Multiple endocrine neoplasia type 1 (MEN 1, Wermer syndrome) is a tumor syndrome with a prevalence of 2–10 per 100,000 persons in the United States. About 90% of affected patients harbor a detectable germline mutation in the menin gene. This gene is located on the long arm of chromosome 11 (11q13). Genetic testing is able to detect the specific mutation in 60–95% of cases. If no mutation is detected, genetic linkage analysis can be done if there are several affected members in the kindred.
The presentation of MEN 1 is quite variable, even in the same kindred. Affected patients are prone to many different tumors, particularly involving the parathyroids, endocrine pancreas and duodenum, and anterior pituitary (Table 26–11). Incidental adrenal nodules are found in about 50% of affected patients but are rarely secretory. In some affected individuals, tumors may start developing in childhood, whereas in others, tumors develop late in adult life. The initial biochemical manifestations (usually hypercalcemia) can often be detected as early as age 14–18 years in patients with a MEN 1 gene mutation, although clinical manifestations usually present in the third or fourth decade.
Hyperparathyroidism is the first clinical manifestation of MEN 1 in two-thirds of affected patients, but it may present at any time of life. The hyperparathyroidism of MEN 1 is notoriously difficult to treat surgically, due to multiple gland involvement and the frequency of supernumerary glands and ectopic parathyroid tissue. Typically, three and one-half glands are resected, leaving one-half of the most normal-appearing gland intact. Also, during neck surgery, a thymectomy is performed to resect any intrathymic parathyroid glands or occult thymic carcinoid tumors. Nevertheless, the surgical failure rate is about 38%, and there is a recurrence rate of about 16%, with hypercalcemia often recurring many years after neck surgery. Aggressive parathyroid resection can cause permanent hypoparathyroidism. Patients with persistent or recurrent hyperparathyroidism should avoid oral calcium supplements and thiazide diuretics; oral therapy with a calcimimetic drug, such as cinacalcet, may be effective. Interestingly, germline menin mutations can also present with familial isolated hyperparathyroidism with parathyroid adenomas rather than hyperplasia.
GEP-NETs and carcinoids occur in up to 70% of patients with MEN 1. The GEP-NETs may secrete only pancreatic polypeptide or be nonsecretory altogether (20–55%). Gastrinomas occur in about 40% of patients with MEN 1. Concurrent hypercalcemia, due to hyperparathyroidism in MEN 1, stimulates gastrin and worsens gastric acid secretion; control of the hypercalcemia often reduces serum gastrin levels and gastric acid secretion. Gastrinomas of MEN 1 tend to be small, multiple, and ectopic; they are frequently found outside the pancreas, usually in the duodenum. They can metastasize to the liver. In patients with MEN 1 (depending on the kindred), hepatic metastases tend to be less aggressive than those from sporadic gastrinomas. Treatment of gastrinomas of MEN 1 is usually conservative, using long-term high-dose proton pump inhibitor therapy and control of hypercalcemia; surgery is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum. Carcinoid tumors can arise in the lung or abdomen and can metastasize, especially to the liver. (See Chapter 39.)
Insulinomas occur in about 10% of patients with MEN 1. Surgery is usually attempted, but the tumors can be small, multiple, and difficult to detect. (See Chapter 27.) Glucagonomas occur in 1.6% of patients with MEN 1, VIPomas in 1%, and somatostatinomas in 0.7%. Extrapancreatic neuroendocrine tumors are common in MEN 1, are frequently malignant, and include carcinoid tumors usually in foregut locations (69%), such as the lung, thymus, duodenum, or stomach.
Pituitary adenomas are the presenting tumor in 29% of patients with MEN 1 and eventually are found in about 42% of patients with MEN 1. About 78% of these pituitary adenomas occur in women. In MEN 1 patients with a pituitary adenoma, hyperparathyroidism is more common (92%). The majority of pituitary adenomas are found on routine screening of patients with known MEN 1. About 42% of the pituitary adenomas secrete PRL, while others secrete GH (6%), ACTH (3%), gonadotrophins (2%), or multiple hormones (5%). The prolactinomas usually respond to medical therapy with cabergoline. In MEN 1, aAbout 42% of such pituitary adenomas are nonsecretory. While nonsecretory pituitary microadenomas (less than 1 cm and detected on routine MRI screening) are usually indolent, about 25% of nonsecretory pituitary adenomas are macroadenomas (1 cm or more) and more aggressive.
Adrenal adenomas or hyperplasia occur in about 40% of patients with MEN 1 and 50% are bilateral. They are generally benign and nonfunctional, but a feminizing adrenal carcinoma has been reported. These adrenal lesions are ACTH-independent.
Thymic neuroendocrine tumors occur in 3.4% of affected patients, mostly in males, with a 10-year survival of 25%. Lung neuroendocrine tumors occur in 13%, with a 10-year survival of 71%.
Benign thyroid adenomas or multinodular goiter occurs in about 55% of MEN 1 patients who may undergo a thyroidectomy at the time of parathyroidectomy.
Nonendocrine tumors occur commonly in MEN 1, particularly small head-neck angiofibromas (85%) and lipomas (30%). Collagenomas are common (70%), presenting as firm dermal nodules. Affected patients may also be more prone to meningiomas, breast cancer, colorectal cancers, prostate cancer, and malignant melanomas.
The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. H2-blocker or proton pump inhibitor therapy causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide cause hyperprolactinemia, simulating a pituitary prolactinoma.
Variants of MEN 1 also occur. Kindreds with MEN 1 Burin variant have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors. Overall, patients with MEN 1 have an increased mortality rate with a mean life expectancy of only 55 years.