Endocrine Surgery Round H.K. Oh M.D. Department of Surgery

Multiple Endocrine Neoplasia Syndrome

Introduction Genetic basis Tumor development MEN I MEN II A MEN II B Tumor suppressor gene, Proto-oncogene Predisposition to neoplastic transformation in multiple target endocrine tissues Tumor development synchronously or metachronously diffuse preneoplastic hyperplasia -> multifocal carcinoma MEN I Parathyroid hyperplasia, Pancreaticoduodenal neuroendocrine tumor, Pituitary adenoma MEN II A MTC, Pheochromocytoma, parathyroidal hyperplasia MEN II B MTC, Pheochromocytoma, mucosal neuroma, marfanoid habitus

MEN type 1

MEN type 1 Wermer's syndrome Genetic studies and Pathogenesis since his description in 1954 of the autosomal dominant mode of inheritance Genetic studies and Pathogenesis Allelic deletion; two mutational model (two hits theory) Germ line mutation + somatic mutation MEN 1 gene (1997) located on chromosome 11q13 10 exons spanning 9kb of genomic DNA Encodes a 610 amino acid protein product (menin) Tumor suppressor gene More than 300 independent mutations are known. Mutations are found in >90% of families with the syndrome.

MEN type 1 - Clinical Features AD dominant inheritance complete penetrance, but variable expressivity When compared with sporadic tumors Early onset Multifocal involvement Concurrent neoplasm in multiple endocrine tissues Manifestations Overproduction of hormone Local mass effect Malignant progression Principal cause of mortality Duodenopancreatic neuroendocrine malignancy

MEN type 1 – Parathyroid glands Hyperparathyroidism ; major endocrine abnormality in MEN 1 (95%) Involvement of all 4 glands Histology ; generalized chief cell hyperplasia Hypercalcemia ; Renal stones, nephrocalcinosis Surgery Subtotal parathyroidectomy (3 1/2 glands) and cervical thymectomy Total parathyroidectomy and cervical thymectomy with heterotopic parathyroid autotransplantation (usually the brachioradialismuscle of the non-dominant forearm or the pectoralis major) Recurrence -> excision of a grafted tissue under local anesthesia

MEN type 1 – pancreas and duodenum Characteristics Multifocal, diffuse islet cell hyperplasia, microadenoma Neuroendocrine tumor, High malingant potental Gatrinoma Peptic ulcer, reflux esophagitis, secretory diarrhea Usually malignant, frequent within duodenal wall Small size ; CT, Endoscopic US, Angiography Diagnosis Gastric acid hypersecretion + elevated fasting serum gastrin(>100pg/ml) Secretin test ; secretin iv injection(2u/kg) -> serum gastrin (>200pg/ml) Resection; controversial effect, parathyroidectomy

MEN type 1 – pancreas and duodenum Insulinoma Small, even distribution throughout the pancreas Recurrent symptom of neuroglycopenia Sweating, dizziness, confusion, or syncope Diagnosis Symptomatic hypoglycemia + elevated plasma insulin and C-peptide (during 72hr fast) Surgery ; absent ideal medical therapy Preoperative regional localization is important. Complete mobilization of pancreas and careful examination of the gland by inspection and palpation Intraoperative Ultrasonography ; maybe helpful. Enucleation ; small, benign insulinomas Partial pancreatectomy ; multiple or potentially malignant tumors Blind subtotal pancreatectomy ; not recommended

MEN type 1 – pituitary gland Prolactinoma Mass effect ; visual field defects, hypopituitarysm Hypersecretion of hormone Amenorrhea, galactorrhea in women, and hypogonadism in men Treatment ; Surgery, dopamine agonist (bromocripine) Acromegaly ; Growth hormone Cushing’s disease ; Corticotropin

