Chapter 52: Multiple Endocrine Neoplasia

Multiple endocrine neoplasia (MEN) is characterized by a predilection for tumors involving two or more endocrine glands. Four major forms of MEN are recognized and referred to as MEN types 1–4 (MEN 1–4) (Table 52-1). Each type of MEN is inherited as an autosomal dominant syndrome or may occur sporadically; that is, without a family history. However, this distinction between familial and sporadic forms is often difficult because family members with the disease may have died before symptoms developed. In addition to MEN 1–4, at least six other syndromes are associated with multiple endocrine and other organ neoplasias (MEONs) (Table 52-2). These MEONs include the hyperparathyroidism-jaw tumor syndrome, Carney complex, von Hippel-Lindau disease (Chap. 53), neurofibromatosis type 1 (Chap. 48), Cowden’s syndrome, and McCune-Albright syndrome; all of these are inherited as autosomal dominant disorders, except for McCune-Albright syndrome, which is caused by mosaic expression of a postzygotic somatic cell mutation (Table 52-2).

A diagnosis of a MEN or MEON syndrome may be established in an individual by one of three criteria: (1) clinical features (two or more of the associated tumors [or lesions] in an individual); (2) familial pattern (one of the associated tumors [or lesions] in a first-degree relative of a patient with a clinical diagnosis of the syndrome); and (3) genetic analysis (a germline mutation in the associated gene in an individual, who may be clinically affected or asymptomatic). Mutational analysis in MEN and MEON syndromes is helpful in clinical practice to: (1) confirm the clinical diagnosis; (2) identify family members who harbor the mutation and require screening for relevant tumor detection and early/appropriate treatment; and (3) identify the ~50% of family members who do not harbor the germline mutation and can, therefore, be alleviated of the anxiety of developing associated tumors. This latter aspect also helps to reduce health care costs by reducing the need for unnecessary biochemical and radiologic investigations.

Clinical manifestations

MEN type 1 (MEN 1), which is also referred to as Wermer’s syndrome, is characterized by the triad of tumors involving the parathyroids, pancreatic islets, and anterior pituitary. In addition, adrenal cortical tumors, carcinoid tumors usually of the foregut, meningiomas, facial angiofibromas, collagenomas, and lipomas may also occur in some patients with MEN 1. Combinations of the affected glands and their pathologic features (e.g., hyperplastic adenomas of the parathyroid glands) may differ in members of the same family and even between identical twins. In addition, a nonfamilial (e.g., sporadic) form occurs in 8–14% of patients with MEN 1, and molecular genetic studies have confirmed the occurrence of de novo mutations of the MEN1 gene in approximately 10% of patients with MEN 1. The prevalence of MEN 1 is approximately 0.25% based on randomly chosen postmortem studies but is 1–18% among patients with primary hyperparathyroidism, 16–38% among patients with pancreatic islet tumors, and <3% among patients with pituitary tumors. The disorder affects all age groups, with a reported age range of 5 to 81 years, with clinical and biochemical manifestations developing in the vast majority by the fifth decade. The clinical manifestations of MEN 1 are related to the sites of tumors and their hormonal products. In the absence of treatment, endocrine tumors are associated with an earlier mortality in patients with MEN 1, with a 50% probability of death by the age of 50 years. The cause of death is usually a malignant tumor, often from a pancreatic neuroendocrine tumor (NET) or foregut carcinoid. In addition, the treatment outcomes of patients with MEN 1–associated tumors are not as successful as those in patients with non–MEN 1 tumors. This is because MEN 1–associated tumors, with the exception of pituitary NETs, are usually multiple, making it difficult to achieve a successful surgical cure. Occult metastatic disease is also more prevalent in MEN 1, and the tumors may be larger, more aggressive, and resistant to treatment.

Parathyroid tumors

Primary hyperparathyroidism occurs in approximately 90% of patients and is the most common feature of MEN 1. Patients may have asymptomatic hypercalcemia or vague symptoms associated with hypercalcemia (e.g., polyuria, polydipsia, constipation, malaise, or dyspepsia). Nephrolithiasis and osteitis fibrosa cystica (less commonly) may also occur. Biochemical investigations reveal hypercalcemia, usually in association with elevated circulating parathyroid hormone (PTH) (Table 52-3). The hypercalcemia is usually mild, and severe hypercalcemia or parathyroid cancer is a rare occurrence. Additional differences in the primary hyperparathyroidism of patients with MEN 1, as opposed to those without MEN 1, include an earlier age at onset (20–25 years vs 55 years) and an equal male-to-female ratio (1:1 vs 1:3). Preoperative imaging (e.g., neck ultrasound with ^99mTc-sestamibi parathyroid scintigraphy) is of limited benefit because all parathyroid glands may be affected, and neck exploration may be required irrespective of preoperative localization studies.

Pancreatic tumors

(See also Chap. 51) The incidence of pancreatic islet cell tumors, which are NETs, in patients with MEN 1 ranges from 30 to 80% in different series. Most of these tumors (Table 52-1) produce excessive amounts of hormone (e.g., gastrin, insulin, glucagon, vasoactive intestinal polypeptide [VIP]) and are associated with distinct clinical syndromes, although some are nonfunctioning or nonsecretory. These pancreatic islet cell tumors have an earlier age at onset in patients with MEN 1 than in patients without MEN 1.

