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

2. Multiple Endocrine Neoplasia Syndrome

3. 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

4. MEN type 1

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

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

13. 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%)

14. MEN type 2 – ret gene

15. MEN type 2 – ret gene

16. MEN type 2A

17. 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

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

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

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

21. 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)

22. 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)

23. 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

24. MEN type 2B – Clinical features
Marfanoid habitus
Ganglioneuroma

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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:
Bordi et al : Multiple endocrine neoplasia (MEN)-associated tumours: Digestive and Liver Disease 36 (Suppl. 1) (2004) S31–S34

34. Thank you for your attentions.