Multiple Endocrine Neoplasia Hitomi Sakano 7/15/2010

Case 17yo M w/ Abdominal Pain & Diarrhea PMH: unremarkable FHx: multiple paternal family members on affected by hyperparathyroidism, pancreatic tumors and pituitary adenomas. Lab: confirmed MEN-1 gene mutation (CGA-TGA @codon 460): Ca total 11 (H), Ca ionized 1.49 (H), PTH 80 (H), vitD 11 (L), TSH<0.01 (L), free T4 2.5 (H), catecholamines (nml) Rad: sestimibi scan, 4hr delay shows an intensity inferior L lobe of thyroid (less than expected intensity for parathyroid adenoma)

MEN MEN type 1 MEN type 2a and 2b mutations in the MEN1 gene Menin, tumor suppressor MEN type 2a and 2b mutations in the RET oncogene

MEN1 Parathyroid adenoma (95%) Enteropancreatic Foregut Carcinoid Gastrinoma (40%)    Insulinoma (10%)    Nonfunctioning,[*] including pancreatic polypeptide-oma[†] (20%)    Other: glucagonoma, VIPoma, somatostatinoma, etc. (each <2%) Foregut Carcinoid    Thymic carcinoid nonfunctioning (2%)    Bronchial carcinoid nonfunctioning (4%)    Gastric enterochromaffin-like tumor nonfunctioning (10%) Anterior Pituitary    Prolactinoma (25%)    Other: nonfunctioning (10%), growth hormone + prolactin, growth hormone (5%), ACTH (2%), thyrotropin (5%) Adrenal    Cortex: Nonfunctioning (30%); functioning or cancer (2%)    Medulla: Pheochromocytoma (<1%) NONENDOCRINE FEATURES (ESTIMATED AVERAGE PENETRANCE)    Nonendocrine Features Facial angiofibroma (85%)    Collagenoma (70%)    Lipoma (30%)    Leiomyoma (5%)    Meningioma (5%)

Parathyroidectomy with autotransplantation Curative in 90% low transverse cervical incision 2 finger breaths above the suprasternal notch Dissect superiorly to the thyroid cartilage and inferiorly to suprasternal notch Separate strap muscles at the midline raphe Hemostasis between sternothyroid and thryoid capsule Ligate the middle thyroid veins. Bring the thyroid anteromedially to approach the posterior thyroid. (facilitated by dissecting the pretracheal fascia) Identify the recurrent laryngeal nerve to prevent injury Normal parathyroid is beefy red Superior glands are nearthe entrance of the laryngeal nerve under the cricothyroid muscle, inferior glands are less predictable but are typically adjacent to the inferior pole of the thyroid or thyrothymic ligament Glands are surrounded in fat and are easy to miss Blocks of gland can be reimplanted in the brachioradialis muscle Intraoperative PTH levels, half life <5min, test takes 15min

Postoperatively Tetany, symptoms of hypocalcemia may occur due to a precipitous drop in Ca++ despite normal levels of Ca++, due to hyperexcitability of neurons and hypomagnesemia Ca++ nadir typically seen 48hrs post-op

Autotransplantation Success rate >50% Typically placed in the brachioradialis m. Autotransplantation of cryopreserved gland (frozen >11mo) is not successful: retrospective study in 20 patients (Borot et al, 2010) found only 10% functionality. IM Injection in deltoid or brachioradialis: (Tan et al 2010), mean f/u ~40mo 87% success in implant group (n=31), 69% success in inject group (n=35) Recurrence in 12.9% implant, 2.9% inject

Genetics Tumor suppressor Need a loss of heterozygosity Theoretically, reintroduction menin should rescue the phenotype Mechanism unclear, thought to bind to transcription factors Men1+/- mice: 5% tumors age <9mo, 84% >=1yr Men1 +/- mice shorter survival than Men-/- mice after 12 mo Men1+/- mice do not develop gastrinoma 85% hyperparathyroidism 60% pancreatic islet cell tumor >35% anterior pituitary tumors >10% adrenal cortical tumors, including pheochromocytoma >15% thyroid tumors (follicular) testicular tumors (>65%) , ovarian tumors (>40%)

References OMIM Cummings, Head and Neck Surgery, 4th edition Agarwal et al, Molecular pathology of the MEN1 gene, Ann NY Acad Sci, 2004, v1014:189-98 Harding et al, Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia, Endocr Relat Cancer, 2009, 16(4):1313-27 Borot et al, Results of cryopreserved parathyroid autografts: A retrospective multicenter study, Surgery v147(4):529-535, 2010 Tan et al, Intramuscular injection of parathyroid autografts is a viable option after total parathyroidectomy, World J Surg, 2010, v34(6):1332-6