Gastrinoma

Gastrin-secreting tumors (gastrinomas) are associated with marked gastric acid production and recurrent peptic ulcerations, a combination referred to as the Zollinger-Ellison syndrome. Gastrinomas occur more often in patients with MEN 1 who are older than age 30 years. Recurrent severe multiple peptic ulcers, which may perforate, and cachexia are major contributors to the high mortality. Patients with Zollinger-Ellison syndrome may also suffer from diarrhea and steatorrhea. The diagnosis is established by demonstration of an elevated fasting serum gastrin concentration in association with increased basal gastric acid secretion (Table 52-3). However, the diagnosis of Zollinger-Ellison syndrome may be difficult in hypercalcemic MEN 1 patients, because hypercalcemia can also cause hypergastrinemia. Ultrasonography, endoscopic ultrasonography, computed tomography (CT), nuclear magnetic resonance imaging (MRI), selective abdominal angiography, venous sampling, and somatostatin receptor scintigraphy are helpful in localizing the tumor prior to surgery. Gastrinomas represent more than 50% of all pancreatic NETs in patients with MEN 1, and approximately 20% of patients with gastrinomas will be found to have MEN 1. Gastrinomas, which may also occur in the duodenal mucosa, are the major cause of morbidity and mortality in patients with MEN 1. Most MEN 1 gastrinomas are malignant and metastasize before a diagnosis is established.

TREATMENT

Insulinoma

These β islet cell insulin-secreting tumors represent 10–30% of all pancreatic tumors in patients with MEN 1. Patients with an insulinoma present with hypoglycemic symptoms (e.g., weakness, headaches, sweating, faintness, seizures, altered behavior, weight gain) that typically develop after fasting or exertion and improve after glucose intake. The most reliable test is a supervised 72-h fast. Biochemical investigations reveal increased plasma insulin concentrations in association with hypoglycemia (Table 52-3). Circulating concentrations of C peptide and proinsulin, which are also increased, are useful in establishing the diagnosis. It also is important to demonstrate the absence of sulfonylureas in plasma and urine samples obtained during the investigation of hypoglycemia (Table 52-3). Surgical success is greatly enhanced by preoperative localization by endoscopic ultrasonography, CT scanning, or celiac axis angiography. Additional localization methods may include preoperative and perioperative percutaneous transhepatic portal venous sampling, selective intraarterial stimulation with hepatic venous sampling, and intraoperative direct pancreatic ultrasonography. Insulinomas occur in association with gastrinomas in 10% of patients with MEN 1, and the two tumors may arise at different times. Insulinomas occur more often in patients with MEN 1 who are younger than 40 years, and some arise in individuals younger than 20 years. In contrast, in patients without MEN 1, insulinomas generally occur in those older than 40 years. Insulinomas may be the first manifestation of MEN 1 in 10% of patients, and approximately 4% of patients with insulinomas will have MEN 1.

TREATMENT

Glucagonoma

These glucagon-secreting pancreatic NETs occur in <3% of patients with MEN 1. The characteristic clinical manifestations of a skin rash (necrolytic migratory erythema), weight loss, anemia, and stomatitis may be absent. The tumor may have been detected in an asymptomatic patient with MEN 1 undergoing pancreatic imaging or by the finding of glucose intolerence and hyperglucagonemia.

TREATMENT

Vasoactive intestinal peptide (Vip) tumors (VIPomas)

VIPomas have been reported in only a few patients with MEN 1. This clinical syndrome is characterized by watery diarrhea, hypokalemia, and achlorhydria and is also referred to as the Verner-Morrison syndrome, the WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, or the VIPoma syndrome. The diagnosis is established by excluding laxative and diuretic abuse, by confirming a stool volume in excess of 0.5–1.0 L/d during a fast, and by documenting a markedly increased plasma VIP concentration.

TREATMENT

Pancreatic polypeptide-secreting tumors (Ppomas) and nonfunctioning pancreatic NETs

PPomas are found in a large number of patients with MEN 1. No pathologic sequelae of excessive polypeptide (PP) secretion are apparent, and the clinical significance of PP is unknown. Many PPomas may have been unrecognized or classified as nonfunctioning pancreatic NETs, which likely represent the most common enteropancreatic NET associated with MEN 1 (Fig. 52-1). The absence of both a clinical syndrome and specific biochemical abnormalities may result in a delayed diagnosis of nonfunctioning pancreatic NETs, which are associated with a worse prognosis than other functioning tumors, including insulinoma and gastrinoma. The optimum screening method and its timing interval for nonfunctioning pancreatic NETs remain to be established. At present, endoscopic ultrasound likely represents the most sensitive method of detecting small pancreatic tumors, but somatostatin receptor scintography is the most reliable method for detecting metastatic disease (Table 52-3).

TREATMENT

Other pancreatic NETs

NETs secreting growth hormone–releasing hormone (GHRH), GHRHomas, have been reported rarely in patients with MEN 1. It is estimated that ~33% of patients with GHRHomas have other MEN 1–related tumors. GHRHomas may be diagnosed by demonstrating elevated serum concentrations of growth hormone and GHRH. More than 50% of GHRHomas occur in the lung, 30% occur in the pancreas, and 10% are found in the small intestine. Somatostatinomas secrete somatostatin, a peptide that inhibits the secretion of a variety of hormones, resulting in hyperglycemia, cholelithiasis, low acid output, steatorrhea, diarrhea, abdominal pain, anemia, and weight loss. Although 7% of pancreatic NETs secrete somatostatin, the clinical features of somatostatinoma syndrome are unusual in patients with MEN 1.

