Multiple endocrine neoplasia
1. What are the multiple endocrine neoplasia (MEN) syndromes?
There are three well-characterized, inherited pluriglandular disorders in which several endocrine glands simultaneously undergo neoplastic transformation and become hyperfunctional. All these disorders are genetically transmitted in an autosomal dominant fashion. These disorders are MEN-1, MEN-2A, and MEN-2B.
MEN-1 consists of hyperplasia or neoplastic transformation of the parathyroid glands, pancreatic islets, and pituitary.
MEN-2A consists of hyperplasia or neoplastic transformation of the thyroid parafollicular cells (medullary thyroid carcinoma [MTC]), parathyroid glands, and adrenal medulla (pheochromocytoma).
MEN-2B consists of hyperplasia or neoplastic transformation of the thyroid parafollicular cells (MTC) and adrenal medulla (pheochromocytoma) with concomitant development of mucosal neuromas.
5. How can so many various endocrine organs be affected in these syndromes?
The cells that comprise many endocrine organs are able to decarboxylate various amino acids and convert the molecules to amines or peptides that act as hormones or neurotransmitters. These cells have been classified as amine precursor uptake and decarboxylation (APUD) cells and are considered to be embryologically of neuroectodermal origin. APUD cells contain markers of their common neuroendocrine origin, including neuron-specific enolase and chromogranin A. Neoplastic transformation of APUD cells long after organogenesis is complete appears to result from a germline mutation (loss of a tumor suppressor gene in MEN-1 or mutation of a protooncogene to an oncogene in MEN-2A and MEN-2B) in a gene that is expressed only in neuroectodermal cells. When neuroectodermal cells later migrate to specific developing organs, the genetic mutation similarly is distributed to those organs. This explains the common mutations manifested in this class of neuroendocrine tumors (NETs).
This is the eponym for the MEN-1 syndrome. Wermer first recognized the association of parathyroid hyperplasia, multicentric pituitary tumors, and pancreatic islet-cell tumors in several kindreds and described the syndrome in 1954. Although neoplastic transformation occurs most commonly in the parathyroid glands, pituitary, and pancreas, hyperplastic adrenal cortical and nodular thyroid disorders have been described. Carcinoid tumors, especially involving the foregut (thymus, lung, stomach, and duodenum), are uncommon but also have been reported in MEN-1 syndrome.
7. How common is Wermer syndrome?
Wermer syndrome is the most common form of MEN. Its prevalence is estimated to vary between 2 and 20 per 100,000 population. The syndrome is characterized by a high degree of penetrance; expression increases with age.
8. Is hyperparathyroidism in MEN-1 similar to sporadic primary hyperparathyroidism?
No. Hyperparathyroidism associated with MEN-1 results from hyperplasia of all four glands, whereas sporadic primary hyperparathyroidism is usually characterized by adenomatous change in a single gland. Hyperparathyroidism is the most common and earliest manifestation of MEN-1, and it occurs in 80% to 95% of cases. It has been described in patients as young as 17 years and develops in nearly all patients with MEN-1 by age 40 years.
9. What causes the hyperplasia of parathyroid glands affected by MEN-1?
Hyperplasia of parathyroid glands affected by MEN-1 results from expansion of multiple cell clones, whereas sporadic parathyroid adenomas result from activation of a single cell clone. A mitogenic factor, similar to basic fibroblast growth factor (bFGF), has been found in MEN-1. The factor may originate from the pituitary and specifically stimulate angiogenesis of parathyroid cells. Complications of MEN-1 hyperparathyroidism are similar to those of sporadic hyperparathyroidism; they include nephrolithiasis, osteoporosis, mental status changes, and muscular weakness.
