Multiple Endocrine Neoplasia
Glen Sizemore
Norma Lopez
Two sets of multiple endocrine neoplasia (MEN) syndromes and multiple tumor associations are characterized by the work of Steiner et al. [1]. Table 9.1 lists the syndrome components and their penetrance. MEN1 describes a combination of two or more tumors of pituitary, enteropancreatic, and parathyroid origin. Wermer [2] confirmed genetic origin by reporting disease in successive generations of one family. MEN2, originally described by Sipple [3], refers to the combination of medullary thyroid carcinoma (MTC), pheochromocytoma (P), and parathyroid tumors. MEN2 has three variants: MEN2A patients have a normal phenotype; MEN2B patients have a distinct phenotype (vide infra) with oral ganglioneuromas, marfanoid habitus, prominent corneal nerves, and general lack of parathyroid disease; and familial MTC (FMTC) was initially used to describe families with MTC only; currently, it is considered to be a phenotypic variant of MEN2A with decreased penetrance of P and parathyroid hyperplasia rather than a distinct entity [4].
The MEN syndromes are rare. Probably underestimated prevalence ranges from 0.2 to 2.0/100,000 for MEN1 and 2.0 to 10/100,000 for MEN2. Initially, cases were thought to be more common in people of northern European ancestry; with time, more cases are being reported from southern and eastern Europe, Asia, and, less commonly, Africa and South America. Because the patients with these diseases are limited and spread among multiple institutions, there have been no randomized double-blind studies of means to confirm diagnosis, results of different therapies, or cost-effectiveness.
Both MEN syndromes are inherited with an autosomal dominant pattern of transmission. MEN1 derives from mutations of a gene at chromosome 11q13. This gene encodes a 613-amino-acid intranuclear protein called menin, which is considered a putative tumor suppressor. In 10% of MEN1 patients, the mutation arises de novo, and in familial index cases of MEN1 there is a 60% to 80% prevalence of an identifiable mutation—one of approximately 800 germline codon mutations that are “inactivating” and remove tumor suppression [5, 6]. If loss of the second suppressor allele occurs, tumor development begins in a manner consistent with Knudson and Strong’s “two-hit” mutational model [7]. There is no genotype-phenotype correlation in MEN1.
In MEN2 patients, there may be at least 12 germline, missense, codon mutations of the RET (rearranged during transfection) protooncogene at chromosome
10q11.2. More than 95% of MEN2 cases have been found to have such mutations. This “activating” gene encodes receptor tyrosine kinases, which signal cell growth and differentiation, and it starts tumor genesis. First, a germinal mutation occurs that increases cell susceptibility to malignant transformation; the second event is a somatic mutation that transforms the mutant cell into a tumor cell. In MEN2, there is a strong genotype-phenotype correlation.
10q11.2. More than 95% of MEN2 cases have been found to have such mutations. This “activating” gene encodes receptor tyrosine kinases, which signal cell growth and differentiation, and it starts tumor genesis. First, a germinal mutation occurs that increases cell susceptibility to malignant transformation; the second event is a somatic mutation that transforms the mutant cell into a tumor cell. In MEN2, there is a strong genotype-phenotype correlation.
Table 9.1. MEN: Organ or Feature Involvement with Estimated Penetrance in Adults | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The heritable MEN tumors have important characteristics that contrast with those of sporadic endocrine tumors: genetic origin and transmission; precursor hyperplasias that predispose to younger clinical presentations and earlier diagnosis; multiplicity and multicentricity of tumor involvement (90%, 70%, and 100% of insulin-, gastrin-, and calcitonin-secreting tumors, respectively, vs. 10%, 40%, and 10% in their sporadic counterparts); a clinicopathologic spectrum with early, occult hyperplasia developing into later, symptomatic tumor; and, to some extent, more malignant biologic behavior of some of the tumors—MTC, enteropancreatic, and carcinoid in some families.
Generally, there is no overlap between MEN1 and MEN2. However, Frank-Raue et al. [8] and Scillitani et al. [9] have each reported a family with the coexistence of these syndromes and mutations of MEN1 and MEN2 genes. Furthermore, rare, isolated, mutation-negative cases that shared tumors from each syndrome have been reported [10, 11].