Pituitary tumors

Pituitary tumors occur in 15–50% of patients with MEN 1 (Table 52-1). These occur as early as 5 years of age or as late as the ninth decade. MEN 1 pituitary adenomas are more frequent in women than men and significantly are macroadenomas (i.e., diameter >1 cm). Moreover, about one-third of these pituitary tumors show invasive features such as infiltration of tumor cells into surrounding normal juxtatumoral pituitary tissue. However, no specific histologic parameters differentiate between MEN 1 and non–MEN 1 pituitary tumors. Approximately 60% of MEN 1–associated pituitary tumors secrete prolactin, <25% secrete growth hormone, 5% secrete adrenocorticotropic hormone (ACTH), and the remainder appear to be nonfunctioning, with some secreting glycoprotein subunits (Table 52-1). However, pituitary tumors derived from MEN 1 patients may exhibit immunoreactivity to several hormones. In particular, there is a greater frequency of somatolactotrope tumors. Prolactinomas are the first manifestation of MEN 1 in ~15% of patients, whereas somatotrope tumors occur more often in patients older than 40 years of age. Fewer than 3% of patients with anterior pituitary tumors will have MEN 1. Clinical manifestations are similar to those in patients with sporadic pituitary tumors without MEN 1 and depend on the hormone secreted and the size of the pituitary tumor. Thus, patients may have symptoms of hyperprolactinemia (e.g., amenorrhea, infertility, and galactorrhea in women, or impotence and infertility in men) or have features of acromegaly or Cushing’s disease. In addition, enlarging pituitary tumors may compress adjacent structures such as the optic chiasm or normal pituitary tissue, causing visual disturbances and/or hypopituitarism. In asymptomatic patients with MEN 1, periodic biochemical monitoring of serum prolactin and insulin-like growth factor I (IGF-I) levels, as well as MRI of the pituitary, can lead to early identification of pituitary tumors (Table 52-3). In patients with abnormal results, hypothalamic-pituitary testing should characterize the nature of the pituitary lesion and its effects on the secretion of other pituitary hormones.

TREATMENT

Associated tumors

Patients with MEN 1 may also develop carcinoid tumors, adrenal cortical tumors, facial angiofibromas, collagenomas, thyroid tumors, and lipomatous tumors.

Carcinoid tumors

(See also Chap. 51) Carcinoid tumors occur in more than 3% of patients with MEN 1 (Table 52-1). The carcinoid tumor may be located in the bronchi, gastrointestinal tract, pancreas, or thymus. At the time of diagnosis, most patients are asymptomatic and do not have clinical features of the carcinoid syndrome. Importantly, no hormonal or biochemical abnormality (e.g., plasma chromogranin A) is consistently observed in individuals with thymic or bronchial carcinoid tumors. Thus, screening for these tumors is dependent on radiologic imaging. The optimum method for screening has not been established. CT and MRI are sensitive for detecting thymic and bronchial tumors (Table 52-3), although repeated CT scanning raises concern about exposure to repeated doses of ionizing radiation. Octreotide scintigraphy may also reveal some thymic and bronchial carcinoids, although there is insufficient evidence to recommend its routine use. Gastric carcinoids, of which the type II gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) are associated with MEN 1 and Zollinger-Ellison syndrome, may be detected incidentally at the time of gastric endoscopy for dyspeptic symptoms in MEN 1 patients. These tumors, which may be found in >10% of MEN 1 patients, are usually multiple and smaller than 1.5 cm. Bronchial carcinoids in patients with MEN 1 occur predominantly in women (male-to-female ratio, 1:4). In contrast, thymic carcinoids in European patients with MEN 1 occur predominantly in men (male-to-female ratio, 20:1), with cigarette smokers having a higher risk for these tumors; thymic carcinoids in Japanese patients with MEN 1 have a less marked sex difference (male-to-female ratio 2:1). The course of thymic carcinoids in MEN 1 appears to be particularly aggressive. The presence of thymic tumors in patients with MEN 1 is associated with a median survival after diagnosis of approximately 9.5 years, with 70% of patients dying as a direct result of the tumor.

TREATMENT

Adrenocortical tumors

(See also Chap. 53) Asymptomatic adrenocortical tumors occur in 20–70% of patients with MEN 1 depending on the radiologic screening methods used (Table 52-1). Most of these tumors, which include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, and carcinomas, are nonfunctioning. Indeed, <10% of patients with enlarged adrenal glands have hormonal hypersecretion, with primary hyperaldosteronism and ACTH-independent Cushing’s syndrome being encountered most commonly. Occasionally, hyperandrogenemia may occur in association with adrenocortical carcinoma. Pheochromocytoma in association with MEN 1 is rare. Biochemical investigation (e.g., plasma renin and aldosterone concentrations, low-dose dexamethasone suppression test, urinary catecholamines, and/or metanephrines) should be undertaken in those with symptoms or signs suggestive of functioning adrenal tumors or in those with tumors >1 cm. Adrenocortical carcinoma occurs in approximately 1% of MEN 1 patients but increases to >10% for adrenal tumors larger than 1 cm.

