The tumors which comprise the MEN syndromes arise from APUD neuroendocrine cells. Each of the syndromes is inherited as an autosomal dominant trait. Advances in molecular biology and genetics have led to the identification of specific genetic defects which will improve the understanding and ability to diagnose these tumors. There are three distinct MEN syndromes as well non-MEN familial medullary thyroid carcinoma.
MEN-1 syndrome is quite rare. It has an incidence of 0.25% determined from postmortem studies, and an estimated prevalence of between 0.02 and 0.2 per thousand [1-3]. It is inherited in an autosomal dominant pattern, with a high degree of penetrance. MEN-1 is characterized by hyperplasia and/or neoplasm of the parathyroid glands, pancreatic islets, and pituitary glands. Hyperparathyroidism occurs in about 90% of patients, endocrine pancreatic tumors in 60% of patients, and pituitary adenomas in 40% of patients[2, 4, 5]. Hyperparathyroidism is usually the first manifestation of the syndrome. However, the presence of hyperparathyroidism may not be detected until clinical disease of the pancreas or pituitary has brought the patient to medical attention. The presence of hyperparathyroidism may also be detected when screening immediate family members of those with proven MEN-1. Cutaneous lesions, especially angiofibromas and collagenomas are quite common in MEN-1 patients, occurring in more than 60%, and these lesions are usually multiple [6].
MEN-1 patients with hyperparathyroidism typically have multiple gland nodular hyperplasia. The disease usually takes a slow but progressive course. The individual gland involvement is often variable and asymmetric, resulting in enlargement of only one or two glands. Hyperparathyroidism is commonly diagnosed during the second decade of life.
The most frequent islet cell neoplasm in patients with MEN-1 is gastrinoma. This was usually identified during the third or fourth decade of life. However, with the advent of biochemical screening, it is now typically detected earlier [7-9]. Approximately one third of patients with gastrinomas are associated with MEN-1[10-13]. However, fewer than 5% of insulinomas are found in MEN-1 patients[14]. Gastrinomas in MEN-1 syndrome are usually small, multiple adenomas in the pancreas or duodenum[15]. The malignant potential of MEN-1 associated gastrinomas is probably less than sporadic tumors. Other tumor types identified in MEN-1 patients include vipomas, glucagonomas, somatostatinomas, and PPomas[16]. More than one clinical syndrome may develop in the same patient either synchronously, or more often metachronously. Some patients may have lymph node or liver metastases with no clinical manifestations.
It has become apparent that gastrinomas in MEN-1 patients are often located in the duodenum. These tumors are small, usually multiple, and may be associated with pancreatic gastrinomas as well[15, 17]. Immunohistochemical studies of the pancreas from MEN-1 patients demonstrate that most tumors that stain positively for gastrin are in the duodenum, or in the head or uncinate process of the pancreas[13]. It has been shown that proliferative gastrin cell changes and the duodenal mucosa precede the development of duodenal gastrinoma, in MEN-1, but not sporadic duodenal gastrinomas[18]. Patients with clinical syndromes usually have discrete tumors rather than diffuse islet cell disease as the cause of the syndrome[19, 20]. Even though diffuse islet cell dysplasia is found in most patients, these cells do not stain for either gastrin or insulin. At least 50% of patients with elevated serum gastrin have metastases already[8].
Pituitary tumors are common in patients with MEN-1, and may be micro or macro adenomas[1, 2]. The tumors are generally functionally active and often secrete prolactin[21]. Less commonly, the pituitary tumors may secrete ACTH leading to Cushing's syndrome, or growth hormone leading to acromegaly. It is especially important to establish that Cushing's syndrome in the MEN-1 patient is pituitary dependent (i.e., Cushing disease) rather than pituitary independent caused by an adrenal adenoma, an islet cell tumor, or a bronchial carcinoid tumor secreting ACTH or corticotrophin-releasing factor.
There is an increased frequency of adrenal lesions in patients with MEN-1 syndrome[14, 22-24]. The patients may have functional or non-functional adrenal cortical hyperplasia or adenomas. There is some evidence to suggest that the frequency of adrenal cortical carcinoma is increased in MEN-1 patients.
Carcinoid tumors also occur more frequently in MEN-1 patients[25]. Although they have been reported in a variety of locations, bronchial carcinoids occur more commonly in women, and thymic carcinoids occur more commonly in men. Patients with MEN-1 and gastrinoma who are on long term H2 blockers or proton pump inhibitors may develop gastric carcinoids[26].
The MEN-1 gene locus was first mapped to the long arm of chromosome 11 (11q13), by Larsson et al[27]. The gene is a tumor suppressor gene and has recently been identified and cloned[28, 29]. The gene contains 10 exons and spans 10kb of genomic DNA. More than 300 different MEN-1 germ line mutations have been identified thus far[30]. The mutations are spread over the entire genome without significant clustering. There are no true "hot spots". Up to 20% of mutations involve intron sequences, thus these regions must be searched for germ line mutations[31]. About 70% of the mutations are non-sense and frame shift mutations, resulting in truncation of the protein product. Despite detailed study, no correlation between the genetic mutation and the phenotypic expression has been identified[32]. However, the likelihood of finding a mutation appears to correlate with the number of MEN-1 associated tumors, and the presence of a family history[33]. About 20% of MEN-1 kindreds lack an identified mutation in the MEN-1 gene.
Endocrine tumors from MEN-1 patients have loss of heterozygosity (LOH). The allelic loss is always from the normal chromosome belonging to the unaffected parent, analogous to the second hit in retinoblastoma. A mouse model of MEN-1 has been generated through homologous recombination[34]. Tumors in these mice show loss of the wild-type MEN-1 allele, as would be expected in a tumor suppressor gene.
The gene product has recently been identified and is a 610 amino acid protein called menin[27, 29]. Menin is a nuclear protein, the function of which is unknown. It has no homology to known proteins. There are different patterns of expression in pancreatic exocrine and islet cells[35]. Menin interacts with the transcription factor Jun-D[36], suggesting a potential role in transcriptional regulation. Menin has been shown to bind directly to double stranded DNA, with regulatory effects on cell proliferation[37]. Menin interacts with activator S-phase kinase (ASK) with regulatory effects on cell proliferation[38]. It appears that regulation of cyclin-dependant kinase inhibitor transcription by cooperative interaction between menin and mixed lineage leukemia (MLL) proteins plays a major role in menin-related tumor suppression[39]. Menin has been shown to interact with numerous proteins including JunD, and nuclear factor - KappaB, Smad3, Pem, Nm23H1, glial fibrillary acidic protein, vimentin, and probably p53 [40]. Thus, the effects of menin on transcriptional regulation and cellular proliferation appear to be complex due to its effects on multiple pathways.
Deletions of chromosome 11q13 have also been found in a significant portion of sporadic adenomas of the parathyroid gland, pancreas, and pituitary gland. For example, mutations of the MEN-1 gene have been identified in 31% of sporadic gastrinomas. However, the mutations are clustered between amino acids 66-166, unlike MEN-1, where mutations are scattered through the gene[41]. MEN-1 mutations are identified less often in sporadic insulinoma, 17% in one series[42]. Mutations in the MEN-1 gene are believed to be an early event, since mutations have been identified in both benign and malignant pancreatic endocrine tumors[43]. Thus, the MEN-1 gene appears to play an important role in both sporadic and familial endocrine tumorigenesis. A variety of other chromosomes and genetic changes may also be involved, such as PRAD1 in parathyroid adenoma, and Gs L-chain gene in pituitary adenoma.
The clinical features of MEN-1 are dependent on the individual tumors which are present in the patient and their functionality. Overall, patients with familial MEN-1 neoplasms have a better survival than patients with sporadic neoplasms[4, 5]. In patients without a family history, the diagnosis of MEN-1 requires a high level of clinical suspicion. Patients presenting with hyperparathyroidism or hypergastrinemia should be carefully questioned regarding a family history[44]. If after careful questioning MEN-1 syndrome is suspected, then biochemical screening should be performed. A biochemical screening program which gives the highest yield includes measurements of intact PTH, serum calcium, prolactin, somatomedin C, glucose, insulin, pro-insulin, gastrin, pancreatic polypeptide, glucagon, and ingestion of a test meal followed by measurement of pancreatic polypeptide and gastrin. If biochemical testing indicates the presence of MEN-1, this can be confirmed by genetic testing for mutations in the MEN-1 gene.
Once MEN-1 is diagnosed in the proband, genetic counseling and genetic testing should be considered in all family members. Those family members who carry the mutated MEN-1 gene should undergo yearly biochemical screening from childhood and continued for life. Indeed, genetically positive patients have biochemical evidence of neoplasia on average of 10 years prior to clinically evident disease[45]. Early detection and early treatment of endocrine abnormalities should reduce morbidity and mortality from this disease. Peptic ulcer disease, renal complications, and malignant tumors are the common causes of morbidity and mortality in MEN-1 patients[46].
