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. [PMC free article: PMC4490627] [PubMed: 25810047]
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. [PubMed: 11857563]
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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. [PubMed: 17667967]
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. [PubMed: 3789026]
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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 may be made when an individual has two of the three major endocrine tumors listed above, especially if he/she was diagnosed with these tumors at a young age. Alternatively, familial MEN1 may be defined as having at least one MEN1 case in the family plus at least one first-degree relative (FDR) with one of these three tumors, or two FDRs with a germline pathogenic variant.[2-5]

Initial clinical presentation of symptoms typically occurs between the ages of 20 and 30 years. However, in many cases, an MEN1 diagnosis may not be confirmed for many years after initial symptoms occur. 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.[2,5-7] To date, there are no well-established genotype-phenotype correlations to guide clinical management of patients with MEN1.

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.[8,9] MEN1-associated parathyroid tumors are typically multiglandular and hyperplastic. This differs from sporadic parathyroid tumors, which often present with a solitary adenoma.[10] The mean age of PHPT onset is 20 to 25 years in individuals with MEN1. In contrast, PHPT onset occurs in the general population at age 50 to 59 years. When MEN1 presents in childhood, the most common presenting feature is multi-gland hyperparathyroidism.[11] Parathyroid carcinoma in MEN1 is rare but has been described.[12-14]

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 normalize calcium and PTH levels. This can help relieve an individual's symptoms. However, there have been high recurrence rates of parathyroid tumors after surgery in some series.[15-17] For more information, see the Interventions section.

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[2,8] 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.[18] Furthermore, duodenopancreatic NETs are associated with early mortality even after surgical resection.[19]

Duodenopancreatic NETs seen in MEN1 include the following:

• Gastrinomas.
• Nonfunctioning NETs.
• Insulinomas.
• Vasoactive intestinal peptide tumors (VIPomas).
• Glucagonomas.
• Somatostatinomas.

Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,15] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[23] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[5,15,23,24]

Originally, nonfunctioning duodenopancreatic NETs were thought to be uncommon in individuals with MEN1. However, recognition of these tumors has increased with advanced genetic testing and improved imaging techniques. For example, a prospective study showed that MEN1 pathogenic variant carriers had a nonfunctioning duodenopancreatic NET frequency of 55% by age 39 years when they underwent endoscopic ultrasonography of the pancreas.[21,25] These tumors can be metastatic. One study of 108 MEN1 pathogenic variant carriers with nonfunctioning duodenopancreatic NETs showed a positive correlation between tumor size, rate of metastasis, and death. Individuals with tumors larger than 2 cm had significantly higher rates of metastasis than those with tumors smaller than 2 cm.[26] For more information, see the Molecular Genetics of MEN1 section.

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[2,8] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting.[27] Other pituitary tumors can include somatotropinomas and corticotropinomas, or they may be nonfunctioning.

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).[28] Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients),[29] including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[30-32] The following manifestations have also been reported:[33-35]

• Thyroid adenoma.
• 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.[36] 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.[6,31] 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).[36] 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.[37] 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.[38] 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.[38] 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%.[19] 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.[39,40] 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.[8] For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 pathogenic variant.[41,42] In individuals with apparently isolated PHPT or pituitary adenomas, the pathogenic variant prevalence is lower, on the order of 2% to 5%,[27,43,44] 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:[8,45-47]

• 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.[3,48,49] Over 1,300 pathogenic variants have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[50,51] Most (~65%) of these are nonsense or frameshift variants. The remainder are missense variants (20%) (which lead to the expression of an altered protein), splice-site variants (9%), or partial- or whole-gene deletions (1%–4%).[52] In MEN1, phenotypic variation is common within a family and between unrelated individuals. Data suggested that anticipation may also occur in families with MEN1 pathogenic variants.[8,53-55] One large study demonstrated that pituitary, adrenal, and thymic NETs had the highest rates of heritability.[56]

