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1. Agarwal SK, Ozawa A, Mateo CM, et al.: The MEN1 gene and pituitary tumours. Horm Res 71 (Suppl 2): 131-8, 2009. [PMC free article: PMC6413329] [PubMed: 19407509]
2. Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335 (13): 943-51, 1996. [PubMed: 8782503]
3. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [PubMed: 11739416]
4. Mulligan LM, Kwok JB, Healey CS, et al.: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 (6428): 458-60, 1993. [PubMed: 8099202]
5. Donis-Keller H, Dou S, Chi D, et al.: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2 (7): 851-6, 1993. [PubMed: 8103403]
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7. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed July 1, 2015.

Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant syndrome, with an estimated incidence in the general population of 1 to 2 cases per 100,000.[1] The major endocrine features of MEN1 include the following:

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

A diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative with one of these three tumors.[2-4] The age-related penetrance of MEN1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years.[2,5]

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.[2,6-8] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic.[1] The average age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.[9-12]

Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:

• Constipation.
• Nausea and vomiting.
• Dehydration
• Decreased appetite and abdominal pain.
• Anorexia.
• Diuresis.
• Kidney stones.
• Increased bone resorption with resultant increased risk of bone fracture.
• Lethargy.
• Depression.
• Confusion.
• Hypertension.
• Shortened QT interval.

Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series.[13-15] (Refer to the Interventions section of this summary for more information.)

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[2,8] Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,13] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[16] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[13,16,17]

Other functioning pancreatic NETs seen in MEN1 include the following:

• Insulinomas (10%–20% penetrance).
• Vasoactive intestinal peptide tumors (VIPomas) (~1% penetrance).
• Glucagonomas (1%–5% penetrance).
• Somatostatinomas (~1% penetrance).

Nonfunctioning pancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%.[18,19] With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in MEN1 mutation carriers undergoing prospective endoscopic ultrasound of the pancreas.[20,21] These tumors can be metastatic. One study of 108 MEN1 mutation carriers with nonfunctioning pancreatic NETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm.[22] (Refer to the Molecular Genetics of MEN1 section of this summary for more information about MEN1 gene mutations.)

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.[23] Other functioning pituitary tumors can include somatotropinomas and corticotropinomas.

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).[24] Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[25-27] The following manifestations have also been reported:[28-30]

• Thyroid adenomas.
• Pheochromocytoma.
• Spinal ependymoma.
• Meningioma.
• Leiomyoma (e.g., esophageal, lung, and uterine).

Making the Diagnosis of MEN1

MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation 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.[31] This may be 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. Other studies have shown similar findings, with median time between the first presenting symptom and diagnosis of MEN1 ranging from 7.6 years to 12 years.[5,26] 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 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; P < .001).[31] In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 years), compared with a mean age 27 years (range: 14–56 years; P < .05) in family members diagnosed by predictive genetic testing.[32] 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. Figure 1 illustrates some of the challenges in identifying MEN1 in a family.

Figure

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 (more...)

Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene mutation 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 mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 mutation.[33,34] In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%,[23,35,36] 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 mutations in MEN1 if one of the following conditions is present:[37-39]

• 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; pancreatic NET; pituitary tumor; adrenal tumor.
• Parathyroid adenoma and a family history of hyperparathyroidism, pituitary adenoma, pancreatic NET, or foregut carcinoid tumor.
• Multiple primary pancreatic NETs in the same person.

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[3,40,41] Over 1,300 mutations have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[42] The majority (~65%) of these are nonsense or frameshift mutations. The remainder are missense mutations (20%), which lead to expression of an altered protein, splice-site mutations (9%), or partial- or whole-gene deletions (1%–4%). There is currently no evidence of genotype-phenotype correlations, and inter- and intra-familial variability is common.[43,44]

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 mutations is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90% [43,45] but may be lower in simplex cases.[46] Individuals with isolated parathyroid and/or pituitary tumors are less likely to have an identifiable mutation than those with pancreatic tumors.[46] The majority of commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method.[47] Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.

