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Multiple Endocrine Neoplasia MEN I/MEN II Todd A. Nickloes, DO, FACOS, FACS Associate Professor Division of Trauma/Critical Care Department of Surgery University of Tennessee Medical Center-Knoxville MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN I/MEN II MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN I/MEN II MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN I Parathyroid ◦ Hyperparathyroidism occurs in over 90% of pts. Typically first detectable abnormality Nephrolithiasis/Hypercalcemia ◦ Usual presentation: 25-35 y/o presents with predominantly urinary complaints ◦ Nephrolithiasis ◦ Polyuria ◦ Hypercalcemia ◦ Muscle weakness ◦ Anorexia/Nausea Not as in primary hyperparathyroidism (more on this later) ◦ Postmenopausal women ◦ Nephrolithiasis ◦ Hypertension ◦ Osteoporosis ◦ Emotional disturbances MEN I Parathyroid ◦ This is a multi-glandular process Diffuse hyperplasia Metachronous development of multiple adenomas 4 gland enlargement ◦ Not as in primary HPT ◦ Single adenoma Preop sestimibi will reveal diffuse glandular involvement MEN I Parathyroid ◦ Autosomal dominant Genetic testing ◦ Found on MENIN gene ◦ Chromosome 11q13 Family screening ◦ should be accomplished on 1st degree relatives ◦ early teen years ◦ Include serum ◦ Calcium ◦ Glucose ◦ Gastrin Fasting Insulin Pancreatic Polypeptide Growth Hormone VIP Prolactin b-human Gonadotropin ◦ Annual calcium screening should occur in 1st degree relatives MEN I ◦ Parathyroid There is no curative operation ◦ Preferred corrective strategy employs 3.5 gland excision ◦ Optional total parathyroidectomy with autotransplantation to forearm ◦ Achieves cure > 90% of cases ◦ Recurrent hyperparathyroidism after autotransplantation to forearm ~ 50% recurrence Resection of autotransplanted material Hypoparathyroidism postop occurrence < 5% Treated with oral supplementation MEN I MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN I Pituitary ◦ Occur in 40% of MEN I pts Most commonly benign prolactin secreting adenomas May produce ◦ Growth hormone ◦ ACTH ◦ rarely nonfunctional adenomas Presenting symptoms ◦ Headache ◦ Diplopia ◦ Symptoms associated with hormone overproduction Galactorrhea, Gynecomastia Acromegally Cushing’s Syndrome ◦ thin skin/stretch marks ◦ proximal muscle weakness ◦ hyperglycemia MEN I Pituitary ◦ Bromocriptine mesylate Dopamine agonist First line therapy Inhibits prolactin production Reduces tumor bulk Cabergoline is second line therapy for pts unable to tolerate Bromocriptine mesylate ◦ Trans-sphenoidal hypophysectomy for medical failures 3 months of therapy Failure to improve prolactin levels or diplopia Cabergoline more effective in tumor shinkage MEN I MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN I Pancreatic islet cells ◦ Poses most difficult clinical challenge Pancreas is diffusely involved ◦ Islet cell hyperplasia ◦ Multifocal tumors Accounts for most morbidity and mortality ◦ ◦ ◦ ◦ ◦ Gastrinoma (Zollinger-Ellison) Vasoactive intestinal polypeptidoma (VIPoma) Insulinoma Glucagonoma Somatostatinoma 90% found in gastrinoma triangle and are malignant ◦ Junction of cystic duct and CBD ◦ Junction of 2nd and 3rd portions of duodenum ◦ Junction of body and neck of pancreas Therapy directed at palliation of symptoms and the malignant process MEN I Junction of cystic duct and CBD Junction of 2nd and 3rd portions of duodenum Junction of body and neck of pancreas Gastrinoma Triangle MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN I/MEN II MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia MEN II-A Medullary carcinoma of thyroid ◦ Present in all pts ◦ Autosomal dominant syndrome Gain-of-function mutation in RET proto-oncogene Prophylactic thyroidectomy indicated for all RET-mutation carriers upon discovery1 ◦ Greatest survival benefit if thyroidectomy completed < 5 yoa for MEN II-A2 ◦ Age specific progression from C cell hyperplasia to medullary thyroid cancer to nodal metastasis ◦ After primary resection – recurrence in over 50% pts No recurrence/nodal metastasis in pts < 14 yoa Re-operation for locally recurrent disease No accepted adjuvant therapy for metastatic disease 1Machens et al. N Engl J Med 2003;349:1517 2Brandi ML, et al. J Clin Ednocrinol Metab 2001;86:5658 MEN II-A MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia MEN II-A Pheochromocytoma ◦ Present in 40-50% of pts ◦ Biochemical testing recommended in all: Medullary thyroid cancer pts MEN II pts Includes ◦ 24 hour urinary catecholamines/metanephrines/VMA ◦ Plasma metanephrines ◦ Discontinue antihypertensives 24 hours prior to collection MEN II-A MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia MEN II-A Parathyroid hyperplasia ◦ Arises in 25-35% of pts ◦ Similar to MEN I Diffuse/multiglandular Metachronous development of multiple adenomas Preferred corrective strategy employs 3.5 gland excision MEN II-A MEN I ◦ Involves the 3 P’s Pituitary Parathyroid Pancreatic islet cells MEN II ◦ MEN II-A Medullary carcinoma of thyroid Pheochromocytoma Parathyroid hyperplasia ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN I/MEN II MEN II ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN II-B MEN II ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN II-B Medullary carcinoma of thyroid ◦ Present in all pts ◦ Autosomal dominant syndrome Gain-of-function mutation in RET proto-oncogene Prophylactic thyroidectomy indicated for all RET-mutation carriers upon discovery1 ◦ Greatest survival benefit if thyroidectomy completed < 1 yoa for MEN II-B2 ◦ Age specific progression from C cell hyperplasia to medullary thyroid cancer to nodal metastasis ◦ After primary resection – recurrence in over 50% pts No recurrence/nodal metastasis in pts < 14 yoa Re-operation for locally recurrent disease No accepted adjuvant therapy for metastatic disease 1Machens et al. N Engl J Med 2003;349:1517 2Brandi ML, et al. J Clin Ednocrinol Metab 2001;86:5658 MEN II-B MEN II ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN II-B Pheochromocytoma ◦ Present in 40-50% of pts ◦ Biochemical testing recommended in all: Medullary thyroid cancer pts MEN II pts Includes ◦ 24 hour urinary catecholamines/metanephrines/VMA ◦ Plasma metanephrines ◦ Discontinue antihypertensives 24 hours prior to collection MEN II-A MEN II ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN II-B Multiple mucosal neuromas Ganglioneuromatosis (mucosal neuromas) Multiple mucosal neuromas Ganglioneuromatosis (mucosal neuromas) Multiple mucosal neuromas Ganglioneuromatosis (mucosal neuromas) MEN II ◦ MEN II-B Medullary carcinoma of thyroid Pheochromocytoma Ganglioneuromatosis (mucosal neuromas) Marfanoid habitus MEN II-B 00000062 Unknown Mild ptosis Prominent nose and lips Macrognathia MEN II-B 00000062 Unknown Prominent corneal nerves MEN II-B Prominent lips Mucosal neuromas MEN II-B