TREATMENT

Meningioma

Central nervous system (CNS) tumors, including ependymomas, schwannomas, and meningiomas, have been reported in MEN 1 patients (Table 52-1). Meningiomas are found in <10% of patients with other clinical manifestations of MEN 1 (e.g., primary hyperparathyroidism) for >15 years. The majority of meningiomas are not associated with symptoms, and 60% do not enlarge. The treatment of MEN 1–associated meningiomas is similar to that in non–MEN 1 patients.

Lipomas

Subcutaneous lipomas occur in >33% of patients with MEN 1 (Table 52-1) and are frequently multiple. In addition, visceral, pleural, or retroperitoneal lipomas may occur in patients with MEN 1. Management is conservative. However, when surgically removed for cosmetic reasons, they typically do not recur.

Facial angiofibromas and collagenomas

The occurrence of multiple facial angiofibromas in patients with MEN 1 may range from >20 to >90%, and occurrence of collagenomas may range from 0 to >70% (Table 52-1). These cutaneous findings may allow presymptomatic diagnosis of MEN 1 in the relatives of a patient with MEN 1. Treatment for these cutaneous lesions is usually not required.

Thyroid tumors

Thyroid tumors, including adenomas, colloid goiters, and carcinomas, have been reported to occur in >25% of patients with MEN 1. However, the prevalence of thyroid disorders in the general population is high, and it has been suggested that the association of thyroid abnormalities in patients with MEN 1 may be incidental. The treatment of thyroid tumors in MEN 1 patients is similar to that for non–MEN 1 patients.

Genetics and screening

The MEN1 gene is located on chromosome 11q13 and consists of 10 exons, which encode a 610–amino acid protein, menin, that regulates transcription, genome stability, cell division, and proliferation. The pathophysiology of MEN 1 follows the Knudson two-hit hypothesis with a tumor-suppressor role for menin. Inheritance of a germline MEN1 mutation predisposes an individual to developing a tumor that arises following a somatic mutation, which may be a point mutation or more commonly a deletion, leading to loss of heterozygosity (LOH) in the tumor DNA. The germline mutations of the MEN1 gene are scattered throughout the entire 1830-bp coding region and splice sites, and there is no apparent correlation between the location of MEN1 mutations and clinical manifestations of the disorder, in contrast with the situation in patients with MEN 2 (Table 52-1). More than 10% of MEN1 germline mutations arise de novo and may be transmitted to subsequent generations. Some families with MEN 1 mutations develop parathyroid tumors as the sole endocrinopathy, and this condition is referred to as familial isolated hyperparathyroidism (FIHP). However, between 5 and 25% of patients with MEN 1 do not harbor germline mutations or deletions of the MEN1 gene. Such patients with MEN 1–associated tumors but without MEN1 mutations may represent phenocopies or have mutations involving other genes. Other genes associated with MEN 1–like features include: CDC73, which encodes parafibromin, whose mutations result in the hyperparathyroid-jaw tumor syndrome; the calcium-sensing receptor gene (CaSR), whose mutations result in familial benign hypocalciuric hypercalcemia (FBHH); and the aryl hydrocarbon receptor interacting protein gene (AIP), a tumor suppressor located on chromosome 11q13 whose mutations are associated with familial isolated pituitary adenomas (FIPA). Genetic testing to determine the MEN1 mutation status in symptomatic family members within a MEN 1 kindred, as well as to all index cases (e.g., patients) with two or more endocrine tumors, is advisable. If an MEN1 mutation is not identified in the index case with two or more endocrine tumors, then clinical and genetic tests for other disorders such as hyperparathyroid-jaw tumor syndrome, FBHH, FIPA, MEN 2, or MEN 4 should be considered, because these patients may represent phenocopies for MEN 1.

The current guidelines recommend that MEN1 mutational analysis should be undertaken in: (1) an index case with two or more MEN 1–associated endocrine tumors (e.g., parathyroid, pancreatic, or pituitary tumors); (2) asymptomatic first-degree relatives of a known MEN1 mutation carrier; and (3) first-degree relatives of a MEN1 mutation carrier with symptoms, signs, or biochemical or radiologic evidence for one or more MEN 1–associated tumors. In addition, MEN1 mutational analysis should be considered in patients with suspicious or atypical MEN 1. This would include individuals with parathyroid adenomas before the age of 30 years or multigland parathyroid disease; individuals with gastrinoma or multiple pancreatic NETs at any age; or individuals who have two or more MEN 1–associated tumors that are not part of the classical triad of parathyroid, pancreatic islet, and anterior pituitary tumors (e.g., parathyroid tumor plus adrenal tumor). Family members, including asymptomatic individuals who have been identified to harbor a MEN1 mutation, will require biochemical and radiologic screening (Table 52-3). In contrast, relatives who do not harbor the MEN1 mutation have a risk of developing MEN 1–associated endocrine tumors that is similar to that of the general population; thus, relatives without the MEN1 mutation do not require repeated screening.

