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Premium member Presentation Transcript Multiple Endocrine Neoplasia: Multiple Endocrine Neoplasia Dr Anikwe J C Dept of medicineoutline: Definition Classification MEN1/ MEN2 epidemiology Clinical manifestations Diagnosis Treatment conclusion outline 2/16/2011 jcaDefinition : Multiple endocrine neoplasia syndrome is defined as a disorder with neoplasms in two or more different hormonal tissues in several members of a family. Usually at an earlier age. Currently three well-defined MEN syndromes – MEN 1, MEN 2a, MEN 2b. Definition 2/16/2011 jca.: Several distinct genetic disorders predispose to endocrine gland neoplasia and cause hormone excess syndromes . DNA-based genetic testing is now available for these disorders. effective mgt requires an understanding of endocrine neoplasia and the range of clinical features that may be manifested in an individual patient . 2/16/2011 jcaDisease Associations in the Multiple Endocrine Neoplasia (MEN) Syndromes.: MEN1 MEN2 MIXED SYNDROMES Parathyroid hyperplasia or adenoma Islet cell hyperplasia, adenoma, or carcinoma Pituitary hyperplasia or adenoma Other less common manifestations: foregut carcinoid , pheochromocytoma , subcutaneous or visceral lipomas MEN2A MTC Pheochromocytoma Parathyroid hyperplasia or adenoma MEN2A with cutaneous lichen amyloidosis MEN2A with Hirschsprung disease Familial MTC MEN2B MTC Pheochromocytoma Mucosal and gastrointestinal neuromas Marfanoid features (MTC= Medullary thyroid ca.) Von Hippel–Lindau syndrome Pheochromocytoma Islet cell tumor Renal cell carcinoma Hemangioblastoma of central nervous system Retinal angiomas Neurofibromatosis with features of MEN1 or 2 Carney complex, Myxomas of heart, skin, and breast Spotty cutaneous pigmentation Testicular, adrenal, and GH-producing pituitary tumors Peripheral nerve schwannomas Disease Associations in the Multiple Endocrine Neoplasia (MEN) Syndromes. 2/16/2011 jca. MEN1 (Wermer's syndrome): It is inherited as an autosomal dominant trait. Although the mechanism of tumorigenesis at the cellular level is recessive. Clinical manifestations vary Generally manifest by the 3rd or 4th decade Although rare, MEN1 is the most common MEN syndrome with prevalence of 2–20 per 100,000 . . MEN1 ( Wermer's syndrome) 2/16/2011 jca.: The syndrome is xterized by: neoplasia of the parathyroid glands-90% enteropancreatic tumors-80%, anterior pituitary adenomas-55%, adrenal adenomas-30% Thyroid nodules -10% . 2/16/2011 jca.: Also have a high incidence of foregut carcinoids Subtle skin lesions eg lipomas , facial angiofibromas , and skin collagenomas . Various combinations of tumors with 94% penetrance by age 50yrs occur. . 2/16/2011 jca.: Race No racial predilection is known. Sex The incidence is equal for men and women. . 2/16/2011 jcapathphysiology: This syndrome is caused by inactivating mutations of the tumor-suppressor gene MEN1 located at chromosome 11q13. The MEN1 gene codes for a nuclear protein called Menin pathphysiology 2/16/2011 jca.: Normally , Menin interacts with JunD , suppressing the JunD -dependent transcriptional activation. JunD is associated with inhibition of cell growth. When Mutant menin interacts with J unD it no longer inhibits cell growth hence the neoplasia . Each child born to an affected parent has a 50% probability of inheriting the gene. The variable penetrance of the several neoplastic components can make the differential diagnosis and treatment challenging. . 2/16/2011 jcaMortality/Morbidity : Benign endocrine and cutaneous tumors cause morbidity, and malignancies cause most mortality in multiple endocrine neoplasia type 1 (MEN1). Mortality/Morbidity 2/16/2011 jcaPrimary hyperparathyroidism: The most common manifestation of MEN1 (95–100%). Hypercalcemia may develop during the teenage years,(hyperplasia of parathyroid glands) most individuals are affected by age 40 (adenoma of parathyroid gland). One of the cardinal features of endocrine tumors in MEN1—multicentricity. Primary hyperparathyroidism 2/16/2011 jca.: The neoplastic changes inevitably affect multiple parathyroid glands, making surgical cure difficult. Diagnosis : demonstrating elevated levels of serum calcium intact parathyroid hormone. . 