Multiple Endocrine Neoplasia

When talking of multiple endocrine neoplasia type 1 (MEN 1), a proper definition is difficult to establish because the syndrome can result from up to 20 different combinations of endocrine and nonendocrine tumors.1'2 No definition could cover all registered cases or families. Thus, a patient with MEN 1, or Wermer's syndrome, is one who presents with alterations of hypersecretion or hyperplasia, or both, from two of the three main MEN 1-related endocrine tumors—that is, parathyroid adenomas, enteropancreatic endocrine tumors, and pituitary tumors. These alterations may or may not occur simultaneously. Familial MEN 1 is defined as a case of MEN 1 plus at least one first-degree relative with one of the three aforementioned tumors.

The MEN 1 gene location was first described in 1997.3"6 It is located at chromosome 1 lql3 and consists of 10 exons with an 1830-bp coding region that encodes a novel 610-amino acid nuclear protein named menin.7 Genetic linkage and germline mutation studies have established that familial MEN 1 always arises from the same locus at chromosome llql3 and always from the same gene.3-4'8"10 MEN 1 mutations are diverse and have been predicted to change the amino acid chain in menin. These mutations render menin absent or truncated, the so-called first hit. This condition is inherited as an autosomal dominant trait and predisposes the individual to neoplasias of certain tissues. A combination of the first hit with a somatic or postnatal loss of the other copy of MEN 1 in one cell (the second hit) initiates neoplastic clonal expansion. The final result is inactivation of the tumor suppressor MEN 1 gene and tumor growth, hyperplasia, or hypersecretion of the referred glands.1114

The fact that an inherited alteration is the origin of the MEN syndromes explains the aggressive nature of hyperparathyroidism (HPT) in these patients. A different approach in the diagnosis and special considerations before, during, and after surgery are warranted.

Clinical Aspects

Although the occurrence of MEN syndromes in the population is rare (1 in 5000 to 50,000 births),2 primary hyperparathyroidism (PHPT) is by far the most common endocrinopa-thy in MEN 1, reaching almost 100% penetrance by age 50 years.15"17 Patients present with HPT as the primary form of expression of MEN 1. However, symptoms arise at age 20 to 25, 30 years earlier than their sporadic counterparts. Patients usually complain of weakness, fatigue, constipation, or bone pain. Hypercalcemia per se increases secretion of gastrin from gastrinomas, and it is not unusual for patients to present with signs and symptoms of HPT associated with those of acid hypersecretion from Zollinger-Ellison syndrome.18 Less frequently, patients can present with urolithiasis, psychiatric alterations, renal insufficiency, or cardiovascular disease. Mild symptoms of HPT may be masked by those of other endocrine disorders such as gastrinoma, insulinoma, or acromegaly.16


In evaluating patients with PHPT, MEN syndromes should always be considered. An adequate account of the signs and symptoms and family history of endocrine disease should be noted. Upon interview, symptoms of parathyroid disease may be present in 90% to 100% of patients, of endocrine pancreas 80%, pituitary 65%, adrenal cortex 36%, and thyroid 24%. Manifestations of the MEN syndromes may develop at different times, and not all patients present initially with the complete syndrome.16'19

Thus, PHPT is diagnosed pretty much in a straightforward manner as in other cases of HPT. Serum calcium elevation with marked hypersecretion of parathyroid hormone (PTH) is the rule. Mild hypercalciuria and an elevated chloride-to-phosphate ratio can also occur.

Four-gland disease is generally present in these patients. This is the reason why preoperative imaging studies play little part in the diagnostic algorithm for patients with PHPT and MEN 1. Although ultrasonography, 99mTc sestamibi scanning, and magnetic resonance imaging have proven sensitivity, they provide limited information and are not really cost-effective.

The usefulness of the "quick" PTH assay has been demonstrated in surgery for sporadic cases of PHPT. The sensitivity and specificity of the study are high and, although expensive, the study has been proved cost-effective. Most studies have been done in patients with adenomas; however, one report has addressed the use of the assay in patients with MEN 1 undergoing total parathyroidectomy. PTH levels decreased in a stepwise fashion but had good predictive value related to the extent of surgical treatment and postoperative normocalcemia.20

High-frequency ultrasonography and nuclear mapping can help identify ectopic or supernumerary tissue in patients with hyperplasia. To our knowledge, these studies remain to be used in patients with MEN l.21


PHTP in MEN 1 patients poses a clear challenge because of the nature of the disease and high rate of recurrence. This should be explained to the patient and the family before the intervention. Notes of the procedure must describe the technique in detail, and remaining tissue must be marked in case reoperation should become necessary.