Genetic Testing and Differential Diagnosis for MEN1

Genetic testing for MEN1 pathogenic variants is recommended for individuals meeting clinical diagnostic criteria and may be considered in individuals with less common MEN1-associated tumors. For more information, see the Making the diagnosis of MEN1 section. For individuals meeting diagnostic criteria, the pathogenic variant detection rate is approximately 75% to 90%.[53,57] 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. Genetic testing may be warranted in these individuals because a diagnosis of MEN1 would prompt screening for other MEN1-related tumors.[58] Laboratories that offer MEN1 testing primarily use DNA sequencing. Several laboratories offer additional analyses for MEN1 partial- or whole-gene deletion and/or duplication. However, these types of variants are rare. Deletion/duplication testing is often reserved for individuals who have very high clinical suspicions for MEN1 but a detectable pathogenic variant was not found by direct DNA sequencing. Evolving studies continue to reveal causative pathogenic variants in MEN1.[52]

A multigene panel that includes MEN1 and other genes associated with an increased risk of endocrine tumors may also be used. Such genetic testing can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). [Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.] HPT-JT, which is caused by germline pathogenic variants in the CDC73 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.[59,60] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[61] 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.[62-64] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 pathogenic variants.[63,65,66] Pathogenic variants in the calcium-sensing receptor (CASR) gene cause FHH, which can closely mimic the hyperparathyroidism seen in MEN1.

Genetic diagnosis will help guide management for patients with early-onset hyperparathyroidism. This is especially crucial, since many of the above conditions have different management guidelines that correspond with their features. For example, distinguishing between MEN1 and FHH can be critical for a patient's disease management. Removing the parathyroid glands in FHH does not correct the hyperparathyroidism that is seen in patients with MEN1. This could result in an unnecessary surgery that would not relieve the patient's symptoms. In addition, HPT-JT is unique because it increases parathyroid carcinoma risk. Hence, individuals with this syndrome have different management guidelines than individuals with other forms of hereditary hyperparathyroidism.[67,68] For more information on MEN1 clinical features and other forms of hyperparathyroidism, see Table 3.

Surveillance

Screening and surveillance for MEN1 may include a combination of biochemical tests and imaging techniques.

Traditionally, magnetic resonance imaging (MRI) was used for surveillance and staging. However, ongoing studies have evaluated the role of MRI in functional imaging, including gallium Ga 68-DOTATATE (68Ga-DOTATATE) positron emission tomography (PET)–computed tomography (CT) scanning. A multicenter retrospective study examined 108 MEN1 patients undergoing PET-CT for screening, staging, restaging, or targeted radiotherapy selection. This study demonstrated that PET-CT has the potential to increase diagnostic sensitivity when searching for MEN1-associated NETs.[73] In 51% of cases, PET-CT provided superior lesion detection when compared with conventional imaging techniques. However, the retrospective nature of the study makes it impossible to discern how much selection bias may have impacted the study's findings. Consequently, PET-CT's exact role in detecting metastasis remains unclear. PET-CT's potentially improved diagnostic sensitivity must also be weighed against its increased levels of radiation exposure, which are higher than that of other imaging modalities. Radiation exposure is particularly relevant for MEN1 patients, who are prone to developing aggressive malignancies. The issue is even more nuanced in young patients who require lifelong screening to detect aggressive MEN1-associated malignancies early.

A study analyzed thoracic screening techniques in 50 patients with MEN1. It found that when patients with MEN1 underwent functional imaging with fluorine F 18-fludeoxyglucose (18F-FDG) PET-CT screening, they had a similar number of lung nodules as individuals in the general population. However, when lesions in MEN1 patients were FDG-avid, they were more likely to progress during the follow-up period. Therefore, further observation and follow up of FDG-avid lesions may be warranted in patients with MEN1.[74] While lung-specific imaging is not routinely performed in MEN1 patients, the lungs are visualized during MRI surveillance of thymic lesions. When pulmonary lesions are identified, it is important to recognize that lung NETs may grow slowly and may have a good prognosis. Referral to a multidisciplinary team may be beneficial for selective resection of lung NETs.[75]

Recommendations for MEN1 surveillance are summarized in Table 4.[4,8]

Interventions

Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease. Patients with MEN1 have a high risk of tumor recurrence, even after surgery. Additionally, these patients may have an increased risk of developing venous thromboembolisms.[79] Clinicians should be aware of this risk, particularly in the perioperative period. It is critical to establish an MEN1 diagnosis before making surgical decisions, in order to prevent unnecessary and/or inappropriate surgeries. Furthermore, it is recommended that individuals with MEN1 use a surgeon who has experience treating this disease.

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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., perithyroidal, 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] When thyroidectomy is performed before local nodal metastases occur, distant metastases are rare.[5] Metastatic PHEOs have not been reported in individuals with MEN2.[6] In MEN2, parathyroid abnormalities can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Historically, individuals with MEN2 were given one of the following clinical subtypes based on the presence or absence of certain endocrine tumors in the individual/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.[7] 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 RET germline 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.[8] 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.[1,9-11] 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.[12] 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.[13-15]

MTC accounts for 1% to 2% of new cases of thyroid cancer diagnosed annually in the United States.[16] 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.[3,17] 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.[18]

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,[19,20] larger series indicate a prevalence range of 1% to 7%.[21,22] On the basis of these data, testing for pathogenic variants in the RET gene is widely recommended for all cases of MTC.[1,23]

Level of evidence (Screening): 3

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.[33-38] 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.[39] Confirmation of the diagnosis can be made using iodine I 131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[14,39-41]

In individuals with a personal history of PHEO, an MEN2 diagnosis is often considered in those with bilateral PHEOs, those with early age of PHEO onset (age <35 y), and those with a personal and/or family history of MTC or hyperparathyroidism. For more information, see the Familial PHEO and PGL Syndrome section. However, MEN2 is not the only genetic disorder with a predisposition to PHEOs; other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[42] and the hereditary paraganglioma syndromes.[43] For more information on VHL, see von Hippel-Lindau Disease.

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.[44] 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.[45-47]

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.[48] Since genetic testing for RET pathogenic variants has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC.[14,49-51]

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.[14,50] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 years and 25 years (mean, 15 y).[14] 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.[1,3,52,53] Up to 30% of patients with MTC present with diarrhea and advanced disease.[54]

MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[55-57] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[55,58] MEN2-associated PHEOs usually present after MTC, typically with intractable hypertension.[59]

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[54,60] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[60] 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.[61-63] 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.[64,65]

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.[66] 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.[67] 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.[68 ,69] Certain loss-of-function RET variants have been associated with isolated HSCR,[70] 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.[71] Current management guidelines [1] recommend that patients thought to have pure FMTC also be screened for PHEO and hyperparathyroidism.

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited pathogenic variants in the RET gene, located on chromosome region 10q11.2.[83-85] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[86,87]

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.[32,88,89] 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.[88] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules.

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.[1,93,100] 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.[93] This stratification has been revised by the American Thyroid Association (ATA).[1,101,102] 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.[103] 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.[102] 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.[104] 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.[104] 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.[103,105-109] Approximately 95% of individuals with MEN2B will have the M918T pathogenic variant.[105-107,110] 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.[103] In addition to variants at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline variants.[111-115] 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.[49] In general, pathogenic variants at codon 634 are associated with PHEOs and PHPT.[49,116] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with pathogenic variants at codon 634.[49,51,117] 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.[118] Codon 634 pathogenic variants have also been described in FMTC but are almost exclusively C634Y.[49]

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%).[49,119] Individuals with codon 634 pathogenic variants (but not codon 883 or 918 variants) also have an increased risk of PHPT.[49]

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).[21,49,100,120-124] 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.[49,125-129] Although PHEO and PHPT are not commonly associated with these pathogenic variants, they have been described.[129]

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.[130] 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.[130] Still others may be benign polymorphisms of no clinical significance. For example, some studies show compelling evidence that RET variants Y791F (p.Tyr791Phe) and S649L (p.Ser649Leu) are likely benign polymorphisms; this was based on the equal frequencies seen between cases and healthy controls and co-occurrence with other disease-causing variants that cosegregate with disease in the family.[131,132] 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).[133] Therefore, carriers of these variants are not followed with MEN2 management guidelines; asymptomatic family members are generally not tested for these variants. Comprehensive testing of all hotspot variants in exon 8 and exons 10–16 may be performed to rule out any other RET pathogenic variants. However, a PHEO diagnosis may warrant extensive testing of other disease-related genes. For more information, see the Familial Pheochromocytoma and Paraganglioma Syndrome section.

