M ULTIPLE E NDOCRINE N EOPLASIA T YPE II: S URGICAL M ANAGEMENT Greta Riedesel, R3 12/9/2010

MEN SYNDROMES Multicentric endocrine hyperplasia and neoplasia Autosomal dominant inheritance Prevalence of 2.5 per 100,000 Often suspected upon diagnosis of affected relatives.

MEN1: M ANIFESTATIONS Hyperparathyroidism Present in 95% cases Hypercalcemia with elevated or inappropriately normal PTH Pancreatic islet cell tumors 75-80% of patients in their lifetime Gastrinoma most common Zollinger-Ellison syndrome Insulinoma,VIPoma Pituitary Symptoms from mass effect and/or hormone effects Prolactinoma

MEN1: G ENETICS MEN1 tumor suppressor gene Protein menin, chromosome 11 Loss of function through many mutations Nonsense, frameshift, large deletions Complicated genetic testing given many mutation types Need additional loss of heterozygosity Loss of remaining normal MEN1 gene Presentation unusual before 20 y/o, rare before 10 y/o.

MEN2: M ANIFESTATIONS MEN 2a Medullary thyroid CA Pheochromocytoma Hyperparathyroidism Cutaneous lichen amyloidosis (CLA) MEN 2b Medullary thyroid CA Pheochromocytoma Mucosal neuromas, intestinal ganglioneuromas +/- marfanoid body habitus Familial Medullary Thyroid Carcinoma (FMTC) Medullary thyroid CA alone May be variant of MEN 2a

MEN2: M ANIFESTATIONS

MEN 2A Accounts for 55-90% of all MEN2 Presentation >90% patients present with MTC Frequent in children 10 years and younger 50% present with pheochromocytoma 10-20% present with parathyroid hyperplasia Cutaneous Lichen Amyloidosis Association with Hirschsprung’s Disease

MEN 2B Most rare and aggressive form of MEN2 Accounts for 5-10% of all MEN2 cases MTC present in 100% of cases Earlier onset More aggressive than MEN2A Marfanoid habitus Neuromas of tongue, lips and eyelids yield characteristic facies Intestinal ganglioneuromas May present with GI disturbances such as constipation

F AMILIAL M EDULLARY T HYROID C ARCINOMA (FMTC) Now considered type of MEN2A with strong predisposition to MTC Accounts for ~35% of MEN2 Does not have other manifestations of MEN2A Requires screening as MEN2A Prior misdiagnosis as FMTC missed diagnosis of pheochromocytoma and hyperparathyroidism. Less aggressive MTC Presents at an older age.

MEN2: G ENETICS REarranged during Transfection (RET) proto-oncogene Cell-surface growth factor Mediates glial-derived neurotrophic factors Expressed in neural crest derived tissues >50 mutations identified yield gain of function MEN2a & FMTC- extracellular domain cysteine residue MEN2b- intracellular domain tyrosine kinase

MEN2: D IAGNOSIS & G ENETIC T ESTING

MEN2: G ENOTYPE -P HENOTYPE C ORRELATIONS

*Evaluation for pheochromocytoma must be performed prior to prophylactic thyroidectomy *

M EDULLARY T HYROID C ARCINOMA 5% thyroid neoplasms are medullary carcinomas Parafollicular C cells Most common cause of death in MEN2 patients Diagnosis: Palpation of thyroid nodule or LN mets Diarrhea with significant hypercalcitoninemia Screening after MEN genetic testing or other MEN tumor diagnosis Age related progression C cell hyperplasia, micro-MTC, intrathyroidal MTC, lymphatic & distant MTC metastases.

MTC: T UMOR M ARKERS Calcitonin production increased in C-cell hyperplasia and MTC CT levels monitor presence and progression of MTC Also used post-thyroidectomy to detect persistent/recurrent disease.