2/16/2011 jcaclinicalManifestations: : Hyperparathyroidism of MEN1 do not differ substantially from those in sporadic hyperparathyroidism and include: calcium-containing kidney stones, kidney failure, nephrocalcinosis , bone abnormalities (i.e., osteoporosis, osteitis fibrosa cystica ), gastrointestinal and musculoskeletal complaints clinicalManifestations : 2/16/2011 jca.: . Management of MEN1 is challenging because of; early onset, significant recurrence rates, multiplicity of parathyroid gland involvement. Ectopic/ occult glands. . 2/16/2011 jca.: Hyperparathyroidism of MEN1 can be differentiated from other forms of familial primary hyperparathyroidism based on; family history, histology of resected parathyroid tissue, presence of a MEN1 mutation and, long-term observation to determine whether other manifestations of MEN1 develop. . 2/16/2011 jcatreatment: Criteria for surgery Individuals with serum calcium levels >3.0 mmol /L (12 mg/ dL ), evidence of calcium nephrolithiasis or renal dysfunction, neuropathic or muscular symptoms, or bone involvement (including osteopenia ) or individuals <50 years of age . treatment 2/16/2011 jca.: When surgery is indicated , there are two approaches. All parathyroid tissue are identified and removed and parathyroid tissue is implanted in the nondominant forearm. + Thymectomy because of development of malignant carcinoid tumors. 2. Remove 3–3.5 parathyroid glands from the neck (leaving ~50 mg of parathyroid tissue), . 2/16/2011 jcaEnteropancreatic tumors: Second most common manifestation of MEN1, 30% are malignant estimated penetrance of 50%. They tend to occur in parallel with hyperparathyroidism. tumors secrete peptide hormones that cause specific clinical syndromes. Enteropancreatic tumors 2/16/2011 jca1. Gastrinomas: most common enteropancreatic tumors in MEN1 patients result in the Zollinger -Ellison syndrome (ZES). ZES is caused by excessive gastrin production Occurs in > ½ of MEN1 pts with small carcinoid -like tumors in the duodenal wall or, less often, by pancreatic islet cell tumors. There may be > one gastrin -producing tumor, making localization difficult. 1. Gastrinomas 2/16/2011 jcamanifestation: The robust acid production may cause; esophagitis , duodenal ulcers throughout the duodenum, ulcers involving the proximal jejunum, and diarrhea. The ulcer diathesis is commonly refractory to conservative therapy such as antacids. manifestation 2/16/2011 jca diagnosis : Increased gastric acid secretion, elevated basal gastrin levels in the serum [generally >115 pmol /L an exaggerated response of serum gastrin to either secretin or calcium. NB:Approximately one-fourth of all ZES occurs in the context of MEN1 diagnosis 2/16/2011 jca Other causes of elevated serum gastrin levels should be excluded , such as : : achlorhydria , treatment with H 2 receptor antagonists or proton pump inhibitors, retained gastric antrum , small-bowel resection, gastric outlet obstruction, and hypercalcemia , Other causes of elevated serum gastrin levels should be excluded , such as : 2/16/2011 jca2 . Insulinomas: second most common enteropancreatic tumors in MEN1. Unlike gastrinomas , most insulinomas originate in the pancreas bed, becoming the most common pancreatic tumor in MEN1. The tumors may be benign or malignant (25%). 2 . Insulinomas 2/16/2011 jcadiagnosis : hypoglycemia during a short fast inappropriate elevation of serum insulin and C-peptide levels. Large insulinomas may be identified by CT or MRI scanning. Intraoperative ultrasonography . diagnosis 2/16/2011 jca3 . Glucagonoma: seen occasionally in MEN1, manifestations : causes a syndrome of, hyperglycemia, skin rash ( necrolytic migratory erythema ), anorexia, glossitis , anemia, depression, diarrhea, and venous thrombosis. 3 . Glucagonoma 2/16/2011 jca.: glucagon level is high. +/- plasma ghrelin levels. The glucagonoma syndrome may represent a complex interaction between glucagon/ ghrelin overproduction and the nutritional status of the patient. . 2/16/2011 jca.: VIPomas (1%) secrete VIP and cause profuse watery diarrhea, hypokalemia , and achlorhydria (WDHA, Verner –Morrison syndrome). 5. Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea , and cholelithiasis . . 