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.[134-137] 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.[138]

Surveillance

Interventions

Genetic Counseling

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210. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000. [PubMed: 10969494]
211. 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. [PubMed: 9355573]
212. Giarelli E: Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research. Psychooncology 11 (1): 59-73, 2002 Jan-Feb. [PubMed: 11835593]
213. 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. [PubMed: 10751081]
214. 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. [PubMed: 11038446]
215. 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. [PubMed: 14603352]
216. 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. [PubMed: 12087618]

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%.[3-5] 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 for MEN4

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 variants 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.[8-10]

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 not been established yet.[8,13] Currently, surveillance is mainly clinical and focuses on finding an excess of growth hormone. It is recommended that annual biochemical testing for insulin-like growth factor-1 and annual blood work be done to assess for PHPT.[13] For known CDKN1B carriers, surveillance begins at adolescence. The role of imaging has not been established.

Interventions

Similar to the treatment used in other familial syndromes, surgical treatment is recommended for parathyroid and pituitary disease. For more information, see the MEN1 section.

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. [PubMed: 20980721]
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. [PMC free article: PMC1622862] [PubMed: 17030811]
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. [PubMed: 17519308]
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. [PMC free article: PMC2684477] [PubMed: 19141585]
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. [PMC free article: PMC3051264] [PubMed: 20824794]
6. Lee M, Pellegata NS: Multiple endocrine neoplasia type 4. Front Horm Res 41: 63-78, 2013. [PubMed: 23652671]
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. [PubMed: 11237531]
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. [PMC free article: PMC5623937] [PubMed: 28824003]
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. [PubMed: 22129891]
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. [PMC free article: PMC3605397] [PubMed: 23555276]
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. [PubMed: 20833334]
12. Lee M, Pellegata NS: Multiple endocrine neoplasia syndromes associated with mutation of p27. J Endocrinol Invest 36 (9): 781-7, 2013. [PubMed: 23800691]
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. [PMC free article: PMC5547889] [PubMed: 28674121]
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. [PMC free article: PMC5109674] [PubMed: 27842554]

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. They can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PHEOs and PGLs may occur sporadically, as manifestations of a hereditary syndrome, or as the sole tumor in one of several hereditary PHEO/PGL syndromes. Some individuals with a predisposition to PHEOs/PGLs do not have a known family history of these tumors. For example, a study of 108 patients with PHEOs/PGLs found that 33% of patients with a germline pathogenic variant did not have family histories of a hereditary PHEO/PGL syndrome. Similarly, 36% of the patients with SDHB germline pathogenic variants did not have family histories of PHEOs/PGLs or personal histories of PHEOs/PGLs at presentation.[7]

Most sporadic PHEOs occur unilaterally. Bilateral PHEOs are more likely to occur in a hereditary condition. A single-center study of patients with PHEOs found that up to 7% of adults and 37.5% of children had bilateral PHEOs. Synchronous tumors were seen in 80% of patients with bilateral PHEOs. When metachronous PHEOs were identified, the median time to develop a second PHEO was 4.5 years (range 1–38 y). Hereditary cancer syndromes were identified in 80% of individuals with bilateral PHEOs. These syndromes included multiple endocrine neoplasia type 2A (MEN2A) (found in 42.6% of patients), von Hippel-Lindau Disease (VHL) (found in 19.1% of patients), MEN2B (found in 9.6% of patients), and neurofibromatosis type 1 (found in 8.5% of patients).[8] In another retrospective series that spanned nearly 50 years, 15 of 49 patients (30%) who presented with a unilateral PHEO and had unilateral total adrenalectomy developed a PHEO in the contralateral adrenal gland. This occurred at a median period of 8.2 years after a patient's initial diagnosis (range, 1–20 y).[9] Of the 15 patients who developed PHEOs in the contralateral adrenal gland, 8 had MEN2A, 2 had MEN2B, 2 had VHL, and 1 had a familial PHEO. The risk of developing a contralateral PHEO increased over time. Twenty-five percent of patients developed PHEOs after a median period of 6 years, and 43% of patients developed PHEOs after a median period of 32 years.