Genetic testing for MEN1 mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) (OMIM), 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 mutations in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[48,49] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[50] 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.[51-53] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations.[52,54,55] Mutations in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient’s hyperparathyroidism and results in unnecessary surgery without relief of symptoms.[56] Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families.[57] Refer to Table 1 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 2.[4,37]

Interventions

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

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72. Ito T, Igarashi H, Uehara H, et al.: Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore) 92 (3): 135-81, 2013. [PMC free article: PMC3727638] [PubMed: 23645327]
73. O'Riordain DS, O'Brien T, van Heerden JA, et al.: Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg 18 (4): 488-93; discussion 493-4, 1994 Jul-Aug. [PubMed: 7725733]
74. Crippa S, Zerbi A, Boninsegna L, et al.: Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg 147 (3): 261-6, 2012. [PubMed: 22430908]
75. Sakurai A, Yamazaki M, Suzuki S, et al.: Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan. Endocr J 59 (10): 859-66, 2012. [PubMed: 22785103]
76. Akerström G, Stålberg P: Surgical management of MEN-1 and -2: state of the art. Surg Clin North Am 89 (5): 1047-68, 2009. [PubMed: 19836484]
77. Grant CS: Insulinoma. Best Pract Res Clin Gastroenterol 19 (5): 783-98, 2005. [PubMed: 16253900]
78. Giudici F, Nesi G, Brandi ML, et al.: Surgical management of insulinomas in multiple endocrine neoplasia type 1. Pancreas 41 (4): 547-53, 2012. [PubMed: 22228047]
79. Mignon M, Cadiot G: Diagnostic and therapeutic criteria in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. J Intern Med 243 (6): 489-94, 1998. [PubMed: 9681847]
80. Cadiot G, Vuagnat A, Doukhan I, et al.: Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. Groupe d'Etude des Néoplasies Endocriniennes Multiples (GENEM and groupe de Recherche et d'Etude du Syndrome de Zollinger-Ellison (GRESZE). Gastroenterology 116 (2): 286-93, 1999. [PubMed: 9922308]
81. Dickson PV, Rich TA, Xing Y, et al.: Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important. Surgery 150 (6): 1143-52, 2011. [PubMed: 22136834]
82. Akerström G, Stålberg P, Hellman P: Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 1. Clinics (Sao Paulo) 67 (Suppl 1): 173-8, 2012. [PMC free article: PMC3328819] [PubMed: 22584725]
83. Goudet P, Murat A, Binquet C, et al.: Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg 34 (2): 249-55, 2010. [PubMed: 19949948]
84. Lévy-Bohbot N, Merle C, Goudet P, et al.: Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol 28 (11): 1075-81, 2004. [PubMed: 15657529]
85. Vergès B, Boureille F, Goudet P, et al.: Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab 87 (2): 457-65, 2002. [PubMed: 11836268]
86. Pieterman CR, Vriens MR, Dreijerink KM, et al.: Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer 10 (1): 157-71, 2011. [PubMed: 21061174]

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[1] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

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

1. MEN2A (OMIM).
2. Familial medullary thyroid carcinoma (FMTC) (OMIM).
3. MEN2B (OMIM).

Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype.[4]

Clinical findings in the three MEN2 subtypes are summarized in Table 3. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of pheochromocytoma, and MEN2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

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 diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells.[10,11] Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[12,13] 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.[14] CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family.[12,13,15]

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States,[16] although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which 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.[2,17] 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.[7]

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 mutations,[18,19] larger series indicate a prevalence range of 1% to 7%.[20,21] Based on these data, it is widely recommended that RET gene mutation testing be performed for all cases of MTC.[22-25]

Level of evidence (Screening): 3

Pheochromocytoma

Pheochromocytomas (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor 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.[36-41] When biochemical screening in an individual who has or is at risk of MEN2 suggests pheochromocytoma, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[42] Confirmation of the diagnosis can be made using I¹³¹-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[13,42-44]

A diagnosis of MEN2 is often considered in individuals with bilateral pheochromocytoma, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[45] and the hereditary paraganglioma syndromes.[46] (Refer to the von Hippel-Lindau Syndrome section in the PDQ summary on the Genetics of Kidney Cancer for more information about VHL.) A large European consortium that included 271 patients from Germany,[47] 314 patients from France,[48] and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD).[49] The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline mutations were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET mutations and pheochromocytoma will have a positive family history or other manifestations of the disease.

These data indicate that a significant proportion of individuals presenting with apparently sporadic pheochromocytoma are carriers of germline genetic mutations. Of those with apparently sporadic disease, up to 33% have a mutation in one of the susceptibility genes.[47,50-52] Studies have identified additional susceptibility genes that predispose to pheochromocytoma, including TMEM127, MAX, and SDHAF2.[53-56] Mutations in these genes are thought to account for a small proportion of all hereditary pheochromocytoma. Since testing for mutations in multiple genes in every patient may not be feasible or cost-effective, clinical and genetic screening algorithms have been proposed to assist clinicians in deciding which genes to test and in which order.[42,48,49,57-59]

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 results of a single adenoma.[60] 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.[61-63]

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 three MEN2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).