MTC: T HYROIDECTOMY Pre-RET testing: thyroidectomy only for thyroid nodule or elevated calcitonin levels. Post-RET testing: prophylactic thyroidectomy for asymptomatic carriers. 80% of children who undergo thyroidectomy for RET mutation will have foci of MTC within thyroid. Multivariate analysis association between older age at time of thyroidectomy and persistent/recurrent disease Recurrent disease mean age 12.1 (range 1-19) Disease free mean age 8.6 (range 1-19) (p= 0.002, 95%, CI )

MTC: T HYROIDECTOMY Total thyroidectomy in known MTC given high incidence of bilateral disease Central Neck dissection: all MEN 2B MEN 2A older than 11 y/o

P HEOCHROMOCYTOMA Catecholamine-secreting tumors of adrenal medulla 40% of MEN2A and MEN 2B Familial tumors account for 10% pheochromocytomas in children Rarely presents before MTC in MEN2

P HEOCHROMOCYTOMA Symptoms Paroxysmal hypertension Orthostatic hypotension Catecholamine induced cardiomyopathy Hypertensive encephalopathy Diagnosis Increased plasma metanephrines Evaluate for bilateral disease with MRI

P HEOCHROMOCYTOMA : T REATMENT Preoperative alpha and beta blockade Unilateral adrenalectomy Some advocate bilateral given 30% have bilateral disease eventually Monitor blood pressure and urine catecholamine levels yearly for recurrence

P RIMARY H YPERPARATHYROIDISM Incidence 2-5 per 100,000 Multigland hyperplasia in MEN Diagnosed at the time of MTC or pheo <5% diagnosed before MTC or pheo Hypercalcemia, inappropriately high PTH

P RIMARY HPT: T REATMENT Intervene if symptomatic hyperCa, nephrolithiasis and/or bone disease. Cure rate 95% Prophylactic parathyroidectomy with autotransplantation at time of thyroidectomy HPT more rare in pts post-thyroidectomy Less common in MEN 2A than MEN1 Excise only enlarged glands

RET PROTO - ONCOGENE & H IRSCHSPRUNG ’ S D ISEASE RET responsible for 50% familial and 7-35% sporadic HD HD associated with mutations in C618 & C620 (as with MEN2A) Requires dual RET function Loss of function of RET to halt ganglion migration in Hirschsprung’s Disease Gain of function to give rise to MEN2

RET PROTO - ONCOGENE & H IRSCHSPRUNG ’ S D ISEASE Familial HD patients Consider genetic screening for RET/MEN Investigate family history of sporadic MTC. MEN 2A patients (specifically C618 & C620 mutations) Prenatal counseling on possible HD in newborn Investigate for HD symptoms and perform rectal bx if needed

M ULTIPLE E NDOCRINE N EOPLASIA : T YPE II

R EFERENCES Chernausek D (2003) Adrenal medulla, pheochromocytoma and multiple endocrine neoplasia syndromes. Rudolph’s Pediatrics, 21 st edition. Iqbal C, Wahoff D (2009) Diagnosis and management of pediatric endocrine neoplasms. Current Opinion in Pediatrics 21: Moore S, Appfelstaedt J, Zaahl M (2007) Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2. Journal of Pediatric Surgery Moore W, Zaahl M (2010) Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation. Journal of Pediatric Surgery 45, Moore S, Zaahl M (2009) Clinical and genetic differences in total colonic aganglionosis in Hirschsprung’s disease. Journal of Pediatric Surgery 44: Raue F, Frank-Raue K (2010) Update multiple endocrine neoplasia type 2. Familial Cancer 9: Scheinemakers J, Vriens M, Valk G, de Groot JW, Plukker JT, et al. (2010) Factors predicting outcome of total thyroidectomy in young patients with multiple endocrine neoplasia type 2: a nationwide long-term follow-up study. World J Surg 34: Skinner M, Moley J, Dilley W, Owzar K, DeBenedetti M, Wells S (2005) Prophylactic Thyroidectomy in multiple endocrine neoplasia type 2a. N Engl J Med 353: Skinner M, DeBenedetti M, Moley J, Norton J, Wells S (1996) Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2a and 2b. Journal of Pediatric Surgery 31,1: