodules based on size of the nodule, imaging characteristics, and associated patient risk factors.[64,65] Most current guidelines recommend consideration of FNA biopsy of all nodules measuring 10 mm or larger. Those nodules with less suspicious sonographic features may be considered for FNA at a larger size threshold. Nodules smaller than 10 mm in greatest dimension may still warrant cytologic evaluation if radiographic imaging demonstrates features concerning for malignancy, such as suspicious lymphadenopathy or extrathyroidal extension. Consideration may also be given to perform FNA of sonographically suspicious nodules, regardless of size, for patients with a strong family history of thyroid cancer. Ultrasonographic features suspicious for malignancy include hypoechogenicity, solid composition, taller-than-wide shape, infiltrative borders, and microcalcifications.

Although positron emission tomography scanning is not recommended for thyroid nodule assessment, concentrated uptake of contrast in the thyroid gland may be detected when the scan is obtained for other reasons. Incidental increase in fluorine F 18-fludeoxyglucose avidity, and an increase in nodule size (more than 50% volume) during surveillance may also be indications for FNA biopsy of nodules.[60]

Cytologic evaluation and indeterminate thyroid nodules

The Bethesda Thyroid Cytology Classification standardizes the cytologic interpretation of thyroid biopsies. Pathologic results are classified into one of the following six categories:[66]

• Nondiagnostic or unsatisfactory.
• Benign.
• Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS).
• Follicular neoplasm or suspicious for follicular neoplasm.
• Suspicious for malignancy.
• Malignant.

Patients with biopsy-proven malignant nodules (or nodules suspicious for malignancy) may be considered for surgical resection as discussed below. Nodules classified as AUS/FLUS fall into the indeterminate category because the extent of architectural or cytologic atypia excludes a benign diagnosis, but the degree of atypia is insufficient for a definitive malignant classification.[66] These lesions may be considered for repeat FNA, surveillance ultrasonography, molecular testing, or surgical removal on the basis of clinical concern for malignancy, comorbid conditions, and/or family history of thyroid cancer.[60]

Surgical treatment of thyroid cancer

Patients with a diagnosis of FNMTC may have increased aggressiveness of disease in comparison with sporadic cases.[67] If there are three affected members of a kindred, the tumor is more likely to have aggressive features at a younger age; this suggests a more aggressive surgical management may be warranted.[68] Most experts support total thyroidectomy because of the risk of increased frequency of multicentric disease, lymph node metastases, local invasion, and recurrence of aggressive disease.[67,69] Most surgeons would agree that patients with FNMTC and radiographically, clinically, or intraoperatively suspicious or biopsy-proven metastatic lymph nodes warrant total thyroidectomy and therapeutic compartment-based removal of the lymph node basin(s). Controversy exists, however, as to the appropriate treatment of nonenlarged lymph nodes of the central neck at the time of initial thyroidectomy. Specifically, some groups advocate routine prophylactic central node dissection (PCND) for all patients with known FNMTC to decrease the risk of local recurrence, although there are no specific, prospective, randomized data to support a survival benefit.[70,71] While two retrospective studies (not specific to hereditary thyroid cancer) have reported a reduction in disease recurrence rates associated with PCND,[72,73] two meta-analyses have shown that PCND does not reduce recurrence rates in a clinically significant manner.[74,75] The current recommendations published by the American Thyroid Association (ATA) state that prophylactic or bilateral Level VI lymph node dissection is recommended in patients with T3/T4 papillary cancer (whether familial or not), clinically involved lateral neck nodes or if the information will be used to plan further therapy such as radioactive iodine ablation. The ATA also states that this recommendation should be interpreted in light of available surgical expertise, acknowledging that PCND may lead to increased perioperative morbidity.[60] Currently, selective, rather than routine PCND seems the most reasonable option to guide the decision process.[76]

After total thyroidectomy, patients will need lifelong thyroid hormone replacement therapy.[60] The levothyroxine replacement therapy dose is approximately 1.6 µg/kg/day and is then titrated to reach an appropriate level of TSH suppression.[77,78] The degree of TSH suppression is also individualized on the basis of the patient's disease status, risk of recurrence, an individual's risk of cardiovascular and bone complications with aggressive TSH suppression,[60] and clinicopathological tumor features. Patients typically undergo a surveillance regimen for recurrence consisting of laboratory evaluation and ultrasonography. In papillary and follicular cancer, thyroxine and TSH demonstrate the level of thyroid suppression, and thyroglobulin and thyroglobulin antibody levels are important markers for possible disease recurrence or metastases.

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Changes to This Summary (03 / 18 / 2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Multiple Endocrine Neoplasia Type 2

Updated American Cancer Society as reference 23.

Added level of evidence 4.

Added level of evidence 3dii.

Familial Pheochromocytoma and Paraganglioma Syndrome

Revised text to state that some experts view local invasion into surrounding tissue as an additional marker of malignancy, whether the tumor is resectable or unresectable (cited Fishbein et al. as reference 8).

Revised text to state that malignant paragangliomas have a dense fibrous capsule that may adhere to surrounding vascularity, which can make complete resection difficult or unfeasible.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of endocrine and neuroendocrine neoplasias. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Genetics of Endocrine and Neuroendocrine Neoplasias are:

• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Samuel Hyde, MMSc, LCGC (Guardant Health, Inc.)
• Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
• Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Jennifer Sipos, MD (The Ohio State University)
• Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Endocrine and Neuroendocrine Neoplasias. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389271]

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Last Revised: 2022-03-18