MEN2A

MEN2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma and/or hyperplasia) in a single individual or in close relatives.

The MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[64] Since genetic testing for RET mutations has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC; about 50% will develop pheochromocytoma; and about 15% to 30% will develop hyperparathyroidism.[13,65-67]

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[13,66] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean 15 years).[13] If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain at about age 5 to 20 years. More than 50% of such patients have cervical lymph node metastases.[2] Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of greater than 10 ng/mL and implies a poor prognosis.[2] Up to 30% of patients with MTC present with diarrhea and advanced disease.[68]

MEN2-associated pheochromocytomas are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[69-71] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[69,72] MEN2-associated pheochromocytomas usually present after MTC, typically with intractable hypertension.[6]

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[68,73] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[73] 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.[74-76] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands.

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.[77,78]

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

Figure

Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a deleterious RET mutation across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. (more...)

In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[79] Some authors have recommended referral to genetic counseling for an individual with medullary thyroid cancer or any of the following features:[79,80]

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

Genetically Related Disorder

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited mutations in the RET gene, located on chromosome region 10q11.2.[94-96] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[97,98]

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.[99] 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.[99] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[100-102]

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 mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[23,25,81] 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.[23] This stratification was revised by the American Thyroid Association (ATA).[25] The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in Table 4 and Table 5 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.

ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC.[25] These mutations, which are typically seen in MEN2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[25]

A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years.[110] Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.[23] Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.[111,112]

Mutations 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.[113-117] Approximately 95% of individuals with MEN2B will have the M918T mutation.[113-115,118] As discussed above, 50% of individuals with MEN2B will develop pheochromocytoma but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline mutations.[119-123] It is likely that as testing for RET becomes more common in clinical practice, additional double mutation phenotypes will be described.

Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation.[65] In general, mutations at codon 634 are associated with pheochromocytomas and PHPT.[65,124] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with mutations at codon 634.[65,67,125] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 mutation.[126] Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.[65]

In summary, ATA-level D and level C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of pheochromocytoma (up to 50%).[65,127] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.[65]

ATA-level B mutations, located in exon 10 of the RET gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[20,65,81,128-132] The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of pheochromocytoma and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).[33] Another large study of 390 exon 10 mutation carriers showed an age-related risk of pheochromocytoma for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of pheochromocytoma was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.[133]

Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20 years.[65,134-138] Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.[138]

In addition to the mutations categorized in Table 4, a number of rare or novel RET mutations have been described. Some of these represent mutations that lead to an FMTC or MEN2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. 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 is being analyzed for its impact on the likelihood for development of pheochromocytoma, hyperparathyroidism, and metastatic involvement with MTC.[196-198] 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 mutation online database repository was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[199]

Interventions

Genetic Counseling

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Introduction

Paragangliomas (PGLs) and pheochromocytomas are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized pheochromocytomas as tumors arising in the adrenal gland.[1] (Refer to the Pheochromocytoma section of this summary for more information). Extra-adrenal neoplasms, referred to as PGLs, may arise in various sites from the glomera along the parasympathetic nerves or the paraganglia in the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. PGLs found in the skull base or head and neck region are usually from parasympathetic paraganglia and rarely secrete catecholamines. Representing 3% of all PGLs,[2] the tumors in the cervical region typically arise in the glomus cells, near the aortic body, along the vagal nerve, in the temporal bone, in the jugular fossa (middle ear space), or in the nose and parasinus.[3] Tumors below the neck are most commonly located in the upper mediastinum, adrenal medulla (pheochromocytoma), 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] These tumors have an equal sex distribution.[5,6] PGLs can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PGLs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/pheochromocytoma syndromes. Up to 40% of patients presenting with apparently sporadic PGLs actually have a recognizable germline mutation in one of the known PGL/pheochromocytoma susceptibility genes.[7,8] One study found that in individuals with a single tumor and a negative family history, the likelihood of an inherited mutation was 11.6%,[7] whereas other groups detected mutations in 41% of such patients.[8,9]

PGLs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. Conversely, a minority of these tumors may be malignant and present with a more aggressive clinical course. PGL and pheochromocytoma malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[10,11] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[12] There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors,[13] although some studies have shown a higher rate in SDHB carriers [14] and in individuals with larger tumors.[15] Consequently, estimation of the rate of malignancy in PGLs is difficult; rates from 5% to 20% have been reported.[7,16,17] Common sites of metastases include bone, liver, and lungs.[1]

