Multiple Endocrine Neoplasia (MEN)

Essentials of Diagnosis

• MEN 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, anterior pituitary, adrenal, thyroid; carcinoid tumors; lipomas and facial angiofibromas

• MEN 2 (formerly MEN 2A): medullary thyroid cancers, hyperparathyroidism, pheochromocytomas, Hirschsprung disease

• MEN 3 (formerly MEN 2B): medullary thyroid cancers, pheochromocytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty

• MEN 4: tumors of the parathyroid glands, anterior pituitary gland, adrenal gland, ovary, testicle, kidney

General Considerations

MULTIPLE ENDOCRINE NEOPLASIA (MEN) 1 (WERMER SYNDROME)

• Parathyroid, enteropancreatic, and pituitary tumors

• Nonendocrine tumors

  • Small head-neck angiofibromas (85%)

  • Lipomas (30%)

  • Collagenomas (70%)

• Incidental adrenal nodules are found in about 50% of affected patients but are rarely secretory

• Mutations in the menin gene (11q13) detectable in 60–95% of cases

• Variants of MEN 1 occur, eg, kindreds with MEN 1 Burin have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors

• In patients with MEN 1 gastrinomas, depending on the kindred, hepatic metastases tend to be less aggressive than in those with sporadic gastrinomas

MEN 2 (FORMERLY MEN 2A; SIPPLE SYNDROME)

• Medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas

• Nonendocrine: Hirschsprung disease

• Caused by a mutation of the ret proto-oncogene (RET) on chromosome 10 (95%)

• Each kindred has a certain ret codon mutation that correlates with the particular variation in the MEN 2 syndrome, such as the age of onset and aggressiveness of medullary thyroid cancer

MEN 3 (FORMERLY MEN 2B)

• Adrenal pheochromocytomas, medullary thyroid carcinoma, mucosal neuromas

• Nonendocrine manifestations

  • Intestinal ganglioneuromas

  • Marfan-like habitus

  • Skeletal abnormalities

  • Delayed puberty

MEN 4

• Rare autosomal-dominant familial tumor syndrome caused by germline mutations in the gene CDKN1B

• Affected patients are particularly prone to parathyroid adenomas (80%), pituitary adenomas (less aggressive than those seen with MEN 1), pancreatic neuroendocrine tumors, and adrenal tumors

• They also appear to be prone to adrenal tumors, renal tumors, testicular cancer, neuroendocrine cervical carcinoma, and primary ovarian failure

OTHER SYNDROMES RELATED To MEN

• Carney complex

  • Adrenocortical nodular hyperplasia that can produce skin abnormalities

  • Cushing syndrome

  • GH-secreting pituitary adenomas or hyperplasia with acromegaly

  • Thyroid tumors

  • Gonadal Sertoli cell tumors

  • Myxomas of heart and breast

  • Other malignancies

• McCune-Albright syndrome:

  • Precocious puberty (particularly girls) due to gonadal hypersecretion

  • Cushing syndrome caused by multiple adrenal nodules

  • Hyperthyroidism from functioning thyroid nodules

  • Acromegaly caused by GH-secreting pituitary tumors may develop

  • Fibrous dysplasia of bones and hypophosphatemia, and bone fractures are common

  • Sudden death has been reported

• Type 2 von Hippel Lindau (VHL) syndrome

  • Associated with pheochromocytomas, pancreatic/duodenal neuroendocrine tumors, hyperparathyroidism, and pituitary tumors

  • Hemangiomas and renal cell carcinomas

• Hypoxia Inducible Factor 2A (HIF2A) germline mutations predispose to

  • Pheochromocytomas, pancreatic/duodenal somatostatinomas

  • Erythrocytosis

  • Retinal abnormalities

• Neurofibromatosis type 1 (NF1)

  • Associated with pheochromocytomas and pancreatic/duodenal somatostatinomas as well as neurofibromas and hypothalamic hamartomas

• Beckwith Wiedemann syndrome is associated with an increased risk for malignancies, particularly Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, neuroblastoma, pheochromocytoma, and paraganglioma

Symptoms and Signs

MEN 1

• Tumors may develop in childhood or adulthood; presentation variable, even in same kindred

