Overview
Multiple endocrine neoplasia syndrome (MEN) is an autosomal dominant hereditary tumor syndrome involving multiple endocrine organs. The clinical manifestations are diverse, with the simultaneous or sequential development of functional tumors in two or more endocrine glands, resulting in clinical syndromes of hormonal excess. The syndrome is divided into four types: MEN-1, MEN-2A, MEN-2B, and mixed MEN-1 and MEN-2.
MEN-1 type is characterized by multifocal endocrine tumors mainly involving parathyroid glands, endocrine pancreas, anterior pituitary, adrenal cortex, thymus and other endocrine tissues, of which adrenocortical diseases account for 20% to 40%, often with bilateral proliferative, nonfunctional lesions.
Etiology
The development of multiple endocrine gland tumor syndrome type I is associated with a mutation in a gene located on the long arm of chromosome 11 (11q13). This gene contains 10 exons and is a tumor-suppressor gene; MEN-I is autosomal dominant in the mode of inheritance, but recessive in the mechanism of tumorigenesis, requiring mutations in both alleles. The disease is mostly familial, but there are also sporadic cases of new mutations.
Symptoms
Symptoms and signs of MEN-I depend on the type of tumor involved in the patient. more than half of patients with MEN-I may have two endocrine adenomas, and 20% of patients have three or more endocrine gland tumors, with or without endocrine hyperfunction. Most clinical manifestations are due to lesions of the parathyroid glands (80%-98%), followed by: pancreas and duodenum (40%-85%), and anterior pituitary (9%-40%). Hyperthyroidism and adrenocortical adenomas with hyperfunction are much less common.
The parathyroid glands are the most predominantly affected glands in MEN-I, so hyperparathyroidism is a common symptom, but there are no clinical symptoms for a long time in the early stages. Due to parathyroid hyperplasia or adenoma, parathyroid hormone secretion is increased, resulting in bone metabolism disorders, bone pain, and pathological fractures. Increased blood calcium can cause muscle weakness, fatigue, constipation, nausea and vomiting, and even neuropsychiatric symptoms due to hypercalcemia. Increased urinary calcium excretion can cause urinary tract stones and renal impairment, manifested by renal colic, polyuria and polydipsia.
The second most affected gland in MEN-I is the pancreas. Islet cell tumors of different origins may secrete different kinds of hormones or bioactive substances. Islet cell tumors account for 30% to 75% of patients, and about 40% of these tumors are from beta cells, which secrete insulin and have fasting hypoglycemia. In about 60% of cases, pancreatic islet tumors are from non-β cells. ＜In patients <40 years of age, β-cell tumors are more common; in patients >40 years of age, non-β-cell tumors are common. Gastrin is the most common hormone secreted by non-β-cell tumors with refractory and compound peptic ulcers. ＞Peptic ulcers are present in >50% of MEN-I patients, most of whom have multiple ulcers with atypical sites and a correspondingly high incidence of bleeding, perforation, and obstruction. Very high gastric acid secretion accompanied by inactivation of pancreatic lipase in these patients leads to diarrhea and steatorrhea. Although previously known to occur in patients with MEN only from the pancreas, gastrinomas of the duodenal bulb have also been seen in recent reports. When Zo-E syndrome was initiated for further evaluation it was found that 20% to 60% of these proved to be MEN-I syndrome.
Non-β-cell tumors are accompanied by severe secretory diarrhea that causes fluid and electrolyte loss. This combination, known as watery diarrhea, hypokalemia, and gastric acid deficiency syndrome, has been attributed in some patients to the action of vasoactive intestinal peptide, although some other intestinal hormones or prokinetic hormones including prostaglandins may also be involved. Many patients with islet cell tumors have increased levels of pancreatic polypeptides, which could prove useful in the diagnosis of MEN-I syndrome, eventually, but the clinical manifestations that accompany excessive production of these hormones have not been clarified. Overproduction of glucagon, growth inhibitor, chromogranin, and calcitonin; ectopic ACTH secretion (producing Cushing’s syndrome); and GHRH overproduction (apparent acromegaly) are also seen in patients with non-beta-cell tumors.
