Parathyroid Management in the MEN Syndromes

Multiple Endocrine Neoplasia (Men) Type 1

MEN 1 is an autosomal dominant disease with a prevalence of 2 to 3 persons per 100,000 population; it is equally common among men and women. MEN 1 is clinically defined as the presence of any two of the three most common tumors in a single patient: parathyroid tumors (manifested as PHPT); pituitary tumors; and pancreatic neuroendocrine tumors (pNETs), most commonly gastrinoma, insulinoma, and nonfunctioning pNETs ( Figure 62.1 ). Other MEN 1-associated tumors include facial angiofibromas, lipomas, carcinoid tumors, thyroid neoplasms, nonfunctional adrenocortical adenomas, and rarely, pheochromocytomas. Familial MEN 1 is defined clinically as an index case of MEN 1 and at least one first-degree relative with tumors in one or more of these sites.

Genetic Testing in Men 1

MEN 1 is caused by a germline mutation in the MEN 1 gene, which is located at chromosome 11q13; it encodes the 610-amino acid protein referred to as menin . The menin protein has a role in DNA replication and repair, and it is involved in transcriptional regulation. MEN 1 gene mutations generally result in a truncated menin protein, and the mechanism of tumor formation appears to occur according to the two-hit hypotheses; the first genetic hit is inherited and is present in all cells. When the second copy of MEN 1 is mutated in any one cell, a neoplastic clonal expansion is initiated, which leads to the development and manifestation of MEN 1–related tumors.

More than 1300 mutations of the MEN 1 gene were identified within the first decade after the gene was identified, including 1133 germline and 201 somatic mutations; these mutations have been found in 70% to 90% of families with MEN 1. Despite this diversity in mutations of the menin gene, studies of patients with MEN 1 have supported the theory that the MEN 1 trait arises from the same chromosomal locus because > 90% of tumors exhibit loss of heterozygosity (LOH) on 11q13; therefore the tumors result from mutations in the menin gene. The heterogeneity of mutations has made mutational analysis in MEN 1 challenging. In addition, at least 10% of MEN 1 germline mutations arise de novo. From a clinical perspective, this heterogeneity has resulted in the lack of a population-level genotype-phenotype correlation (as opposed to MEN 2A). A specific MEN 1 mutation does not appear to be associated with the development and biologic behavior of tumors or the clinical features of disease, such as patient age or sites of tumor development. A review of the literature has demonstrated that, in general, different families with the same clinical manifestations have had diversity in mutations and, likewise, different families with different clinical manifestations have been found to have the same MEN 1 mutation. However, the specific mutation type and location may be associated with the expression of a relatively constant phenotype within an individual family kindred of MEN 1 patients.

Genetic testing allows affected patients with a known germline mutation to be followed prospectively, which facilitates earlier surgical intervention and potentially decreases morbidity and mortality. Furthermore, patients with a negative genetic test can be spared annual clinical testing and are assured that there is no risk of passing a mutation on to their children. The most recent guidelines for the management of patients with MEN 1 include the following recommendations for genetic counseling and MEN 1 germline mutational analysis: (1) an index case with ≥ 2 MEN 1-associated endocrinopathies (parathyroid, pancreas, or pituitary); (2) all first-degree relatives of a known MEN 1 mutation carrier; or (3) in patients with suspicious or atypical features which may be consistent with MEN 1. This latter category would include all patients < 30 years of age already diagnosed with PHPT, multigland PHPT, gastrinoma syndrome, multiple pNETs (at any age), or patients with ≥ 2 MEN 1-associated tumors that are not part of the classical triad of MEN 1-associated tumors (e.g., PHPT and adrenal tumor). The age threshold that should prompt genetic testing for patients with PHPT is not absolute; some experts have suggested genetic testing for patients with PHPT at < 40 years of age.

Periodic screening for MEN 1-associated endocrine tumors in MEN 1 carriers (known germline mutation) is likely to be beneficial because earlier diagnosis and appropriate timing of any necessary treatment may help reduce morbidity and mortality. Age-related penetrance for all features is near zero in patients younger than 5 years of age, greater than 50% by age 20, and above 95% by age 40. In the majority of patients with MEN 1, PHPT will be the first manifestation of the disorder; in approximately 15% of patients, hyperprolactinemia (sometimes asymptomatic) will present first. MEN 1 consensus guidelines currently recommend biochemical screening at least annually to include serum calcium and intact PTH levels beginning by age 8. Other biochemical evaluation would include prolactin, chromogranin A, IGF-1, and gastrointestinal hormones (e.g., gastrin, insulin with a fasting glucose, glucagon, VIP, and pancreatic polypeptide). In addition, imaging studies (i.e., magnetic resonance imaging (MRI) or computed tomography (CT) of the pancreas, adrenal glands, and pituitary) every 1 to 3 years are recommended.

Men 1–Associated Hyperparathyroidism

MEN 1-associated HPT accounts for 2% to 4% of all cases of PHPT. It is characterized by multigland disease (MGD) with the clonal, asymmetric enlargement of all parathyroid glands. The typical age of onset of MEN 1-associated PHPT is in the third or fourth decade and is often the first manifestation of MEN 1. Importantly, there is near complete penetrance (> 90%) of PHPT by age 50. MEN 1-associated HPT occurs approximately 30 years earlier than in patients with sporadic PHPT.