Mutational analysis in asymptomatic individuals should be undertaken at the earliest opportunity and, if possible, in the first decade of life because tumors have developed in some children by the age of 5 years. Appropriate biochemical and radiologic investigations (Table 52-3) aimed at detecting the development of tumors should then be undertaken in affected individuals. Mutant gene carriers should undergo biochemical screening at least once per annum and also have baseline pituitary and abdominal imaging (e.g., MRI or CT), which should then be repeated at 1- to 3-year intervals (Table 52-3). Screening should commence after 5 years of age and should continue for life because the disease may develop as late as the eighth decade. The screening history and physical examination elicit the symptoms and signs of hypercalcemia, nephrolithiasis, peptic ulcer disease, neuroglycopenia, hypopituitarism, galactorrhea and amenorrhea in women, acromegaly, Cushing’s disease, and visual field loss and the presence of subcutaneous lipomas, angiofibromas, and collagenomas. Biochemical screening should include measurements of serum calcium, PTH, gastrointestinal hormones (e.g., gastrin, insulin with a fasting glucose, glucagon, VIP, PP), chromogranin A, prolactin, and IGF-I in all individuals. More specific endocrine function tests should be undertaken in individuals who have symptoms or signs suggestive of a specific clinical syndrome. Biochemical screening for the development of MEN 1 tumors in asymptomatic members of families with MEN 1 is of great importance to reduce morbidity and mortality from the associated tumors.

Clinical manifestations

MEN type 2 (MEN 2), which is also called Sipple’s syndrome, is characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors (Table 52-1). Three clinical variants of MEN 2 are recognized: MEN 2A, MEN 2B, and MTC only. MEN 2A, which is often referred to as MEN 2, is the most common variant. In MEN 2A, MTC is associated with pheochromocytomas in 50% of patients (may be bilateral) and with parathyroid tumors in 20% of patients. MEN 2A may rarely occur in association with Hirschsprung’s disease, caused by the absence of autonomic ganglion cells in the terminal hindgut, resulting in colonic dilatation, severe constipation, and obstruction. MEN 2A may also be associated with cutaneous lichen amyloidosis, which is a pruritic lichenoid lesion that is usually located on the upper back. MEN 2B, which is also referred to as MEN 3, represents 5% of all cases of MEN 2 and is characterized by the occurrence of MTC and pheochromocytoma in association with a Marfanoid habitus; mucosal neuromas of the lips, tongue, and eyelids; medullated corneal fibers; and intestinal autonomic ganglion dysfunction leading to multiple diverticulae and megacolon. Parathyroid tumors do not usually occur in MEN 2B. MTC only (FMTC) is a variant in which MTC is the sole manifestation of the syndrome. However, the distinction between FMTC and MEN 2A is difficult and should only be considered if there are at least four family members above the age of 50 years who are affected by MTC but not pheochromocytomas or primary hyperparathyroidism. All of the MEN 2 variants are due to mutations of the rearranged during transfection (RET) protooncogene, which encodes a TKR. Moreover, there is a correlation between the locations of RET mutations and MEN 2 variants. Thus, ~95% of MEN 2A patients have mutations involving the cysteine-rich extracellular domain, with mutations of codon 634 accounting for ~85% of MEN 2A mutations; FMTC patients also have mutations of the cysteine-rich extracellular domain, with most mutations occurring in codon 618. In contrast, ~95% of MEN 2B/MEN 3 patients have mutations of codon 918 of the intracellular tyrosine kinase domain (Table 52-1 and Table 52-4).

Medullary thyroid carcinoma

MTC is the most common feature of MEN 2A and MEN 2B and occurs in almost all affected individuals. MTC represents 5–10% of all thyroid gland carcinomas, and 20% of MTC patients have a family history of the disorder. The use of RET mutational analysis to identify family members at risk for hereditary forms of MTC has altered the presentation of MTC from that of symptomatic tumors to a preclinical disease for which prophylactic thyroidectomy (Table 52-4) is undertaken to improve the prognosis and ideally result in cure. However, in patients who do not have a known family history of MEN 2A, FMTC, or MEN 2B, and therefore have not had RET mutational analysis, MTC may present as a palpable mass in the neck, which may be asymptomatic or associated with symptoms of pressure or dysphagia in >15% of patients. Diarrhea occurs in 30% of patients and is associated either with elevated circulating concentrations of calcitonin or tumor-related secretion of serotonin and prostaglandins. Some patients may also experience flushing. In addition, ectopic ACTH production by MTC may cause Cushing’s syndrome. The diagnosis of MTC relies on the demonstration of hypercalcitoninemia (>90 pg/mL in the basal state); stimulation tests using IV pentagastrin (0.5 mg/kg) and or calcium infusion (2 mg/kg) are rarely used now, reflecting improvements in the assay for calcitonin. Neck ultrasonography with fine-needle aspiration of the nodules can confirm the diagnosis. Radionucleotide thyroid scans may reveal MTC tumors as “cold” nodules. Radiography may reveal dense irregular calcification within the involved portions of the thyroid gland and in lymph nodes involved with metastases. Positron emission tomography (PET) may help to identify the MTC and metastases (Fig. 52-2). Metastases of MTC usually occur to the cervical lymph nodes in the early stages and to the mediastinal nodes, lung, liver, trachea, adrenal, esophagus, and bone in later stages. Elevations in serum calcitonin concentrations are often the first sign of recurrence or persistent disease, and the serum calcitonin doubling time is useful for determining prognosis. MTC can have an aggressive clinical course, with early metastases and death in approximately 10% of patients. A family history of aggressive MTC or MEN 2B may be elicited.