MEN TYPE 1
This is a syndrome of the three Ps—pituitary, parathyroid, and pancreas. Principal organ involvement is outlined in Table 9.1. Differences in penetrance are considered reflections of the various family characteristics, ages, and years of the studies. MEN1 typically presents after the first decade, with most symptoms developing in the third (women) and fourth (men) decades. The presenting symptoms in an older series of 52 patients were associated with ulcer in 40%, hypoglycemia in 31%, hyperparathyroidism in 15%, and diarrhea and pituitary disease in 6% [12].
Screening
A comprehensive family history (an inexpensive process) and DNA analysis for the MEN1 mutation (expensive) should be pursued in patients having component tumor presentation at a young age, tumor multifocality, having two or more of its component tumors, or known to have heritable risk for MEN1. Genetic counselors are very helpful in this process. Sources and costs of mutation analyses can be found at www.geneclinics.org. Several benefits accrue to mutationpositive patients: clinical surveillance and care will intensify; operations for components such as multiglandular parathyroid disease and multifocal enteropancreatic tumors will differ from those in sporadic patients; and the mandatory case finding in at-risk primary relatives will be simplified (i.e., need to check for one known mutation only). Mutation-negative patients gain emotional reassurance and economic benefit because further clinical testing is not needed. Unfortunately, a mutation is not found in up to 30% of probands in known MEN1 families [8]. Screening in these families must revert to annual measurements of ionized calcium, parathyroid hormone (PTH), gastrin, and prolactin [13] and the recommended abdominal magnetic resonance imaging (MRI) every 2 years. Clinical expression generally occurs after age 10, but the authors recommend that screening begin at age 5 because of reports of prolactinoma in a 5-year-old [14] and insulinoma in a 6-year-old [15].
False-negative mutation screening test results may occur in individual patients within mutation-known families at “guesstimated” frequencies [15]. Analysis of a
second separate sample is recommended to reduce the risk of missing an affected to 0.25%. Thus far, false-positive mutation test results have not been reported, and the author is aware of no estimates of administrative, sampling, or reference laboratory errors.
second separate sample is recommended to reduce the risk of missing an affected to 0.25%. Thus far, false-positive mutation test results have not been reported, and the author is aware of no estimates of administrative, sampling, or reference laboratory errors.
Patients with three other diseases should have mutation testing or screening for MEN1: approximately 33% of patients with the Zollinger-Ellison syndrome (ZES) have MEN1; 4% to 10% of patients with insulinoma have the syndrome [16, 17, 18]; in familial hyperparathyroidism 14% to 16% have MEN1; and in those younger than age 40 thought to have sporadic hyperparathyroidism the prevalence of MEN1 has been estimated at 13%.
Enteropancreatic Disease
Enteropancreatic tumors are present in up to 75% of patients with MEN1. They are generally multicentric and found in the gastric antrum, pancreas, and duodenal submucosa (particularly gastrinomas). Occult malignant disease is present in one-half of these patients by middle age [19]. Most secrete one hormone (see Table 9.1) that produces a distinct clinical syndrome; occasionally, multiple hormones are secreted. Gastrin, insulin, chromogranin A, and pancreatic polypeptide are hormones that may be secreted by these tumors in significant amounts to be used in annual screening as markers for the enteropancreatic tumors.
Gastrin-Secreting Tumors
Gastrin-secreting tumors are the most common functioning tumors and have the greatest malignant potential. Most are small, multiple, and within the pancreas and duodenum; about 90% have duodenal components. Half have metastasized before the diagnosis is made [19]. The clinical syndrome caused by excess gastrin secretion—ZES—does not differ between MEN1 and sporadic tumors [12, 20]. Excess gastrin causes secretory diarrhea and ulcerations in the esophagus, stomach, and duodenum-jejunum, producing abdominal pain. In an early clinical report, 50% of patients exhibited multifocal peptic ulcers and esophagitis, and 13% had watery diarrhea [12].
Diagnosis
Measurement of basal gastrin and hourly gastric acid output is mandatory. High gastrin concentrations (generally above 200 pg/ml) and gastric acid secretion are the hallmarks of ZES in patients with no history of acid-reducing medications or operations. Basal gastric acid secretion that exceeds 15 mEq/hr is found in 68% to 97%. These tests will exclude 88% to 96% of patients who have ordinary duodenal ulcers [21]. To distinguish patients with ZES symptoms and minimally elevated basal gastrin values, a secretin test using 2 U/kg is advised. Gastrin increases of 200 pg/ml or more are diagnostic for ZES, with no false-positive responses and only occasional false-negative responses reported [22, 23]. Protein pump inhibitors must be stopped for at least 1 week before the secretin test. History is an inexpensive way to exclude other causes of high gastrin such as retained gastric antrum, gastric outlet obstruction, and renal failure.