2/16/2011 jca.: The pancreatic neoplasms differ from the other components of MEN1 in that approximately one-third of the tumors display malignant features, including hepatic metastases . 2/16/2011 jcaTx of Pancreatic Islet Cell Tumors : Two features complicate the management. the pancreatic islet cell tumors are multicentric , malignant about a third of the time, and cause death in 10–20% of patients. performance of a total pancreatectomy to prevent malignancy causes diabetes mellitus, a disease with significant long-term complications that include neuropathy, retinopathy, and nephropathy. Tx of Pancreatic Islet Cell Tumors 2/16/2011 jca general concepts in tx; : (1) Islet cell tumors should be resected because medical therapy for the hormonal effects are generally ineffective. (2) Gastrin -producing islet cell tumors that cause ZES are frequently multicentric . Caused by duodenal wall carcinoid tumors and that resection of these tumors improves the cure rate. (3) In families in which there is a high incidence of malignant islet cell tumors that cause death, total pancreatectomy at an early age may be considered to prevent malignancy. general concepts in tx ; 2/16/2011 jca.: Mgt of metastatic islet cell carcinoma is unsatisfactory. Hormonal abnormalities can sometimes be controlled. eg ZES can be treated with H 2 receptor antagonists or proton pump inhibitors; somatostatin analogues eg octreotide or lanreotide , are useful in the management of carcinoid , glucagonoma , and the watery diarrhea syndrome. . 2/16/2011 jca.: Bilateral adrenalectomy for ectopic ACTH syndrome . Islet cell carcinomas frequently metastasize to the liver but may grow slowly. Hepatic artery embolization , radiofrequency ablation, or chemotherapy may reduce tumor mass, control symptoms of hormone excess, and prolong life; however, these treatments are never curative. . 2/16/2011 jcaPituitary tumors: occur in 20–30% of patients These tumors can exhibit aggressive behavior and local invasiveness that makes them difficult to resect . 1 Prolactinomas are most common Diagnosis: serum prolactin levels >200 g/L, with or without a pituitary mass evident by MRI. Values <200 g/L may be due to a prolactin -secreting neoplasm or to compression of the pituitary stalk by a different type of pituitary tumor. 2 Acromegaly due to excessive GH production is the second most common syndrome caused by pituitary tumors in MEN1. Pituitary tumors 2/16/2011 jca.: 3. Cushing's disease: caused by ACTH-producing pituitary tumors or by ectopic production of ACTH or CRH by other components of MEN1 syndrome including islet cell or carcinoid tumors or adrenal adenomas. Diagnosis: pituitary Cushing's disease is generally best accomplished by a high-dose dexamethasone suppression test or by petrosal venous sinus sampling for ACTH after IV injection of CRH. . 2/16/2011 jcaAdrenal adenomas /hyperplasia : : occurs in about 37% of patients with MEN 1 50% are bilateral. They are generally benign and nonfunctional. In one series, one out of 12 patients developed a feminizing adrenal carcinoma. These adrenal lesions are pituitary independent Adrenal adenomas / hyperplasia : 2/16/2011 jcaTx of Pituitary Tumors : Treatment of prolactinomas is with dopamine agonists ( bromocriptine , cabergoline , or quinagolide ) which usually returns the serum prolactin level to normal and prevents further tumor growth. Surgical resection of a prolactinoma not curative but may relieve mass effects. Tx of Pituitary Tumors 2/16/2011 jca.: Octreotide reduces tumor mass in one-third of GH-secreting tumors and reduces GH and insulin-like growth factor I levels in >75% of patients. Pegvisomant , a GH antagonist, rapidly lowers insulin-like growth factor levels in patients with acromegaly . Radiation therapy in large or recurrent tumors. . 2/16/2011 jcaNonendocrine tumors: Small facial angiofibromas subcutaneous lipomas . Collagenomas can present as firm dermal nodules. Malignant melanomas have been reported Nonendocrine tumors 2/16/2011 jcaMEN 2: Sipple 1st described an ass btw thyroid cancer and pheochromocytoma in 1961. The thyroid ca was discovered to be a medullary ca in 1965. This familial constellation of pathology in conjunction with parathyroid hyperplasia was recognized as MEN 2 in 1968. MEN 2 2/16/2011 jca.: Although pts with mucosal neuromas were identified at this time, the distinction btw MEN 2A and MEN 2B was not made until 1975. MEN 2A pts do not have mucosal neuromas and marfanoid habitus found in MEN 2B pts. MEN 2A patients also have a less virulent form of medullary thyroid ca (MTC) than MEN 2B pts. MEN 2A pts may have parathyroid hyperplasia, which is rare in MEN 2B pts. . 