PGLs arise from cells involved in the metabolism of catecholamines, but approximately 95% of tumors located in the head and neck region are parasympathetic and nonsecretory.[11] Only tumors arising from the sympathetic neural chain have secretory capacity. The most recognizable PGL of the head and neck is the tumor arising from the carotid body. These tumors (glomus caroticum) present a significant challenge for surgeons because of their proximity to critical vessels and cranial nerves. The presence of the neoplasm in this critical location frequently results in the compromise of nearby structures; removal of the tumor may cause permanent impairment.

Clinical Diagnosis of 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 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.[1]

Imaging is the mainstay of diagnosis; the initial evaluation includes computed tomography of the neck and chest. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. Magnetic resonance imaging 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.[18]

Nuclear imaging in combination with anatomic imaging may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits). Functional imaging with 18F-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or positron emission tomography–computed tomography (PET-CT) may be particularly helpful in localizing head and neck tumors. Additionally, 123I-metaiodobenzylguanidine plus PET-CT is very specific for PGLs. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, based on the metabolic activity of the various tumors.[14] It has been suggested that patients with SDH and VHL mutations are more likely to have higher 18F-fluorodeoxyglucose activity, which is related to gene activation in response to hypoxia.[14,19] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx mutations may have false-negative results with such scans. Tumors with VHL mutations may likewise be missed with metaiodobenzylguanidine scans.[14] (Refer to Table 7 for a list of various mutations and their optimal imaging modality.)

Genetics, Inheritance, and Genetic Testing

PGLs and pheochromocytomas can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau, multiple endocrine neoplasia type 2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by mutations 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.[24] Mutations in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. More recently, mutations in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL, but these mutations are rare. 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.[25]

The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with mutations in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. In other words, while the mutation can be passed down from mother or father, tumors will develop only if the mutation is inherited from the father.[26,27] In cases of FPGL not caused by SDHD or SDHAF2 mutations, first-degree relatives of an affected individual have a 50% chance of carrying the mutation and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance mutations, it is important to offer genetic testing to all unaffected first-degree relatives once the mutation in the family has been identified. All patients with pheochromocytoma or PGL, even those with apparently sporadic tumors, may be considered for genetic testing because of the high frequency of genetic mutations associated with these conditions.[28]

Genetic testing for hereditary pheochromocytoma and PGL syndromes is largely based on published algorithms,[28] whereby testing is performed stepwise based on factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[7,29,30] This approach has allowed for cost-effective, targeted testing based on clinical features. Within the last several years, however, next-generation sequencing (NGS) technology has led to a dramatic decrease in the cost of genetic testing, and it is now possible to test for mutations in 10 to 30 genes for the same cost of testing two or three genes. These tests may be more appropriate for individuals and families who have an atypical presentation or overlapping clinical features. If the cost associated with multigene testing panels continues to decrease, it is likely that the testing algorithms may soon be obsolete for PGL and pheochromocytoma. A recent series analyzed 85 PGL and pheochromocytoma samples using an NGS panel test for the ten known PGL susceptibility genes and showed a sensitivity of 98.7%.[31]

Genotype-Phenotype Correlations

In FPGL, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the gene that is mutated. While these correlations can help guide genetic testing and screening decisions, caution must be used given the high degree of variability seen in this condition. FPGL syndromes are among the rare inherited diseases in which genomic imprinting occurs. For example, the SDHD mutation is normally not activated when inherited from the mother, and the risk of FPGL syndromes is not increased. However, the mutation is turned on when the gene is inherited from the father, and the risk is increased.

SDHD mutations are mainly associated with an increased risk of parasympathetic PGLs. These are more commonly multifocal and located in the head and neck, while tumors in SDHB carriers are more often located in the abdomen.[32,33] One series showed a risk of 71% for a head and neck tumor in SDHD carriers, as opposed to a 29% risk in SDHB carriers. 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 [32] and 90% by age 70 years in a second series.[33] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[34] The rate of malignancy in SDHD carriers is lower than 5%.[34]

Mutations in the SDHB gene are associated with sympathetic PGLs, although pheochromocytoma and parasympathetic PGLs also have been described. SDHB PGLs are more commonly located in the abdomen and mediastinum than in the head and neck. A review of 1,700 cases suggested a lifetime penetrance of 77%.[34] 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.[32,33] Mutations in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[32,33]