Pheochromocytoma

(See also Chap. 53) These noradrenaline- and adrenaline-secreting tumors occur in >50% of patients with MEN 2A and MEN 2B and are a major cause of morbidity and mortality. Patients may have symptoms and signs of catecholamine secretion (e.g., headaches, palpitations, sweating, poorly controlled hypertension), or they may be asymptomatic with detection through biochemical screening based on a history of familial MEN 2A, MEN 2B, or MTC. Pheochromocytomas in patients with MEN 2A and MEN 2B differ significantly in distribution when compared with patients without MEN 2A and MEN 2B. Extra-adrenal pheochromocytomas, which occur in 10% of patients without MEN 2A and MEN 2B, are observed rarely in patients with MEN 2A and MEN 2B. Malignant pheochromocytomas are much less common in patients with MEN 2A and MEN 2B. The biochemical and radiologic investigation of pheochromocytoma in patients with MEN 2A and MEN 2B is similar to that in non–MEN 2 patients and includes the measurement of plasma (obtained from supine patients) and urinary free fractionated metanephrines (e.g., normetanephrine and metanephrines measured separately), CT or MRI scanning, radionuclide scanning with meta-iodo-(¹²³I or ¹³¹I)-benzyl guanidine (MIBG), and PET using (¹⁸F)-fluorodopamine or (¹⁸F)-fluoro-2-dexoxy-d-glucose (Fig. 52-2).

Parathyroid tumors

Parathyroid tumors occur in 10–25% of patients with MEN 2A. However, >50% of these patients do not have hypercalcemia. The presence of abnormally enlarged parathyroids, which are unusually hyperplastic, is often seen in the normocalcemic patient undergoing thyroidectomy for MTC. The biochemical investigation and treatment of hypercalcemic patients with MEN 2A is similar to that of patients with MEN 1.

Genetics and screening

To date, approximately 50 different RET mutations have been reported, and these are located in exons 5, 8, 10, 11, 13, 14, 15, and 16. RET germline mutations are detected in >95% of MEN 2A, FMTC, and MEN 2B families, with Cys634Arg being most common in MEN 2A, Cys618Arg being most common in FMTC, and Met918Thr being most common in MEN 2B (Tables 52-1 and 52-4). Between 5 and 10% of patients with MTC or MEN 2A–associated tumors have de novo RET germline mutations, and ~50% of patients with MEN 2B have de novo RET germline mutations. These de novo RET germline mutations always occur on the paternal allele. Approximately 5% of patients with sporadic pheochromocytoma have a germline RET mutation, but such germline RET mutations do not appear to be associated with sporadic primary hyperparathyroidism. Thus, RET mutational analysis should be performed in: (1) all patients with MTC who have a family history of tumors associated with MEN 2, FMTC, or MEN 3, such that the diagnosis can be confirmed and genetic testing offered to asymptomatic relatives; (2) all patients with MTC and pheochromocytoma without a known family history of MEN 2 or MEN 3; (3) all patients with MTC, but without a family history of MEN 2, FMTC, or MEN 3, because these patients may have a de novo germline RET mutations; (4) all patients with bilateral pheochromocytoma; and (5) patients with unilateral pheochromocytoma, particularly if this occurs with increased calcitonin levels.

Screening for MEN 2/MEN 3–associated tumors in patients with RET germline mutations should be undertaken annually and include serum calcitonin measurements, a neck ultrasound for MTC, plasma and 24-h urinary fractionated metanephrines for pheochromocytoma, and albumin-corrected serum calcium or ionized calcium with PTH for primary hyperparathyroidism. In patients with MEN 2–associated RET mutations, screening for MTC should begin by 3 to 5 years; for pheochromocytoma by 20 years; and for primary hyperparathyroidism by 20 years of age (Table 52-4).

Clinical manifestations

Patients with MEN 1–associated tumors, such as parathyroid adenomas, pituitary adenomas, and pancreatic NETs, occurring in association with gonadal, adrenal, renal, and thyroid tumors have been reported to have mutations of the gene encoding the 196–amino acid cyclin-dependent kinase inhibitor (CK1) p27 kip1 (CDNKIB). Such families with MEN 1–associated tumors and CDNKIB mutations are designated to have MEN 4 (Table 52-1). The investigations and treatments for the MEN 4–associated tumors are similar to those for MEN 1 and non–MEN 1 tumors.

Genetics and screening

To date, eight different MEN 4–associated mutations of CDNKIB, which is located on chromosome 12p13, have been reported, and all of these are associated with a loss of function. These MEN 4 patients may represent ~3% of the 5–10% of patients with MEN 1 who do not have mutations of the MEN1 gene. Germline CDNKIB mutations may rarely be found in patients with sporadic (i.e., nonfamilial) forms of primary hyperparathyroidism.

Clinical manifestations

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the development of parathyroid tumors (15% are carcinomas) and fibro-osseous jaw tumors. In addition, some patients may also develop Wilms’ tumors, renal cysts, renal hematomas, renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, uterine tumors, testicular mixed germ cell tumors with a major seminoma component, and Hürthle cell thyroid adenomas. The parathyroid tumors may occur in isolation and without any evidence of jaw tumors, and this may cause confusion with other hereditary hypercalcemic disorders, such as MEN 1. However, genetic testing to identify the causative mutation will help to establish the correct diagnosis. The investigation and treatment for HPT-JT-associated tumors are similar to those in non-HPT-JT patients, except that early parathyroidectomy is advisable because of the increased frequency of parathyroid carcinoma.

Genetics and screening

The gene that causes HPT-JT is located on chromosome 1q31.2 and encodes a 531–amino acid protein, parafibromin (Table 52-2). Parafibromin is also referred to as cell division cycle protein 73 (CDC73) and has a role in transcription. Genetic testing in families helps to identify mutation carriers who should be periodically screened for the development of tumors (Table 52-5).