If operation is planned, favored localization studies are somatostatin receptor scintigraphy (SRS) with octreotide and endoscopic ultrasound (EUS). Both have sensitivities in the 80% to 90% range, with the warning that SRS detects only 30% to 75% of tumors smaller than 1.5 cm [24, 25]. However, SRS has the advantage of simultaneous detection of primary pancreatic tumors and liver and other metastases. Some also use MRI and computed tomography (CT) to exclude metastatic disease that would preclude surgical intervention; however, these modalities are insensitive for the detection of smaller tumors, localizing
only 26% and 31% of insulinomas and gastrinomas, respectively [26, 27]. EUS has reported sensitivity of 93% and specificity of 95% in the localization of intrapancreatic lesions [28]. In one case-control study of gastrinoma patients, EUS was 83% accurate, missing tumors in 4 and predicting nonexistent tumors in 2 of 36 patients (i.e., false-positive result) [29]. It was cost-effective, reducing localization costs by 50%. If these procedures are not successful, comparable sensitivity is possible with the more expensive and time-consuming percutaneous transhepatic transvenous sampling or with venous sampling for hormone measurement after arterial injection of secretagogue. Hepatic angiography is an excellent way to demonstrate hepatic metastases.
only 26% and 31% of insulinomas and gastrinomas, respectively [26, 27]. EUS has reported sensitivity of 93% and specificity of 95% in the localization of intrapancreatic lesions [28]. In one case-control study of gastrinoma patients, EUS was 83% accurate, missing tumors in 4 and predicting nonexistent tumors in 2 of 36 patients (i.e., false-positive result) [29]. It was cost-effective, reducing localization costs by 50%. If these procedures are not successful, comparable sensitivity is possible with the more expensive and time-consuming percutaneous transhepatic transvenous sampling or with venous sampling for hormone measurement after arterial injection of secretagogue. Hepatic angiography is an excellent way to demonstrate hepatic metastases.
Treatment
Proton pump inhibitors or occasionally H2 receptor blockers and somatostatin analogues for hormones other than gastrin effectively prevent morbidity in most patients [19].
Operations, when done, should include distal pancreatectomy, intraoperative ultrasonography and palpation (to delineate smaller tumors), enucleation of tumors in the head of the pancreas, exploratory duodenotomy with removal of smaller tumors and carcinoids, and lymphadenectomy around the celiac trunk and hepatic ligament. Indications for operation in MEN are evolving. All clinicians agree with surgery for failed medical treatment or palliation of advanced disease. Otherwise, controversy exists regarding the surgical management of these patients. We do not know whether earlier surgery will reduce death from cancer without increasing morbidity; we lack long-term randomized studies of patients treated with no operation versus a standardized operation that compare survival and operative morbidity. Conservatives cite the 100% survivorship over 15 years in patients with tumors smaller than 1.5 cm who have not had operation [30]. By contrast, a study reporting no operative cure for gastrinomas larger than 2.5 cm [31] weakens arguments for waiting to remove tumors until they reach 3 cm. There is no correlation between the size of the primary tumor and the incidence of regional or distant metastases as shown by the isolated discovery of metastasis associated with a 3-mm primary tumor [32]. In their review of 34 articles on this subject, Schreinemakers et al. [33] stated: “Gastrinoma tumors > 3 cm were associated with a worse outcome. Biochemical cure was observed in 64-77% when all gastrinomas or gastrinomas >1 cm were operated, compared to 0% when tumors > 2.5 cm were operated.” In gastrinoma patients, the presence of hepatic metastases is a major factor associated with poor prognosis. Because the incidence of liver metastases is directly related to size of the primary tumor (4% with tumors <1 cm vs. 61% in tumors >3 cm), operations at earlier stages seem best advised. Fraker et al. [34] found an eightfold reduction in hepatic metastases when they compared patients with large tumors who were managed medically to those with smaller tumors who were operated with intent to cure.