• Hyperparathyroidism in > 90%; initial presentation in two-thirds of patients

• Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in up to 70%

  • Gastrinomas in 40% (Zollinger-Ellison syndrome)

  • Gastrinomas tend to be small, multiple and ectopic

• Occur frequently in the duodenum

• Can metastasize to the liver

  • Concurrent hyperparathyroidism stimulates gastrin and gastric acid secretion

  • Insulinomas in ~10% of patients cause fasting hypoglycemia

  • Glucagonomas (1.6%) cause diabetes mellitus and migratory necrolytic erythema

  • VIPomas (1%) cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome)

  • Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis

• Extrapancreatic neuroendocrine tumors include carcinoid tumors that tend to occur in foregut locations (69%), such as the lung, thymus, duodenum, or stomach; such carcinoid tumors are frequently malignant

• Pituitary adenomas in 42%; presenting tumor in 29%

• Adrenal adenomas or hyperplasia in ~40%; bilateral in 50%; generally benign and nonfunctional

• Nonendocrine tumors are common

  • Small facial angiofibromas and subcutaneous lipomas

  • Collagenomas (firm skin nodules)

  • Malignant melanomas can occur

MEN 2 (FORMERLY MEN 2A)

• Pheochromocytomas (often bilateral)

• Serum calcitonin levels in medullary thyroid carcinoma are usually > 80 pg/mL in women or > 190 pg/mL in men

MEN 3 (FORMERLY MEN 2B)

• Medullary thyroid carcinoma is aggressive and presents early in life

• Mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue

• Marfan-like habitus (75%)

• Adrenal pheochromocytomas (60%), often bilateral and rarely malignant

• Medullary thyroid carcinoma (80%)

• Intestinal abnormalities (eg, ganglioneuromas) (75%)

• Skeletal abnormalities (87%)

• Delayed puberty (43%)

MEN 4

• Adenomas of the pituitary, parathyroid glands, and neuroendocrine tumors of the pancreas

• Adrenal tumors

• Renal tumors

• Testicular cancer

• Neuroendocrine cervical carcinoma

Differential Diagnosis

• Tumors of pituitary, parathyroids, or pancreatic islets

• Other causes of hypercalcemia may increase gastrin levels, simulating gastrinoma

Laboratory Tests

MEN 1

• Genetic linkage analysis can be done if there are several affected members in the kindred

• Menin mutation genetic testing permits the rest of the kindred to be tested for the specific gene defect and allows informed genetic counseling

MEN 2 (FORMERLY MEN 2A)

• RET mutation genetic testing permits first-degree relatives to be tested for the specific gene defect and allows informed genetic counseling

• Serum calcitonin level drawn after 3 days of omeprazole, 20 mg twice daily orally, enables screening for medullary thyroid carcinoma

MEN 3 (FORMERLY MEN 2B)

• Genetic testing of infants who have a parent with MEN 2B is possible

MEN 4

• No mutation in the menin gene, which differentiates MEN 4 from MEN 1

Medications

MEN 1

• Cinacalcet orally may be effective for hyperparathyroidism

• Conservative treatment for patients with gastrinomas in MEN 1

  • High-dose proton pump inhibitor therapy

  • Control of hypercalcemia

Surgery

MEN 1

• Parathyroidectomy (3½ glands resected, along with thymectomy) for patients with hyperparathyroidism is effective in 62%

• Surgery for gastrinomas is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum

• Surgical resection is usually attempted for insulinomas, but the tumors can be small, multiple, and difficult to detect

MEN 2 (FORMERLY MEN 2A)

• Prophylactic total thyroidectomy for children with a MEN 2 RET gene mutation, usually by age 6, though ~30% never manifest endocrine tumors

• Screen MEN 2 mutation carriers for pheochromocytoma before any surgical procedure

Complications

MEN 1

• Aggressive parathyroid resection can cause permanent hypoparathyroidism

• Control of the hypercalcemia can reduce serum gastrin levels, gastric acidity, and frequency of peptic ulcer disease

Prognosis

MEN 1

• Hyperparathyroidism recurrence rate is 16%, with hypercalcemia often recurring many years after neck surgery

• Overall, patients with MEN 1 face an increased mortality risk with a mean life expectancy of only 55 years