2. Introduction
• Rare hereditary cancer syndrome.
• “Wermer’s syndrome”
• Tumors of
1. Parathyroid gland(95% of cases)
2. Endocrine gastroenteropancreatic tract (30-
80% cases)
3. Anterior pituitary (15-90% cases)
3. • Other neoplasms
– Adrenocortical tumors
– Thyroid tumors.
– Visceral and cutaneous lipomas.
– Meningiomoas.
– Facial angiofibromas
– Collagenomas
– Thymic, gastric and bronchial carcinoids.
5. • Usually have a family history of MEN1.
• Autosomal dominant.
• MEN1 gene mutations -70-95% MEN1
patients.
• Leading cause of mortality – entero-pancreatic
gastrinomas, thymic and bronchial carcinoids.
6. Epidemiology
• Incidence 1 in 30,000.
• M:F=1:1
• No racial or ethnic predilection.
• Diagnosis before 10 years of age is rare.
7. Historical background.
• Erdheim reported 1st case of MEN1 in 1903.
• Cushing and Davidoff reported classical MEN1
triad in 1920s.
• Underdahl – first review of 14 cases of MEN1
• Wermer in 1954 – MEN1 –Autosomal dominant.
• 1988- MEN1 locus mapped to 11q13
• 1997 – MEN1 mutations confirmed to cause
MEN1 syndrome.
8. Pathogenesis
• Knudsons two hit model for tumor suppressor
gene carcinogenesis.
• First hit – heterozygous MEN1 germline
mutation inherited from parents.
• Second hit – MEN1 somatic mutation-
deletion
9. Genetics
• MEN1 gene mutation in 75-90% cases.
• Highly penetrant.
• 50% symptomatic by 20 years of age. 95% are
symptomatic by 40 years of age.
• Environmental modifiers unknown.
10. Parathyroid glands
• PHPT – most common in MEN1.
• More than 95% by 50 years of age.
• First manifestation in 90%.
• Multiglandular and earlier in onset than
sporadic.
• Symptoms of hypercalcemia.
• Hypercalcemia may increase gastrin secretion
from gastrinoma
12. GEP tract NETs
• Second most common manifestation of MEN1
• 30-80% cases.
• Multiple nodular lesions.
• 2/3rd are functional.
• Gastrinomas 54%, Insulinomas 15%.
• Non functional and insulinomas are present in
pancreas. Gastrinomas in submucosa of
duodenum and soft tissue around pancreas.
13. Gastrinomas
• 54% of GEP NETs
• 90% located in duodenum.
• ZES – esophagitis, vomiting, epigastric pain,
diarrhea, duodenal ulcers, jejunal ulcers
• 40% manifest before age of 40.
• Frequently multiple and malignant.
• Pancreatic has worse prognosis due to liver
metastasis.
• Other poor prognostic factors – very high gastrin
levels, ectopic cushings and liver metastasis
14. Insulinomas
• 10% MEN1 patients
• Usually occur in third decade.
• Single or multiple macroadenomas.
• Benign.
• May present with hypoglycemia responsive to
glucose.
15. Glucogonomas
• Rare.
• Usually as single macroadenoma>3cm.
• Skin rash(necrolytic migratory erythema),
venous thrombosis, anemia, diarrhea,
anorexia, weight loss, stomatitis,
hyperglycemia, hyperglucogonemia.
18. Anterior pituitary tumors
• Occurs in 15-90% of cases.
• Usually single.
• Invasive in 15-20 %, Malignant change – rare.
• Symptoms – hormone, size related.
• Bitemporal hemianopia and other visual field
defects.
• 60%- prolactin, 25% -GH, 3%- ACTH
• Mean age of diagnosis is 40 years.
19. Prolactinomas
• Most common pituitary
tumors in MEN1.
• Galactorrhoea,
amenorrhea, infertility in
women, hypogonadism,
sexual dysfunction,
impotence.
GH secreting tumors
• Second most frequent.
• Gigantism in children and
acromegaly in adults.
20. Other MEN1 associated tumors
• Adrenocortical tumors – 20-40% of MEN1.
Most are non functional.
• Functional tumors can cause hypercortisolism
, cushings, hyperaldosteronism.
• Pheochromocytoma - <1% cases. Unilateral.