2/16/2011 jcaMEN 2A (Sipple's Syndrome): MEN 2A is a rare familial multiglandular syndrome that is inherited as an autosomal dominant trait. Pts have ret protooncogene (RET) mutation. Their first-degree relatives may have specific RET mutation. MEN 2A ( Sipple's Syndrome) 2/16/2011 jcaPatients may present with:: medullary thyroid carcinoma (> 90%); hyperparathyroidism (20–50%), due to hyperplasia or multiple adenomas in over 70% of cases; pheochromocytomas (20–35%), which are often bilateral; or Hirschsprung's disease . Patients may present with: 2/16/2011 jcaLaboratory Studies : Screening for medullary thyroid carcinoma is done with the pentagastrin stimulation test, Urinary catecholamines and metanephrines screen for pheochromocytomas . Serum calcium level and PTH levels screen for hyperparathyroidism. Laboratory Studies 2/16/2011 jcaImaging Studies : Perform CT scanning or MRI for imaging of the adrenals. If calcitonin levels are elevated at either baseline or with provocative testing, evaluate the chest and abdomen for metastatic disease. Imaging Studies 2/16/2011 jcaTx : MTC : Total thyroidectomy has been recommended for pts as young as age 3 years for MEN 2A if they contain the genetic mutation. Thyroid hormones For supplemental therapy in hypothyroidism Tx 2/16/2011 jcaParathyroid disease : Hyperparathyroidism usually manifests in patients older than 30 years. Histologically , consist of a chief-cell hyperplasia. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60-mg remnant. Cervical thymectomy because of the increased risk of supernumerary parathyroid glands. Parathyroid disease 2/16/2011 jca.: Vitamin D supplements May increase serum calcium levels by improving calcium absorption. . 2/16/2011 jcaTx Pheochromocytoma: Unilateral adrenalectomy avoids the risk of Addisonian crisis and improves the quality of life by not requiring replacement therapy. Some investigators have advocated bilateral adrenalectomy in all patients because of risk of malignancy (rare) and the operative complications from subsequent surgeries. Tx Pheochromocytoma 2/16/2011 jca.: Mineralocorticoids Partial replacement therapy for primary and secondary adrenocortical insufficiency Corticosteroids Cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. . 2/16/2011 jcaMEN 2B : familial, autosomal dominant multiglandular syndrome that is caused by a mutation of the ret protooncogene (RET) on chromosome 10. MEN 2B 2/16/2011 jcaMEN 2B is characterized by;: mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue, Marfan -like habitus (75%), adrenal pheochromocytomas (60%) that are rarely malignant and often bilateral, medullary thyroid carcinoma (80%). intestinal ganglioneuromas , skeletal abnormalities (87%), and delayed puberty (43%). MEN 2B is characterized by; 2/16/2011 jca.: Medullary thyroid carcinoma is aggressive and presents early in life. Therefore, infants having a parent with MEN 2B receive genetic screening; those carrying the RET mutation undergo a prophylactic total thyroidectomy by age 6 months. . 2/16/2011 jcaFollow up: Monitor pts for recurrence of medullary thyroid carcinoma with calcitonin , CEA, and +/- provocative calcitonin testing. Perform annual screening for hyperparathyroidism with serum calcium and PTH levels in MEN 2A patients. Obtain urinary catecholamine levels on an annual basis to assess for pheochromocytoma . Carefully monitor medication dosage and adverse effects Follow up 2/16/2011 jcaconclusion: MEN is rare Inheritance is by autosomal dorminance effective management requires an understanding of endocrine neoplasia Early genetic testing help decisions for prophylactic surgeries for individuals at risk Early treatment of medullary thyroid carcinoma prevents death. Careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes conclusion 2/16/2011 jca.: Thanks for listening . 2/16/2011 jca You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.