Less conservative clinicians argue that patients should have operations because of the difficulty in predicting which primary tumors will metastasize and when they will do so. The University of Michigan group has operated on about 15 presymptomatic patients. Their intervention includes distal pancreatectomy, intraoperative ultrasonography, palpation and removal of tumors localized in the pancreatic head, duodenal submucosa, and antrum, as well as dissection of lymph nodes along the celiac axis and hepatic ligament. All 15 patients continue to have normal gastrin levels, and only 1 patient has developed diabetes mellitus [35]. Skogseid et al. [36] have complementary results. The follow-up is short in both studies, but the early results suggest need for a larger, longer, randomized study.
For patients with metastatic disease the therapeutic options include chemoembolization, chemotherapy, alpha interferon, peptide radioreceptor therapies, and somatostatin analogues. Recent reports about patients with advanced pancreatic neuroendocrine tumors (functional and nonfunctional with limited MEN1 participants) treated with sunitinib malate or everolimus have shown improved progression-free survival and objective response rates with treatment compared to placebo [37, 38]. Further discussion is not within the scope of this text.
Insulin-Secreting and Other Tumor Types
Between 10% and 30% of enteropancreatic tumors secrete insulin. The youngest patient studied was aged 6. Insulinoma is a more common functioning tumor in patients younger than 25. Most tumors are pure insulin secretors; some produce both insulin and gastrin [39]. Both types cause hypoglycemia.
Diagnosis
The diagnosis is based on finding simultaneous fasting serum glucose values below 45 mg/dl and inappropriately high insulin concentrations (>10 mU/ml). Typical requirements for this study are a 72-hour fast with measurement of plasma glucose and insulin every 6 hours or measurement of insulin and C- peptide before and during induced hypoglycemia [37, 38, 39, 40].
Treatment
Operation is recommended in all insulinoma patients. Pre- and operative tumor localization may be done with ultrasonography, CT, endoscopic ultrasonography, and intraoperative ultrasonography. The initial therapy for insulinoma is a distal pancreatectomy, which should remove about 85% of the gland [18, 41]. This procedure is favored for three reasons. First, multicentric insulin-secreting tissue is present in over 90% of patients. Second, 5% to 15% of the tumors are malignant. Third, endocrine and exocrine insufficiency is reduced significantly with distal compared to total pancreatectomy. Intraoperative monitoring of glucose is helpful in determining the degree of pancreatectomy. More than 90% of patients are cured by such operations. If hypoglycemia persists following operation, diazoxide may be used; if metastatic disease is present, streptozocin, dacarbazine, or somatostatin analogues may be effective in decreasing hypoglycemia [42].
A glucagon-secreting tumor without the necrolysis syndrome has been reported in a euglycemic woman, and hyperglucagonemia has been reported in five of six patients studied [14, 43]. Vasoactive intestinal polypeptide and other hormones have been found (see Table 9.1). Malignant behavior is rare. These tumors are resected when not controlled by medication.
Parathyroid Disease
Multigland, asymmetric, hyperplastic parathyroid disease is the most penetrant and generally earliest manifestation of MEN1; it affects 87% to 97% of patients and is detected in the second and third decades [19]. Ectopic gland locations such as thymus, thyroid, and paraesophageal are common, and supernumerary glands occur. MEN1 is rare among cases of hyperparathyroidism. The differential diagnosis includes familial hyperparathyroidism alone and benign familial hypocalciuric hypercalcemia. Although it is commonly asymptomatic, the usual symptoms or signs of hyperparathyroidism may occur including severe osteopenia in 40% [44]. Thus, bone mineral density measurements are necessary for the assessment and follow-up of patients.