10. Summarize the therapy for hyperplastic parathyroid glands.
Therapy of both sporadic adenomas and MEN-1–associated hyperplastic glands depends on surgical resection. In sporadic primary hyperparathyroidism, removal of the solitary adenoma is curative in 95% of cases. In MEN-1–associated hyperplasia, at least 3.5 hyperplastic glands must be resected to restore normocalcemia. Only 75% of patients are normocalcemic postoperatively; 10% to 25% of patients are rendered hypoparathyroid. Unfortunately, the parathyroid remnants in the patient with MEN-1 have a great propensity to regenerate; 50% of patients become hypercalcemic again within 10 years of surgery. This recurrence rate dictates that surgery be delayed until complications of hypercalcemia are imminent or gastrin levels are elevated, as discussed later. Recurrence may be treated surgically or with cinacalcet, which acts at the calcium-sensing receptor, to reduce parathyroid hormone (PTH) secretion.
11. How common is neoplastic transformation of pancreatic islet cells in MEN-1?
Neoplastic transformation of the pancreatic islet cells is the second most common manifestation of MEN-1, and it occurs in approximately 66% to 80% of cases. These pancreatic NETs are commonly referred to as PNETs.
12. What types of pancreatic tumors are found in MEN-1 syndrome?
PNETs in MEN-1 syndrome are usually multicentric and are often capable of elaborating several peptides and biogenic amines. They are, by convention, classified on the basis of the clinical syndrome produced by the predominant secretory product. This group of tumors characteristically progresses from hyperplasia to malignancy with metastases, thus making curative resection unlikely. PNETs may arise from normal islet cells (eutopic) or cells that are not normal constituents of the adult pancreas (ectopic).
13. What is the most common type of functional pancreatic tumor in MEN-1?
Gastrinomas are the most common functional PNETs in MEN-1 syndrome (47%–78% of cases). They are ectopic tumors; G cells are normally present in the fetal pancreas only. Gastrinomas also may occur independently of MEN-1 (only 15%–48% of all patients with a gastrinoma are later found to have MEN-1). Gastrinomas associated with MEN-1 are multiple and often extrapancreatic, occurring in the duodenal wall and retroperitoneal lymphatics.
14. Describe the symptoms of gastrinomas associated with MEN-1.
Excessive gastrin secretion by these tumors causes prolific production of gastric acid with resultant duodenal and jejunal ulcers and diarrhea. Basal acid output exceeds 15 mmol/hour, and basal fasting serum gastrin levels usually exceed 300 pg/mL.
15. What other conditions may cause hypergastrinemia?
Hypergastrinemia also may result from any condition that stimulates normal gastrin secretion (hypercalcemia) or that interferes with normal gastric acid production and feedback to the G cells (achlorhydria, gastric outlet obstruction, retained antrum with a Billroth II procedure, vagotomy, and the use of histamine-2 [H2] blockers and proton pump inhibitors). Hyperparathyroidism (see questions 8 and 9) can therefore falsely elevate serum gastrin levels.
16. How are gastrinomas distinguished from other causes of hypergastrinemia?
A secretin stimulation test may aid in the differentiation of gastrinomas from other hypergastrinemic states; serum gastrin levels in patients with gastrinomas increase by at least 200 pg/mL. More information about gastrinomas is included in Chapter 53.
17. What is the second most common type of functional pancreatic tumor in MEN-1?
Insulinomas are the second most common PNET in the MEN-1 syndrome (12%–36% of islet-cell tumors) and the most common eutopic type. Persistent or disordered insulin secretion causes severe hypoglycemia; inappropriately elevated concentrations of insulin, proinsulin, and C-peptide are present in the serum. Insulinomas associated with MEN-1 syndrome are more frequently multicentric and malignant than are the sporadic tumors. Approximately 1% to 5% of all patients with an insulinoma are eventually discovered to have MEN-1. An excellent discussion of the diagnosis and therapy of insulinomas is found in Chapter 53.
18. What other pancreatic tumors may be seen in MEN-1?
Pancreatic tumors less frequently associated with MEN-1 include glucagonomas, somatostatinomas, and vasoactive intestinal polypeptide–secreting tumors (VIPomas). Associated syndromes and therapy are also described in Chapter 53.
19. How are the most common pancreatic tumors of MEN-1 treated?