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.[1,10,11]

There are a lack of reliable molecular, immunohistochemical, and genetic predictors that distinguish between benign and malignant tumors.[12] However, in some studies, multivariate analysis indicates that certain factors lead to a higher malignancy rate (up to 70% in one study).[13] These factors include the following: an SDHB pathogenic variant,[14,15] young patient age,[13,15] extra-adrenal tumors,[15] and large tumors.[16] Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[11,17,18] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[19-23] 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 malignancy estimates may be higher or lower than these percentages.[24]

Clinical Diagnosis of PHEO and PGL

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.[25]

Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[26] 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).[27] 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.[28] 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.[28]

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.[27] 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.[29] Imaging of PHEOs usually consists of a dedicated CT of the adrenal glands.[30,31]

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).[32] 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).[33] SRS has been reported to be superior to MIBG in detecting metastatic tumors (95% vs. 23%, respectively).[33] 123I-MIBG, however, is highly sensitive for PHEO [33] 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 used for tumor localization should be centered on the patient’s genetic status, on the basis of the metabolic activity of the various tumors.[14] It has been suggested that patients with SDHx and VHL pathogenic variants are more likely to have higher 18F-fludeoxyglucose activity, which is related to gene activation in response to hypoxia.[14,34] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx pathogenic variants may have false-negative results with such scans. Tumors with VHL pathogenic variants may be missed with MIBG scans.[14]

While further study is needed to determine the optimal imaging strategy for each PHEO/PGL case, gallium Ga 68-DOTATATE (68Ga-DOTATATE) PET-CT is a more recently developed, highly sensitive imaging modality that can identify PHEOs/PGLs.[11,35,36] Two small case series found that 68Ga-DOTATATE PET-CT improved PHEO/PGL identification when compared with conventional imaging done with MRI or CT.[37,38] A meta-analysis found that 68Ga-DOTATATE PET-CT exhibited superior performance for PHEO/PGL detection over other functional imaging modalities in patients with PHEOs/PGLs.[36] The pooled detection rate for 68Ga-DOTATATE PET-CT was 93% when compared with 80% for fluorine F 18-fluorohydroxyphenylalanine (18F-FDOPA) PET-CT, 74% for fluorine F 18-fludeoxyglucose (18F-FDG) PET-CT, and 38% for 123I-MIBG scans. However, a recent study of 14 patients examined the performance of 68Ga-DOTATATE PET-CT, 18F-FDG PET-CT, 18F-FDOPA PET-CT, and MRI in visualizing sporadic primary PHEOs. This study found that 18F-FDOPA PET-CT identified 100% of sporadic PHEOs. Further study is needed to determine if a PHEO's genetic status and secretory capacity can drive decision making regarding preferred PHEO imaging modalities.

Genetics, Inheritance, and Genetic Testing for Familial PHEO and PGL Syndrome

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.[21,39-44] 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%,[21] whereas other groups detected pathogenic variants in 41% of such patients.[43,45] A large population study reported that up to 85% of patients younger than 21 years with a PGL/PHEO had a pathogenic variant. Specifically, 50% of these patients had an SDHB pathogenic variant.[13,46] For more information, see Childhood Pheochromocytoma and Paraganglioma Treatment. 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.[47] Genetic testing is recommended for all patients with PHEOs or PGLs, even in those who have a single PHEO/PGL but do not have personal or family histories of these tumors. Genetic testing is recommended in this scenario because of the high frequency of pathogenic variants associated with PHEO/PGL predisposition syndromes.[27,48]

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.[49] 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,[50-53] 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.[54]

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,[55-58] 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.[59,60] 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.[59,60] Potential mechanism(s) of tumorigenesis in individuals with maternally inherited pathogenic variants have been described.[58,61] 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,[27] 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.[21,62,63] 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.[64] 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.[65] 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.[66] 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 which genetic variant an individual has. While these correlations can help guide genetic testing and screening decisions, caution must be used since there is a high degree of variability in these conditions. For more information, see Table 6.