The diagnostic and therapeutic approach to MEN-1 patients is determined by the presence of a clinical syndrome or a clearly elevated hormonal level. The diagnosis is similar to patients with sporadic tumors. For example, hyperparathyroidism is diagnosed by the presence of hypercalcemia associated with elevated or non-suppressible intact PTH levels. Diagnosis of gastrinoma is confirmed by measurements of serum gastrin, the secretin stimulation test, and measurements of basal and stimulated gastric acid output. Insulinoma is diagnosed by the detection of increased insulin or pro-insulin levels with associated hypoglycemia. Pituitary adenomas usually have elevated serum prolactin or somatomedin C.
The localization procedures for patients with MEN-1 associated endocrine tumors are similar to patients with the sporadic counterparts. There are some problems unique to patients with MEN-1. For instance, the pancreatic endocrine tumors in MEN-1 patients are particularly challenging due to their small size, frequent duodenal location, and multiplicity. The main role of imaging in these patients may be to identify those with liver metastases[47]. However, some groups have had good results using endoscopic ultrasound for identifying pancreatic endocrine tumors in patients with MEN-1, even when tumors are small[48, 49]. Although somatostatin receptor scintigraphy may identify occult lesions, the false positive and false negative rates are considerable[50]. Thus, no one imaging modality is consistently useful, and frequently multiple imaging methods are required.
In general, the management of patients with MEN-1 syndrome is the same as for each sporadic tumor comprising the syndrome. Thus, the surgical treatment is dependent on the phenotypic expression in the individual patient. MEN-1 patients must be followed for life for involvement of the parathyroid glands, endocrine pancreas, the pituitary gland, the adrenal glands, the thymus, and for bronchial carcinoids. Because the various components may present sequentially, surgical procedures involving different endocrine organs may be required over a period of many years.
The hyperparathyroidism and resulting hypercalcemia in MEN-1 patients is usually mild and only slowly progressive. Patients with gastrinoma and hyperparathyroidism may require more urgent parathyroidectomy since hypercalcemia increases gastrin secretion and worsens peptic ulcer disease. Patients with MEN-1 and hyperparathyroidism have hyperplasia. Although some patients at the time of diagnosis may have normal sized glands in addition to grossly enlarged glands, the normal sized glands will enlarge given time[51]. Sestamibi scans are not useful in MEN-1 patients prior to initial operation, however they may sometimes be useful in reoperative cases[52]. Because supernumerary glands are identified in as many as 6-20% of MEN-1 patients, cervical thymectomy is an essential component of the neck exploration in these patients[53]. Controversy persists regarding the use of subtotal versus total parathyroidectomy in MEN-I patients. A small study of 16 patients suggests that intraoperative PTH measurements may be useful in these patients[54]. Subtotal parathyroidectomy, leaving only a small remnant of one gland in place, is associated with significant long term recurrence rates, as high as 60% in some series. However, several groups have achieved good results with subtotal parathyroidectomy[55, 56], with much lower recurrence rates (11% at a mean interval of 77 months)[55]. Total parathyroidectomy with forearm auto transplantation is associated with lower recurrence rates[57, 58]. If the disease should recur, it is a simple matter to remove a portion of the transplanted tissue under local anesthesia. Disadvantages are that patients will require vitamin D and oral calcium for at least 3 months or longer, until the transplant functions. In addition, some patients are rendered permanently hypoparathyroid, unless subsequent transplant of cryopreserved parathyroid tissue is successful. The risk of hypoparathyroidism is up to 36%[59]. Thus, the risk of permanent hypoparathyroidism with total parathyroidectomy and auto transplantation needs to be balanced against the risk of recurrent hyperparathyroidism with subtotal parathyroidectomy. Although there are good arguments on both sides, at this time the balance appears to be leaning more towards subtotal parathyroidectomy as the preferred approach.
The surgical management of MEN-1 patients with pancreatic disease remains controversial[19, 20, 60]. Nearly all MEN-1 patients with pancreatic disease have diffuse islet cell dysplasia, such as nesidioblastosis, islet cell hyperplasia, microadenomatosis, and/or discrete islet cell tumors. Thus, a cure can only be achieved in a minority of patients. Fortunately, most patients can be successfully managed medically. Thus, there is little need or justification for total pancreatectomy in these patients. However, a selective surgical approach may be justified. It must be remembered that the majority of duodenal gastrinomas are malignant, and that eventually metastases to lymph nodes and/or liver develop in many or most of these patients[61, 62].