MEN type 1 - Screening restriction enzyme (RE) analysis allele-specific oligonucleotide (ASO) hybridization single-stranded conformational polymorphism (SSCP) An approach to screening in an asymptomatic relative of a patient with multiple endocrine neoplasia type 1 (MEN-1). The relative should ®rst have undergone a clinical evaluation for MEN-1-associated tumours to establish that the individual is asymptomatic. Relatives who are symptomatic, who could also have a test for MEN-1 mutations, should proceed to appropriate investigations and management. Mutational analysis for MEN-1 is not routinely available at present, and this protocol could instead be adapted for ®rst- degree relatives.9 The MEN-1 mutation may be identi®ed directly by DNA sequence analysis, or by restriction enzyme (RE) analysis (see Figure 3), allele-speci®c oligonucleotide (ASO) hybridization40,127 or another method, such as single-stranded conformational polymorphism (SSCP) analysis.40 The use of mutational analysis and such screening methods in children is controversial and varies between countries. It has been suggested that non-essential genetic testing in a child who is not old enough to make important long-term decisions should be deferred.177 However, the ®nding that a child from a family with MEN-1 does not have any MEN-1 mutations removes the burden of repeated clinical, biochemical and radiological investigations and enables health resources to be more e€ectively directed towards those children who are MEN-1 mutant gene carriers. PRL . prolactin. Reproduced from Thakker (2001; In: DeGroot LJ & Jameson JL (eds) Endocrinology, 4th edn, pp 2503±2517. Philadelphia: WB Saunders)178 with permission. Endocrinology, 4th edn

MEN type 2 2A 95% , 2B 5%

MEN type 2 - Etiology Familial cancer syndromes ; AD heritance ret proto-oncogene Location; Chromosome 10 ( region 10q 11.2 ) Encodes a cell-surface glycoprotein related to the family of receptor TK that is expressed in derivatives of neural crest cell. Normally expressed in C-cells(neural crest origin ; thyroid, ardrenal medulla, autonomic plexus), chromaffin and parathyroid cell Activation -> initiation of transformation Point mutations ; genotype-phenotype correlation Extracellular domain -> MEN 2A (97%), FMTC (96%) TK domain -> MEN 2B (95%)

MEN type 2 – ret gene

MEN type 2 – ret gene

MEN type 2A

MEN type 2A – Clinical features Medullary thyroid carcinoma C-cell origin ; calcitonin -> secretory diarrhea, flushing The most common manifestation of MEN 2 Occurs in 95% of gene carriers during life and can be lethal. Muticentric, bilateral, and in a background of C-cell hyperplasia Palpable mass ; cervical LN metastasis ( over 50 % ) Distant metastasis (late course) ; liver, lung, bone etc. Diagnostic markers Basal calcitonin > 10pg/ml Calcium(2mg/kg/min)-Pentagastrin(0.5ug/kg/5sec) stimulated calcitonin > 100pg/ml

MEN type 2A – Clinical features Clinical patterns of sporadic and inherited MTC

MEN type 2A – Clinical features LN metastasis of Palpable MTC

MEN type 2A – Clinical features LN metastasis of Palpable MTC

MEN type 2A – Clinical features Pheochromocytoma The cause of death of the first patient reported in Sipple’s original description of MEN 2 (1961) Diffuse or nodular hyperplasia of the adrenal medulla; precursor Often multifocal, bilateral but rarely malignant, extraadrenal in MEN 2 Symptoms ; due to excess catecholamine secretion headaches, palpitations, nervousness, but uncommon paroxysmal HT Mild clinical presentation, but still life-threatening condition Although often presenting later than MTC, pheochromocytoma need to be excluded before an thyroidectomy on a patient to have ret mutation. Diagnosis Biochemical screening ; measurement of plasma or 24hr urine catecholamines and metanephrines on an annual basis CT, MRI (confirmative on positive or borderline biochemical test)

MEN type 2A – Clinical features Hyperparathyroidism 10 ~ 30 % of patients with MEN 2A Median age ; 38yr, usually asymptomatic Hypercalcemia urinary stone, osteopenia, and altered mentality Multiglandular hyperplasia Cutaneous Lichen Amyloidosis Pruritic, lichenoid skin lesions over the upper back Due to deposition of amyloid at the dermo-epidermal junction Phenotypic marker of MEN 2A (precedes the MTC)

MEN type 2B – Clinical features Medullary thyroid carcinoma Younger age more extensive disease, main cause of death Pheochromocytoma Marfanoid habitus (90%) Tall, slender body, high arched palate, long extremity Ganglioneuroma phenotype (90%) Neuromas of the anterior one third of the tongue, lips, buccal mucosa, conjunctiva, eyelid Diffuse GI ganglioneuromatosis Colonic motility dysfunction, constipation, diarrhea, crampy abdominal pain, abdominal distention, megacolon

MEN type 2B – Clinical features Marfanoid habitus Ganglioneuroma

MEN type 2 - Screening Need for screening Genetic screening Incomplete penetrance Early detection -> Early intervention -> Mortality rate ↓ Genetic screening Molecular linkage techniques Identification of point mutations of the ret gene MEN 2A ; before 5years old, MEN 2B ; after birth Biochemical screening Calcitonin; operation at minimal increase->cure chance ↑ 24hr excretion of catecholamines and metanephrine Calcium, PTH