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.[13,24,67,68] Multiple series showed a risk of 71% for a head and neck tumor in SDHD carriers.[23,69] 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 [69] and 90% by age 70 years in a second series.[68] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[70] 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.[67]

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.[68] 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).[67]

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,[70] newer data suggest that the penetrance ranges from 9% to 35% by age 50 years.[47,71-74] There is some evidence that the penetrance in SDHB carriers may be lower in females than in males.[67,75]

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%.[13] 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.[68,69] However, in one study among nonprobands only, the rate of malignant disease to age 60 was only 4.2 %.[67] 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).[13] Pathogenic variants in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), pituitary tumors, renal cell carcinoma (RCC), and papillary thyroid cancer.[67-69]

SDHC pathogenic variants are rare, accounting for an estimated 0.5% of all PGLs.[70] 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.[40] Another series of 121 index cases from a head and neck PGL registry showed a pathogenic variant rate of 4% (5 of 121), [76] and another series identified 26 SDHC variants among 391 probands with PGL/PHEO (6.6%).[67] SDHC pathogenic variants most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[21,67,77] 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%).[67] 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.[67,78]

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.[65]

Although biallelic pathogenic variants in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[79] 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.[80] Tumors most commonly develop in the head and neck, followed by the adrenal glands and abdomen (extra-adrenal).[81,82] In the same series from the Netherlands,[80] 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.[53]

The MAX gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[50] 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.[83]

The TMEM127 gene is located on chromosome 2q11.2. It encodes a transmembrane protein that is 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.[70] TMEM127-associated tumors were diagnosed at an average age of 45 years, which is older than the average age of diagnosis in other hereditary PGL/PHEO syndromes. However, individuals with TMEM127 pathogenic variants have a high chance to develop multiple tumors, either synchronously or metachronously. One large study suggested that TMEM127-associated tumors metastasized infrequently; however, the follow-up period was short. RCC occurred frequently in this population. Hence, RCC risk should be considered when creating surveillance plans for patients with TMEM127 pathogenic variants.[84]

Another study looked at TMEM127 and other genes. Here, an additional 58 patients from the European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group more than doubled the number of previously reported carriers of rare PGL/PHEO predisposition genes SDHA (n = 29), SDHAF2 (n = 1), MAX (n = 8), and TMEM127 (n = 20).[65] 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.[85]

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.[15] 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.[27,86] 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.[87] 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%.[87] 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.[88] 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.[15] Prospective validation of these findings at another institution would be valuable.

Although the optimal imaging protocol in SDH pathogenic variant carriers remains unclear, annual biochemical testing and clinical surveillance may be considered. A combined approach of imaging and biochemical testing may be beneficial, since biochemical testing can miss up to 29% of SDH-related tumors, and imaging has varying sensitivity rates based on the radioisotope that is used.[89] 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.[90,91] It is unknown whether continued surveillance beyond age 50 to 60 years is beneficial when a patient is asymptomatic. This is an active area of investigation.[92] One highly specialized center has recommended beginning surveillance at age 6 years for SDHB carriers.[13]