Clinical manifestations

von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by hemangioblastomas of the retina and CNS; cysts involving the kidneys, pancreas, and epididymis; renal cell carcinomas; pheochromocytomas; and pancreatic islet cell tumors (See also Chap. 53). The retinal and CNS hemangioblastomas are benign vascular tumors that may be multiple; those in the CNS may cause symptoms by compressing adjacent structures and/or increasing intracranial pressure. In the CNS, the cerebellum and spinal cord are the most frequently involved sites. The renal abnormalities consist of cysts and carcinomas, and the lifetime risk of a renal cell carcinoma (RCC) in VHL is 70%. The endocrine tumors in VHL consist of pheochromocytomas and pancreatic islet cell tumors. The clinical presentation of pheochromocytoma in VHL disease is similar to that in sporadic cases, except there is a higher frequency of bilateral or multiple tumors, which may involve extra-adrenal sites in VHL disease. The most frequent pancreatic lesions in VHL are multiple cyst-adenomas, which rarely cause clinical disease. However, nonsecreting pancreatic islet cell tumors occur in <10% of VHL patients, who are usually asymptomatic. The pancreatic tumors in these patients are often detected by regular screening using abdominal imaging. Pheochromocytomas should be investigated and treated as described earlier for MEN 2. The pancreatic islet cell tumors frequently become malignant, and early surgery is recommended.

Genetics and screening

The VHL gene, which is located on chromosome 3p26-p25, is widely expressed in human tissues and encodes a 213–amino acid protein (pVHL) (Table 52-2). A wide variety of germline VHL mutations have been identified. VHL acts as a tumor-suppressor gene. A correlation appears to exist between the type of mutation and the clinical phenotype; large deletions and protein-truncating mutations are associated with a low incidence of pheochromocytomas, whereas some missense mutations in VHL patients are associated with pheochromocytoma (referred to as VHL type 2C). Other missense mutations may be associated with hemangioblastomas and RCC but not pheochromocytoma (referred to as VHL type 1), whereas distinct missense mutations are associated with hemangioblastomas, RCC, and pheochromocytoma (VHL type 2B). VHL type 2A, which refers to the occurrence of hemangioblastomas and pheochromocytoma without RCC, is associated with rare missense mutations. The basis for these complex genotype-phenotype relationships remains to be elucidated. One major function of pVHL, which is also referred to as elongin, is to downregulate the expression of vascular endothelial growth factor (VEGF) and other hypoxia-inducible mRNAs. Thus, pVHL, in complex with other proteins, regulates the expression of hypoxia-inducible factors (HIF-1 and HIF-2) such that loss of functional pVHL leads to a stabilization of the HIF protein complexes, resulting in VEGF overexpression and tumor angiogenesis. Screening for the development of pheochromocytomas and pancreatic islet cell tumors is as described earlier for MEN 2 and MEN 1, respectively (Tables 52-3 and 52-4).

Clinical manifestations

Neurofibromatosis type 1 (NF1), which is also referred to as von Recklinghausen’s disease, is an autosomal dominant disorder characterized by the following manifestations: neurologic (e.g., peripheral and spinal neurofibromas); ophthalmologic (e.g., optic gliomas and iris hamartomas such as Lisch nodules); dermatologic (e.g., café au lait macules); skeletal (e.g., scoliosis, macrocephaly, short stature, and pseudoarthrosis); vascular (e.g., stenoses of renal and intracranial arteries); and endocrine (e.g., pheochromocytoma, carcinoid tumors, and precocious puberty). Neurofibromatosis type 2 (NF2) is also an autosomal dominant disorder but is characterized by the development of bilateral vestibular schwannomas (acoustic neuromas) that lead to deafness, tinnitus, or vertigo. Some patients with NF2 also develop meningiomas, spinal schwannomas, peripheral nerve neurofibromas, and café au lait macules. Endocrine abnormalities are not found in NF2 and are associated solely with NF1. Pheochromocytomas, carcinoid tumors, and precocious puberty occur in about 1% of patients with NF1, and growth hormone deficiency has been also reported. The features of pheochromocytomas in NF1 are similar to those in non-NF1 patients, with 90% of tumors being located within the adrenal medulla and the remaining 10% at an extra-adrenal location, which often involves the para-aortic region. Primary carcinoid tumors are often periampullary and may also occur in the ileum but rarely in the pancreas, thyroid, or lungs. Hepatic metastases are associated with symptoms of the carcinoid syndrome, which include flushing, diarrhea, bronchoconstriction, and tricuspid valve disease. Precocious puberty is usually associated with the extension of an optic glioma into the hypothalamus with resultant early activation of gonadotropin-releasing hormone secretion. Growth hormone deficiency has also been observed in some NF1 patients, who may or may not have optic chiasmal gliomas, but it is important to note that short stature is frequent in the absence of growth hormone deficiency in patients with NF1. The investigation and treatment for tumors are similar to those undertaken for each respective tumor type in non-NF1 patients.

Genetics and screening

The NF1 gene, which is located on chromosome 17q11.2 and acts as a tumor suppressor, consists of 60 exons that span more than 350 kb of genomic DNA (Table 52-2). Mutations in NF1 are of diverse types and are scattered throughout the exons. The NF1 gene product is the protein neurofibromin, which has homologies to the p120GAP (GTPase activating protein) and acts on p21ras by converting the active GTP bound form to its inactive GDP form. Mutations of NF1 impair this downregulation of the p21ras signaling pathways, which in turn results in abnormal cell proliferation. Screening for the development of pheochromocytomas and carcinoid tumors is as described earlier for MEN 2 and MEN 1, respectively (Tables 52-3 and 52-4).