MEN type 2 - Screening Indication for genetic testing in MEN syndrome de novo gene mutation Shapiro et al : The Role of Genetics in the Surgical Management of Familial Endocrinopathy Syndromes J Am Coll Surg November 2003

MEN type 2 - therapy Medullary thyroid carcinoma Considerations compared by differentiated thyroid ca. Usually aggressive, higher recurrence, and mortality rates Don’t take up RAI, ineffective RT, and chemotherapy Multicentricity, higher nodal metastasis Total thyroidectomy with central LN dissection ± Bilateral cervical LN dissection Gross parathyroid enlargement or hyperparathyroidism -> Parathyroidectomy with autotransplantation Follow up Calcitonin ; 1~ 4wks after operation If WNL -> Excellent prognosis CEA ; 6wks after operation (long half life) Persistent / recurrent disease reoperation ; curative(with completion of LND) or palliative Central node dissection ; hyoid bone, innominate vein, carotid sheet triangle

MEN type 2 - therapy Medullary thyroid carcinoma Preventive thyroidectomy MEN 2A, FMTC ; before age six MEN 2B ; during infancy Central node dissection ; hyoid bone, innominate vein, carotid sheet triangle Jimenes et al : Genetic testing in endocrinology: lessons learned from experience with multiple endocrine neoplasia type 2 Growth Hormone & IGF Research 14 (2004) S150–S157

MEN type 2 - therapy Pheochromocytoma Preoperative Medical stabilization alpha-adrenergic blocker; 5days ~ 2wks phenoxybenzamine, prazocin, doxazocin beta-adrenergic blocker ; adjuvant Subtotal(Cortical-sparing) adrenalectomy Remained cortex prevent adrenal insufficiency, and steroid use Recurrence in the remnant adrenal gland ; rare Total adrenalectomy Unilateral (involved adrenal only) adrenalectomy Contra lateral tumor development (50%) , mean interval 12yrs Bilateral adrenalectomy Adrenal insufficiency Laparoscopic adrenalectomy in MEN 2 Due to rarely malignant, and almost never extra-adrenal distribution Central node dissection ; hyoid bone, innominate vein, carotid sheet triangle

Optimal surgical strategy TA; Total adrenalectomy CS; Cortical-sparing adrenalectomy Adrenal operations performed in 56 patients with hereditary pheochromocytoma. *Bilateral completion adrenalectomy was performed for presumed recurrent pheochromocytoma, but histopathology showed bilateral cortical hyperplasia with no evidence of recurrent pheochromocytoma. †Recurrent pheochromocytoma in contralateral nonoperated gland. ‡Recurrent pheochromocytoma in ipsilateral operated gland. CS, cortical-sparing adrenalectomy; TA, total adrenalectomy. Unilateral pheochromocytoma => Laparoscopic total adrenalectomy Bilateral pheochromocytoma => Open Unilateral CS with contralateral TA Metachronous pheochromocytoma => Open CS Yip et al : Surgical Management of Hereditary Pheochromocytoma J Am Coll Surg April 2004

MEN type 2 - Prognosis MTC Life expectancy Indolent, slow growing, but lethal with distant metastasis MEN 2A , FMTC > Sporadic MTC > MEN 2B Life expectancy Before current screening technique 50yrs for MEN 2A 30yrs for MEN 2B Modern era Becoming more clear

New Patient with Suspicious MCT Hoarseness/dysphagia/cough ? Renal stone Hx.? HA/Palpitation/Nervousness GI problem ; obstruction, pain General appearance (marfanoid?) BP, HR Neck mass, LAP Skin lesion ; upper back

References Harrison’s Principles of Internal Medicine (online) Sabiston Textbook of Surgery 17ed Randolph Surgery of the thyroid and parathyroid glands. Shapiro et al : The Role of Genetics in the Surgical Management of Familial Endocrinopathy Syndromes J Am Coll Surg November 2003; 197:5. Yip et al : Surgical Management of Hereditary Pheochromocytoma J Am Coll Surg April 2004. KAHRAMAN et al : Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a Eur J Sur Onc 2003; 29: 331±335. Simon et al : Multiple Endocrine Neoplasia 2A Syndrome: Surgical Management J Pediatr Surg 37:897-900. Bordi et al : Multiple endocrine neoplasia (MEN)-associated tumours: Digestive and Liver Disease 36 (Suppl. 1) (2004) S31–S34

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