There is no universal agreement as to the indications for surgery for pancreatic disease in MEN-I patients[63]. Many believe that patients suspected of having duodenal gastrinomas should be explored, because of the high risk of malignancy. Patients with larger lesions of the pancreas, particularly those more than 3cm in size, also have a greater risk of malignancy and liver metastases. This was confirmed in a French multi-center trial involving 71 patients. However, resecting the lesions did not prevent subsequent liver metastases[64]. Another recent study in 48 patients showed no correlation between pancreatic tumor size and metastases in MEN-1 patients[65]. Patients in whom a discrete anatomic abnormality is identified, which is functionally active, can also be considered for exploration. The importance of aggressive preoperative localization studies in MEN-1 patients considered for exploration cannot be over emphasized. Other factors which need to be considered are the patient's age, overall medical condition, and the difficulty in managing the patient medically.
Some groups have recommended an aggressive approach in selected MEN-1 patients with hypergastrinemia[19, 20, 66]. This approach includes distal pancreatectomy, usually preserving the spleen. Tumors identified in the head of the pancreas or uncinate process by palpation or intraoperative ultrasound are enucleated. A longitudinal duodenotomy is made to allow for careful palpation and removal of submucosal duodenal tumors. These tumors may be as small as 1-2 mm. Any enlarged peripancreatic lymph nodes are removed. A peripancreatic lymph node dissection is performed in patients with duodenal tumors or pancreatic tumors greater than 3cm in diameter[43]. Initially, most patients can be rendered eugastrinemic with this approach. Patients with two or more lesions, or with large lesions, who underwent a thorough exploration, aggressive resection, and lymph node dissection, appear to have survival comparable to those without identified tumor or those with more limited disease[67]. Long term, many or most such patients do recur. Other groups favor a more conservative approach, believing that most MEN-1 gastrinomas patients are not curable. Patients with unresectable disease, metastatic disease, or recurrent disease can in many instances be successfully managed medically, with histamine II receptor blockers or proton pump inhibitors[68].
Unlike patients with sporadic insulinoma, MEN-1 patients with hyperinsulinism usually have multiple tumors. However, if these tumors can be identified and removed, the syndrome is cured, and recurrences are rare.
Most patients with MEN-1 associated pituitary disease have a prolactinoma. Patients with prolactinoma should initially be treated with bromocriptine or other dopamine analogs. Both the prolactin level and tumor size will decrease in many patients. However, the response rate appears to be lower in MEN-1 patients (42%), compared to non-MEN-1 patients (90%)[69]. Transsphenoidal hypophysectomy is reserved for prolactinoma patients who fail to respond to medical therapy. Surgery is the treatment of choice for growth hormone-secreting pituitary adenomas. An alternative is octreotide, which reduces tumor size and circulating growth hormone and somatomedin C levels in a significant number of patients[70]. Patients with Cushing's disease are best treated with transsphenoidal hypophysectomy. Radiation therapy can be used as an alternative to surgery, or in patients who have failed other modalities. The use of modern stereotaxic radiosurgery can minimize the problem of hypopituitarism, often seen after conventional radiation therapy[21].
Periodic chest CT scans should be used in the follow-up of MEN-1 patients, to help detect the development of thymic carcinoids. Thymic carcinoids develop in from 3.1 to 8 percent of MEN-1 patients, occur in males, have very aggressive behavior, and are often lethal [71, 72]. Bronchial carcinoids occur in about 5% of MEN-1 patients, occur primarily in females, and appear to have a much more benign clinical course[73]. Gastric carcinoids can occur in 15-50% of MEN-1 gastrinoma patients, and traditionally have been felt to be benign. However, patients with longstanding MEN-1 gastrinomas may develop gastric carcinoids with aggressive behavior, including metastases to the liver[74]. Surgical resection should be considered for carcinoid tumors when they are identified. Serial measurements of chromogranin A levels may be useful for following those patients with pancreatic endocrine tumors[75].
The prognosis of MEN-1 patients is generally good. In a large series of gastrinoma patients, patients with MEN-1 had a 15 year survival of 93%, compared to 68% in sporadic patients[76]. However, one cannot take a cavalier attitude towards this disorder. Studies have clearly shown that MEN-1 patients have an increased risk of premature death, often related to metastatic islet cell tumor[77, 78].