Level of evidence: 4

Interventions

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96. Miura Y, Yoshinaga K: Doxazosin: a newly developed, selective alpha 1-inhibitor in the management of patients with pheochromocytoma. Am Heart J 116 (6 Pt 2): 1785-9, 1988. [PubMed: 2904751]
97. Prys-Roberts C, Farndon JR: Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 26 (8): 1037-42, 2002. [PubMed: 12192533]
98. Zhu Y, He HC, Su TW, et al.: Selective α1-adrenoceptor antagonist (controlled release tablets) in preoperative management of pheochromocytoma. Endocrine 38 (2): 254-9, 2010. [PubMed: 21046486]
99. Groeben H, Nottebaum BJ, Alesina PF, et al.: Perioperative α-receptor blockade in phaeochromocytoma surgery: an observational case series. Br J Anaesth 118 (2): 182-189, 2017. [PubMed: 28100521]
100. Ross EJ, Prichard BN, Kaufman L, et al.: Preoperative and operative management of patients with phaeochromocytoma. Br Med J 1 (5534): 191-8, 1967. [PMC free article: PMC1840518] [PubMed: 4381157]
101. Hack HA: The perioperative management of children with phaeochromocytoma. Paediatr Anaesth 10 (5): 463-76, 2000. [PubMed: 11012949]
102. Proye C, Thevenin D, Cecat P, et al.: Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheochromocytomas: hemodynamics and free catecholamine assays in ten consecutive patients. Surgery 106 (6): 1149-54, 1989. [PubMed: 2588118]
103. Vargas HI, Kavoussi LR, Bartlett DL, et al.: Laparoscopic adrenalectomy: a new standard of care. Urology 49 (5): 673-8, 1997. [PubMed: 9145969]
104. Perrier ND, Kennamer DL, Bao R, et al.: Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg 248 (4): 666-74, 2008. [PubMed: 18936580]
105. Dickson PV, Jimenez C, Chisholm GB, et al.: Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg 212 (4): 659-65; discussion 665-7, 2011. [PubMed: 21463807]
106. Ober WB: Emil Zuckerkandl and his delightful little organ. Pathol Annu 18 Pt 1: 103-19, 1983. [PubMed: 6348671]
107. Mundschenk J, Lehnert H: Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 106 (5): 373-6, 1998. [PubMed: 9831301]
108. 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. [PubMed: 24745698]

Clinical Description

Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. CSS is distinct from similarly named syndromes, Carney Complex and Carney Triad (for more information, see Table 7). 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.[1-3] 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.

Genetics, Inheritance, and Genetic Testing for CSS

The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function variants in the KIT gene or the PDGFRA gene, as 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.[3,11-13] 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] For more information about genetic testing for Carney-Stratakis syndrome, see the section on Genetics, Inheritance, and Genetic Testing in the Familial Pheochromocytoma and Paraganglioma Syndrome section.

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 fluorine F 18-fluorohydroxyphenylalanine (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. [PubMed: 11857563]
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. [PubMed: 17804857]
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. [PubMed: 17667967]
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. [PMC free article: PMC3415983] [PubMed: 20890271]
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. [PubMed: 17549339]
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. [PMC free article: PMC3652406] [PubMed: 19935059]
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. [PMC free article: PMC4929866] [PubMed: 26173966]
8. Boikos SA, Stratakis CA: Carney complex: pathology and molecular genetics. Neuroendocrinology 83 (3-4): 189-99, 2006. [PubMed: 17047382]
9. Correa R, Salpea P, Stratakis CA: Carney complex: an update. Eur J Endocrinol 173 (4): M85-97, 2015. [PMC free article: PMC4553126] [PubMed: 26130139]
10. Hensen EF, Bayley JP: Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer 10 (2): 355-63, 2011. [PMC free article: PMC3100491] [PubMed: 21082267]
11. Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008. [PMC free article: PMC3805121] [PubMed: 18483389]
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. [PMC free article: PMC3193596] [PubMed: 21997692]
13. Sawhney SA, Chapman AD, Carney JA, et al.: Incomplete Carney triad--a review of two cases. QJM 102 (9): 649-53, 2009. [PubMed: 19561114]
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. [PubMed: 21358303]
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. [PubMed: 20098451]
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. [PubMed: 17538171]
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. [PMC free article: PMC2795662] [PubMed: 19864450]
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. [PubMed: 24390286]
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. [PubMed: 17624289]
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. [PMC free article: PMC4492234] [PubMed: 26070915]
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. [PMC free article: PMC4271129] [PubMed: 24356634]
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. [PubMed: 20305538]
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. [PubMed: 19326424]

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 8 outlines the various hereditary syndromes associated with NMTC.

Genetics, Inheritance, and Genetic Testing for Familial NMTC

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.[5-8] 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.[5,12-15] 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]

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]

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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.

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

• Erica Blouch, MS, CGC (Massachusetts General Hospital Cancer Center)
• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Suzanne C. O'Neill, PhD (Georgetown University)
• Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Charite Ricker, MS, CGC (University of Southern California)
• Jennifer Sipos, MD (The Ohio State University)
• 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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