Symptoms in patients with MEN 1-associated PHPT are similar to those in patients with sporadic PHPT; they include the following: nephrolithiasis, decrease in bone mineral density, muscle weakness, aches and pains, and neurocognitive symptoms of fatigue, depression, mood changes, sleep impairment, and difficulty with memory and concentration. Patients with MEN 1-associated PHPT may have a long asymptomatic phase but often have more aggressive disease due to recurrent HPT. Even if asymptomatic, gene carriers have a detectable decrease in bone mass density by age 35. MEN 1 can cause simultaneous PHPT and Zollinger-Ellison syndrome (gastrinoma), and hypercalcemia increases the secretion of gastrin from gastrin-secreting tumors of the pancreas and duodenum.

Given the two-hit etiology of MEN 1-associated PHPT, parathyroid gland involvement is often asynchronous and asymmetric. Macroscopically-normal parathyroid glands have been reported in 12% to 55% of patients at the time of initial surgery, particularly in younger patients. It has been postulated that the prospect of having simultaneous second hits in each of the parathyroid glands is extremely low, but that the probability that the second hit would occur in a parathyroid gland increases with time. Therefore the likelihood of having a phenotypically normal-appearing parathyroid gland decreases with age. Supernumerary (more than four) and ectopic parathyroid glands have also been reported in up to 20% of affected patients; these glands may be found intrathymic, intrathyroidal, or in the anterior mediastinum. This may be related to the presence of parathyroid rests (embryonic parathyroid remnants) that are stimulated. Malignant progression of MEN 1-associated PHPT (parathyroid carcinoma) has not been reported.

Indications for Surgery

Indications for parathyroidectomy are no different in patients with MEN 1 than for those with sporadic PHPT. Parathyroidectomy is recommended for patients with symptomatic PHPT (nephrolithiasis, peptic ulcer disease, fragility fractures), particularly those with hypergastrinemia due to Zollinger-Ellison syndrome (even if asymptomatic) because successful surgery may markedly reduce gastrin secretion. Recent guidelines for the management of patients with asymptomatic PHPT recommend surgery for patients with (1) serum calcium levels 1 mg/dL (0.25 mmol/L) above reference range; (2) age < 50 years; (3) renal effects, including creatinine clearance < 60 mL/min, 24-hour urine calcium > 400 mg/day, increased stone risk by biochemical stone risk analysis, presence of nephrolithiasis or nephrocalcinosis on imaging studies; or, (4) skeletal effects, including bone mineral density by dual energy x-ray absorptiometry (DXA) consistent with a T score of > 2.5 at any site or a vertebral fracture on imaging studies. The American Association of Endocrine Surgeons (AAES) guidelines for the management of PHPT also recommend (strong recommendation, low-quality evidence) parathyroidectomy for patients with neurocognitive and/or neuropsychiatric symptoms thought to be attributable to PHPT.

For patients with MEN 1-associated PHPT, it is unclear if earlier surgical treatment reduces morbidity or mortality, particularly in those patients who are asymptomatic or minimally symptomatic. Early parathyroidectomy, especially in younger patients, would decrease the long-term effects of PHPT, particularly with reference to skeletal effects. Bone mineral density evaluation should therefore play an important role in the planning and timing of surgery. Earlier intervention may also improve the symptoms of other concomitant endocrinopathies, such as hypergastrinemia. However, postponing surgery may facilitate the initial procedure by increasing the likelihood of finding all parathyroid glands as they may be larger and easier to locate, including the presence of supernumerary/ectopic glands. Delayed intervention may also decrease the likelihood of persistent/recurrent disease and the need for a future reoperative parathyroidectomy.

The use of preoperative localization studies (e.g., technetium-99m sestamibi with single photon emission computed tomography cervical ultrasonography, or CT [Tc99m MIBI-SPECT/CT]) before initial parathyroidectomy solely for localization of abnormal parathyroid gland(s) in patients with MEN 1-associated PHPT remains debated when considering the high likelihood of multigland hyperplasia and the need for bilateral exploration and intraoperative identification of all parathyroid glands. However, imaging studies may be helpful in the identification/localization of ectopic or supernumerary glands. Therefore some investigators (including the authors) prefer to use localization studies to prevent a missed ectopic gland from being the cause of a failed operation. In addition, recent studies have advocated for unilateral clearance in select patients with preoperative imaging suggestive of single gland disease. There may also be a role for cervical ultrasonography in all patients; recent guidelines recommend evaluation for any concurrent thyroid pathology that may necessitate thyroidectomy.

Surgical Treatment of Men 1–Associated Hpt

The early and late outcomes of surgical treatment of MEN 1-associated PHPT are inferior to those for sporadic PHPT, because of the development of hyperplasia in parathyroid glands that appeared macroscopically normal at initial surgery (and were left in situ) or in hyperplastic remnants, which over time hypertrophy. The goals of initial surgery are to (1) successfully correct hypercalcemia while minimizing the risk of persistent or recurrent PHPT, (2) avoid permanent hypoparathyroidism, and (3) facilitate the anticipated future surgical treatment of recurrent PHPT. Reasonable options for the initial operation in patients with MEN 1-associated PHPT are subtotal parathyroidectomy (with consideration of transcervical thymectomy) or total parathyroidectomy with heterotopic autotransplantation of resected parathyroid tissue ( Table 62.1 ). More recently, unilateral clearance of both ipsilateral parathyroid glands and thymectomy has been described for young patients with localized disease on preoperative imaging. Resection of only macroscopically enlarged glands has been shown to be associated with significantly higher rates of persistent/recurrent disease.