Treatment should be directed not to a tumor but to all the abnormal or potentially abnormal glands. Therefore, efforts should be directed to identify all four glands. Supernumerary glands are not uncommon, occurring in approximately 15% of the population. One should look for ectopic tissue, especially in the thymus and perithymic fat. As with other forms of HPT, there is no method that best describes how to differentiate an adenoma from hyperplasia. Hyperplasic glands can vary in size, and this asymmetry may cause the surgeon to mistake an enlarged gland for an adenoma. As a consensus, two enlarged glands are considered as hyperplasia.16 Failure to identify all parathyroid tissue results in persistent or recurrent hypercalcemia.

Parathyroidectomy was usually recommended before treating gastrinoma because of the effects of hypercalcemia on acid secretion.22 However, proton pump inhibitors have demonstrated efficacy equal to that of parathyroidectomy, and this has ceased to be considered an indication for surgery.18

Because complete exploration and identification of the four glands are required during surgery, minimally invasive surgery has no role in the treatment of these patients. Complete neck exploration is not feasible using this technique.

Controversy exists about the extension of parathyroidectomy. An aggressive treatment has been proposed as an option because of the high rate of recurrence or persistent hypercalcemia in these patients.23 The fact that cure rates after re-exploration in patients with persistent or recurrent hypercalcemia were lower than those of patients undergoing primary operation is another argument in favor of total resection. Morbidity associated with a second cervical exploration with scarred tissue in case of postoperative hypercalcemia is avoided by removing grafted tissue from the forearm.

After total parathyroidectomy and autotransplantation, 5.6% of patients develop permanent hypoparathyroidism and 30% develop hypercalcemia postoperatively.24 We consider this rate of hypoparathyroidism too high. Autotransplantation does not prevent postoperative hypoparathyroidism, and the most frequent cause of recurrence or persistence of HPT is not overgrowth of hyperplasic grafts but failure to identify and resect one or more supernumerary glands in the neck or mediastinum. Because of this, we advocate subtotal parathyroidectomy with bilateral thymectomy and cryo-preservation. In case hypoparathyroidism develops, transplantation can be accomplished in the forearm with local anesthesia as an outpatient procedure.25 29

Occasionally, a single parathyroid tumor may be encountered during surgery.16'30,31 If this is the case, all glands must be identified and marked and biopsy specimens sent for frozen section evaluation. We recommend removal of the affected and the normal-appearing ipsilateral gland. Inspection of ectopic or supernumerary glands along with thymectomy without damaging the circulation of the normal contralateral glands is recommended. With this procedure, recurrent hypercalcemia and postoperative hypoparathyroidism are avoided in most cases.

It is estimated that 20% to 100% of patients with PHPT and MEN 1 have recurrences 8 to 12 years after operation.28-32'35 Patients operated at an early age are the group with the highest risk of recurrence. This is why the term "cure" is not appropriate in these patients. The first step is to reconfirm the diagnosis. If recurrence is indeed the case, imaging studies are in order. A combination of ultrasonography, 99mTc sestamibi scanning, and/or magnetic resonance imaging is indicated. A diagnostic accuracy of up to 87% is achieved with this combination.33,36,37 Selective venous sampling can be added if the former studies are negative or nonconfirmatory. The latter study improves accuracy by 95%.35,38 This algorithm helps the surgeon to plan the procedure and reduces the complication rate associated with a reintervention. Previous operative notes and pathology reports should be reviewed. Resecting the tissue identified by localization studies is the primary objective. For lesions located in the anterior mediastinum, a cervical approach may be indicated. Thoracoscopy may help avoid a sternotomy in selected cases. Autotransplantation should be performed in the same operation if subtotal parathyroidectomy was the initial procedure, and cryopreser-vation of fresh tissue is recommended.

In the past, medical treatment had no part in the treatment of patients with PHPT and MEN l.39 Calcimimetics, which decrease PTH release directly acting on the calcium-sensing receptor, may also decrease parathyroid growth. Trials are under way to evaluate their role as primary treatment or alternative therapy for recurrent cases of PHPT.

Follow-up and Screening

Long-term follow-up in these patients is warranted to detect recurrences early as well as the development of other endocrine tumors. Annual measurements of calcium and PTH levels should be scheduled, with determinations of the appropriate hormones or markers to detect other pathologies.11

Most laboratories use direct DNA sequencing strategies for screening kindreds of patients with MEN syndromes.

Indications and methods have been described and are beyond the scope of this chapter.40 The process is complicated because family members are tested for a disease for which they are asymptomatic. Psychological syndromes that arise from being identified as carriers or noncarriers during the screening process have also been described.41,42 A multispe-cialty approach is recommended. Whether a positive screening test for MEN 1 could eventually indicate a prophylactic procedure remains to be discussed.43

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