Diagnosis
Diagnosis is established by finding high concentrations of serum calcium and PTH. Because of possible benign familial hypocalciuric hypercalcemia, calcium/creatinine clearance ratios should be calculated. There is general agreement
that multiple parathyroid glands are affected with a disease spectrum from hyperplasia of all glands through combinations of hyperplastic, adenomatous, and ectopically located disease. Parathyroid cancer occurs, but is rare [45]. Such multiplicity requires that all glands be identified at initial surgery; therefore, preoperative imaging studies are unnecessary and not cost-effective. We think that parathyroid operations in MEN1 patients should be done only by very experienced endocrine surgeons and that patients must understand before operation that, because of gland multifocality, recurrence is common, that reoperation is possible, and that hypoparathyroidism is possible.
that multiple parathyroid glands are affected with a disease spectrum from hyperplasia of all glands through combinations of hyperplastic, adenomatous, and ectopically located disease. Parathyroid cancer occurs, but is rare [45]. Such multiplicity requires that all glands be identified at initial surgery; therefore, preoperative imaging studies are unnecessary and not cost-effective. We think that parathyroid operations in MEN1 patients should be done only by very experienced endocrine surgeons and that patients must understand before operation that, because of gland multifocality, recurrence is common, that reoperation is possible, and that hypoparathyroidism is possible.
Treatment
Indications for and goals of operation are similar to those in sporadic disease but include additions to favor ease of second surgery for recurrent disease. In patients having simultaneous occurrence of both hyperparathyroidism and pancreatic tumors, the parathyroidectomy should occur first. This will avoid the risk of major hypercalcemia should immobilization occur following the pancreatic surgery, and, in those with gastrin-secreting tumors, a reduction in serum calcium may lower both gastrin and gastric acid secretion. Major surgical options are subtotal parathyroidectomy (>3.5 glands) with remnant gland marking or total parathyroidectomy with auto transplantation. Randomized trials of these different operations have not been done. Our general impression suggests that the former operation leads to greater rates of persistence or recurrence (8%-12%) and does not reduce the frequency of hypoparathyroidism. In subtotal parathyroidectomy with transcervical thymectomy, there is preservation of 30 to 50 mg of identified tissue. Total parathyroidectomy with autologous autotransplantation of tissue to an ectopic site appears to be gaining favor. It reduces early recurrence rates, but hyperfunctioning autotransplanted grafts do cause late recurrence and autograft failure leads to hypoparathyroidism in 1% to 2%. Hypoparathyroidism occurs with either operation; therefore, cryopreservation of parathyroid tissue is strongly advised [46, 47]. In selected cases, alcohol ablation of parathyroid tissue may be used to treat recurrence when additional glands are successfully localized. Difficult recurrent hypercalcemia, osteoporosis, or renal lithiasis may be treated with bisphosphonates. Faggiano et al. [48] reported treatment with depot somatostatin analogue octreotide normalized serum calcium in 75% of eight treated patients.
The author agrees with the suggestion by Ferolla et al. [49] that thymectomy be done during parathyroidectomy in MEN1 patients as ectopic glands are often in the thymus, and 8 of 180 MEN1 cases in the Italian registry had malignant thymic carcinoid tumors (with subsequent death or metastases in 50%).
Pituitary Disease
The prevalence of pituitary disease in MEN1 ranges from 18% (clinical findings) to 94% (autopsy results), and it is a presenting complaint in 4% of cases [12, 50, 51]. Tumor types are shown in Table 9.1. The pathologic spectrum ranges from hyperplasia through adenoma to carcinoma (rare). In early series, tumors were macroadenomas. Presently, they are smaller because of early screening. Prolactinsecreting tumors are most common—up to 60%—and often are resistant to dopaminergic agents. A prolactin-secreting macroadenoma has been reported in a 5-year-old child [14]. A rare phenotype, the Burin variant, manifests with prolactinoma and hyperparathyroidism [52]. The symptoms, signs, diagnosis, and treatment of the pituitary tumors are similar to those of sporadic disease. Longterm follow-up for the pituitary includes examination, annual measurement of prolactin and insulin-like growth factor, and a pituitary MRI beginning at age 20 and continuing every 2 years.
Associated Diseases
Carcinoid tumors occur in up to 23% of patients [53, 54, 55]. The natural history of such lesions in MEN1 is sparse. Most tumors do not hypersecrete, so symptoms are rare and late. CT and MRI are used for screening and follow-up. Gastric enterochromaffin-like cell carcinoids are common—found in 23% of patients and in a background of universal enterochrommafin-like (ECL) cell proliferative changes [55]. It is proposed that genetic changes in MEN1 patients make ECL cells more sensitive to the proliferative effect of gastrin. Because of the possibility of malignant change in these tumors and observation of local metastases, even though survival is often great, patients are advised to have regular surveillance gastroscopies and biopsy of the mucosal lesions with removal of the carcinoid tumors.
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