Beta-cell and non-beta-cell tumors usually originate from multiple centers and are often seen as multiple adenomas or diffuse islet cell hyperplasia. About 30% of patients with islet cell tumors are malignant with local or distant metastases, but these tumors in MEN-I syndrome have a benign course compared to sporadic islet cell carcinomas. The incidence of malignancy appears to be higher in non-β-cell tumors.
Fifty to 60% of patients with MEN-I syndrome have pituitary tumors, of which about 25% secrete growth hormone or growth hormone and prolactin, and affected patients have acromegaly, which is clinically indistinguishable from the sporadic type. Reports indicate that 25% to 90% of tumors secrete prolactin and about 3% secrete ACTH, causing Cushing’s disease. Most of the rest are nonfunctional. Localized expansion of the tumor may cause visual impairment and headache as well as hypopituitarism.
Examination
1. Genetic screening by DNA restriction segment length polymorphism analysis;
2. Serum calcium, intact parathyroid hormone, gastrin and prolactin;
3. CT or MRI of the pituitary gland.
Diagnosis
MEN-1 is generally considered diagnostic if 2 of the 3 most common endocrine organ tumors (parathyroid, pancreatico-intestinal endocrine glands, and pituitary) are present. MEN-1 is diagnosed in a family if at least one of the first-degree relatives has at least one of these tumors. Testing for the MEN1 gene mutation is an option for those who have it. The diagnostic criteria are listed in the table below.
Diagnostic criteria for MEN-1
The diagnosis of MEN-1 is confirmed by the presence of 2 or more of the following signs and symptoms:
1. primary hyperparathyroidism with polyglandular hyperplasia and/or tumors, or recurrent hyperparathyroidism;
2. endocrine tumors of the duodenum and/or pancreas: functional (gastrinomas, insulinomas, hyperglycemic tumors) and non-functional or polysecretory tumors that have been confirmed by immunohistochemical methods, enterochromatoid tumors of the stomach;
3. anterior pituitary tumors, functional (growth hormone tumors or acromegaly, prolactinomas) and nonfunctional or polysecretory (growth hormone, lactotrophic hormone, luteinizing hormone-follicle-stimulating hormone, thyroid-stimulating hormone) lesions that have been confirmed by immunohistochemical methods;
4. adrenocortical tumors, functional and non-functional;
5. thymic and/or bronchial endocrine tumors (foregut carcinoid);
6. first-degree relatives (parents, siblings, or offspring) with MEN-1 according to the above criteria.
Treatment
For MEN-I, surgical resection of the tumor remains the first choice of treatment, removing the primary tumor and its metastatic foci as completely as possible, reducing the number of tumors, hormones and abnormally increased biologically active substances, resulting in symptomatic relief and improved quality of life. Radiation therapy and chemotherapy can be used adjunctively to improve the cure and improvement rate.
Patients with asymptomatic hypercalcemia generally do not require surgical removal of the parathyroid glands, but should be followed up and verified for symptoms and complications for prompt management. Once clinical symptoms appear, total parathyroidectomy and burial of one parathyroid gland in a slice in the forearm muscle is feasible, and the buried parathyroid gland can be removed in case of recurrence of hypercalcemia, followed by long-term administration of vitamin D. Functional pituitary tumors are, in order of priority, prolactinomas, growth hormone tumors, ACTH tumors, and there are still non-functional pituitary tumors, which can be given medications (sniffing cryptocryptin, otrasound skin), surgery and or radiotherapy. In the case of Zuo Yi Ai syndrome due to excess gastrin, H2 receptor blockers such as cimetidine and ranitidine, the proton pump inhibitor omeprazole or total gastrectomy may be given. Gastrinoma without metastasis should be resected, but in fact, when the diagnosis is clear, there are often most of the extra-pancreatic metastases, non-surgical resection, can be changed to chemotherapy, such as 5-fluorouracil, streptozotocin, octapeptide growth inhibitor, gamma interferon and so on. Surgery is recommended for insulinoma, and the drug diazocine may not be effective. Pancreatic hyperglucagon tumor often occurs in the tail of the pancreas, surgical resection is appropriate, and those who have metastases can use octreotide growth inhibitor, streptozotocin; similar treatment is applicable to VIP (vasoactive intestinal peptide) tumors, carcinoid tumors.