Clinical manifestations

Carney complex (CNC) is an autosomal dominant disorder characterized by spotty skin pigmentation (usually of the face, labia, and conjunctiva), myxomas (usually of the eyelids and heart, but also the tongue, palate, breast, and skin), psammomatous melanotic schwannomas (usually of the sympathetic nerve chain and upper gastrointestinal tract), and endocrine tumors that involve the adrenals, Sertoli cells, somatotropes, thyroid, and ovary. Cushing’s syndrome, the result of primary pigmented nodular adrenal disease (PPNAD), is the most common endocrine manifestation of CNC and may occur in one-third of patients. Patients with CNC and Cushing’s syndrome often have an atypical appearance by being thin (as opposed to having truncal obesity). In addition, they may have short stature, muscle and skin wasting, and osteoporosis. These patients often have levels of urinary free cortisol that are normal or increased only marginally. Cortisol production may fluctuate periodically with days or weeks of hypercortisolism; this pattern is referred to as “periodic Cushing’s syndrome.” Patients with Cushing’s syndrome usually have loss of the circadian rhythm of cortisol production. Acromegaly, the result of a somatotrope tumor, affects ~10% of patients with CNC. Testicular tumors may also occur in one-third of patients with CNC. These may either be large-cell calcifying Sertoli cell tumors, adrenocortical rests, or Leydig cell tumors. The Sertoli cell tumors occasionally may be estrogen-secreting and lead to precocious puberty or gynecomastia. Some patients with CNC have been reported to develop thyroid follicular tumors, ovarian cysts, or breast duct adenomas.

Genetics and screening

CNC type 1 (CNC1) is due to mutations of the protein kinase A (PKA) regulatory subunit 1 α (R1α) (PPKAR1A), a tumor suppressor, whose gene is located on chromosome 17q.24.2 (Table 52-2). The gene causing CNC type 2 (CNC2) is located on chromosome 2p16 and has not yet been identified. It is interesting to note, however, that some tumors do not show LOH of 2p16 but instead show genomic instability, suggesting that this CNC gene may not be a tumor suppressor. Screening and treatment of these endocrine tumors are similar to those described earlier for patients with MEN 1 and MEN 2 (Tables 52-3 and 52-4).

Clinical manifestations

Multiple hamartomatous lesions, especially of the skin, mucous membranes (e.g., buccal, intestinal, and colonic), breast, and thyroid are characteristic of Cowden’s (CWD) syndrome, which is an autosomal dominant disorder. Thyroid abnormalities occur in two-thirds of patients with CWD syndrome, and these usually consist of multinodular goiters or benign adenomas, although <10% of patients may have a follicular thyroid carcinoma. Breast abnormalities occur in >75% of patients and consist of either fibrocystic disease or adenocarcinomas. The investigation and treatment for CWD tumors are similar to those undertaken for non-CWD patients.

Genetics and screening

CWD syndrome is genetically heterogenous, and six types (CWD1–6) are recognized (Table 52-2). CWD is due to mutations of the phosphate and tensin homologue deleted on chromosome 10 (PTEN) gene, located on chromosome 10q23.31. CWD2 is caused by mutations of the succinate dehydrogenase subunit B (SDHB) gene, located on chromosome 1p36.13; and CWD3 is caused by mutations of the SDHD gene, located on chromosome 11q13.1. SDHB and SDHD mutations are also associated with pheochromocytoma. CWD4 is caused by hypermethylation of the Killin (KLLN) gene, the promoter of which shares the same transcription site as PTEN on chromosome 10q23.31. CWD5 is caused by mutations of the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA) gene on chromosome 3q26.32, and CWD6 is caused by mutations of the V-Akt murine thymoma viral oncogene homolog 1 (AKT1) gene on chromosome 14q32.33. Screening for thyroid abnormalities entails neck ultrasonography and fine-needle aspiration with analysis of cell cytology.

Clinical manifestations

McCune-Albright syndrome (MAS) is characterized by the triad of polyostotic fibrous dysplasia, which may be associated with hypophosphatemic rickets; café au lait skin pigmentation; and peripheral precocious puberty; other endocrine abnormalities include thyrotoxicosis, which may be associated with a multinodular goiter, somatotrope tumors, and Cushing’s syndrome (due to adrenal tumors). Investigation and treatment for each endocrinopathy are similar to those used in patients without MAS.

Genetics and screening

MAS is a disorder of mosaicism that results from postzygotic somatic cell mutations of the G protein α stimulating subunit (Gsα), encoded by the GNAS1 gene, located on chromosome 20q13.32 (Table 52-2). The Gsα mutations, which include Arg201Cys, Arg201His, Glu227Arg, or Glu227His, are activating and are found only in cells of the abnormal tissues. Screening for hyperfunction of relevant endocrine glands and development of hypophosphatemia, which may be associated with elevated serum fibroblast growth factor 23 (FGF23) concentrations, is undertaken in MAS patients.

Acknowledgments

The author is grateful to the Medical Research Council (UK) for support and to Mrs. Tracey Walker for typing the manuscript.