SDHC mutations are rare, accounting for an estimated 0.5% of all PGLs.[34] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an SDHC mutation.[35] Another series of 121 index cases from a head and neck PGL registry showed a mutation rate of 4% (5 of 121).[36] SDHC mutations most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[7,37] Mutations in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the dyad of PGLs and GISTs.[38]

Mutations in SDHA, SDAHF2, MAX, and TMEM127 have been described in a small number of cases. Collectively, they account for less than 2% to 3% of all cases. Although biallelic mutations in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[39] it was not until recently that monoallelic mutations were linked to an increased risk of developing PGL. Only a handful of cases have been described. Tumors can develop in the head and neck, the adrenal, or in the abdomen (extra-adrenal).[40,41] The SDHAF2 gene encodes a protein that is responsible for flavination of SDHA and proper functioning of the SDHA subunit of the SDH complex. To date, mutations in SDHAF2 have been described in fewer than 20 cases and only with head and neck PGLs.[42] The MAX gene was first described as a pheochromocytoma susceptibility gene in 2011 through exome sequencing of three unrelated cases.[43] Three different germline mutations were identified, and a follow-up series of 59 cases by the same group identified an additional five mutations. The MAX protein is part of MYC-MAX-MXD1 network, which plays a key role in the development and progression of neural crest cell tumors.[44] The TMEM127 gene is located on chromosome 2q11.2 and encodes a transmembrane protein known to be a negative regulator of mTOR, which regulates multiple cellular processes. A review of 23 patients with TMEM127 mutations showed that 96% (22 of 23) had a pheochromocytoma and 9% (2 of 23) had a PGL.[34]

Interventions

References

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38. 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]
39. Horváth R, Abicht A, Holinski-Feder E, et al.: Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 77 (1): 74-6, 2006. [PMC free article: PMC2117401] [PubMed: 16361598]
40. Burnichon N, Brière JJ, Libé R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010. [PMC free article: PMC2901140] [PubMed: 20484225]
41. Korpershoek E, Favier J, Gaal J, et al.: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 96 (9): E1472-6, 2011. [PubMed: 21752896]
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Clinical Description

Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. Although similarly named, this syndrome is distinctly different from Carney Complex and Carney Triad (see Table 8). CSS is characterized by an autosomal dominant germline mutation 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

The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function mutations in the KIT or PDGFRA gene, as is seen in the vast majority of GISTs.[9] 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 years), specificity to the stomach, multifocality, and resistance to imatinib.[3,10-12] 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.[6,13]

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

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 computed tomography (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-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT is superior to 123I-metaiodobenzylguanidine (123I-MIBG) at identifying SDHx-associated PGLs and, because of the high metabolic activity of GISTs, has excellent sensitivity in identifying them..[14,15] Thus, in patients with SDHx mutations, including those with CSS, 18F-FDG PET/CT is the preferred functional imaging modality to optimally detect and stage all GISTs and PGLs.[16] Some evidence suggests that 18F-fluoro-L-dihydroxyphenylalanine (18F-FDOPA) PET/CT is superior at identifying the primary PGL, while 18F-FDG PET/CT is superior at identifying metastases.

There are no prospective treatment studies involving patients with CSS; therefore, recommendations are based on limited clinical experience, single case series, and extrapolations from genetically-similar tumors with similar clinical behavior. The mainstay of treatment for CSS-associated GISTs and PGLs is complete surgical resection of the tumor. The timing of the operation correlates with the presentation of the tumor. Surgical resection can be accomplished with laparoscopic or open techniques. For PGLs, vascular reconstruction is uncommon. Although PGLs are commonly present in the paraaortic region, the need for major vascular reconstruction is uncommon. GIST tumors can be resected with wedge resection and primary closure and re-anastomosis. Ensuring negative margins is important, as patients for whom a complete resection is accomplished experience the longest survival.[17] 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.[18] 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;[19] 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.[20] Evidence suggests that for these tumors, the second-line targeted agents, including sorafenib, sunitinib, dasatinib, and nilotinib, may be beneficial in the adjuvant setting.[21,22] 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 should be consulted.

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 radial 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 as stated above, 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.[14,16]

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]
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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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

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

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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

• Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
• Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
• Sarah Nielsen, MS, LCGC (The University of Chicago)
• Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
• Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
• Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• Jennifer Sipos, MD (The Ohio State University)
• Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Genetics of Endocrine and Neuroendocrine Neoplasias. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq. Accessed <MM/DD/YYYY>.

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