• Thyroid tumor – adenoma/colloid/carcinoma.
In 25%. Association may not be significant.
21. Carcinoid tumors
• Occurs in 10% of MEN1.
• GI tract, pancreas, bronchi, thymus.
• Thymic carcinoids are aggressive and often
lethal.(mainly male smokers)
• Bronchial carcinoids are indolent.
• Carcinoid syndrome – rare – flushing attacks
and dyspnea
28. GEP NETS
• EUS – most sensitive
• Endoscopy and EUS for duodenal gastrinomas.
• 111In DTPA octreotide scan for pancreatic islet
imaging – to assess spread of disease and liver
metastasis.
• Functional tumors according to the hormone
released.
• Chromogranin A
30. Insulinomas
• 72 hour fasting protocol.
• Fasting hypoglycemia reversed with glucose
with high insulin, elevated C peptide levels
and proinsulin levels.
32. • Adrenocortical tumors – EUS most sensitive.
• Biochemical test – DHEA, normetanephrine,
epinephrine, VMA, norepinephrine.
• Pheochromocytoma – Biochemical tests –
Increased urinary catecholamines and
metabolites.
• Tumor localization by CT/MRI
• Carcinoids – CT or MRI of chest.
• Endoscopy for gastric carcinoids
• Urine 5HIAA, chromogranin A, calcitonin,
corticotropin
34. Management.
• Surgery is the mainstay for treatment.
• Medications to control hormone secretion.
• Chemotherapy and radiation have minimal
role.
35. Parathyroid tumors
• Indications for surgery
– Symptomatic PHPT.
– Hypercalciuria, hypercalcemia and presence of
gastrinoma.
• Recurrence more common than in sporadic
cases.
36. • Subtotal parathyroidectomy or total
parathyroidectomy.
• Subtotal prevents permanent
hypoparathyroidism and reduces temporary post
surgical hypocalcaemia.
• Recurrence in subtotal parathyroidectomy -50%
after 8-12 years.
• Often surgery of choice – Total
parathyroidectomy with autologous graft in
brachioradialis .
• Preventive bilateral cervical total thymectomy.
37. • Rapid intraoperative PTH assays to ensure no
ectopic or supernumerary glands.
• Alternatively total parathyroidectomy
followed by life long treatment with VitD
analogues.
38. • Calcimimetics – calcium sensing receptor
agonists. – reduce PTH release and
parathyroid hyperplasia.
• Cinacalcet- in patients with recurrence or unfit
for operation.
39. Gastrinomas
• Non-metastatic gastrinoma – surgery.
• PPI and somatostatin analogue.
• Chemotherapy with 5FU and streptozotocin.
• Surgical resection recommended for non metastatic
tumors.
• Duodenal gastrinomas <5mm – longitudinal
duodenectomy and enucleation from submucosa.
>5mm- full thickness excision from duodenal wall.
• Tumors more than 2cm have high rate of liver
metastasis.
• Whipples procedure.
40. Insulinomas
• Chemotherapy with streptozotocin or
octreotide for metastatic disease
• Surgical approach by intraoperative
localization by palpation or USG followed by
enucleation.
• Pancreatic resection if multiple large deep
nodules.
41. Glucogonomas, VIPomas, Ppomas,
somatostatinomas and non functional
GEP tumors
• Surveillance by EUS.
• Pancreatic surgery of size of lesion approaches
2 cm.
• No role in the presence of systemic
metastasis.
• Medical treatment with streptozotocin,
octreotide, corticosteroids , indomethacin ,
metoclopramide, lithium carbonate.
42. Anterior pituitary tumors.
• Transphenoidal resection, endoscopic
resection or radioablation are TOC for
macroadenomas.
• Dopamine agonists ( cabergoline,
bromocriptine, pergolide, quinagolide) – PRL
secreting microadenomas.
• Somatostatin analogues for GH secreting
microadenomas.
• Non functional adenomas - surgery
43. Adrenocortical tumors
• No consensus.
• Larger tumors – surgical removal – due to
higher malignant potential.
44. Carcinoids.
• Surgery - TOC for bronchial and thymic carcinoids.
• Thymic carcinoids have 100 % recurrence after 1
year of surgery.
• Prophylactic thymectomy at time of neck surgery.
• Gastric type 2 NETS- somatostatin analogues,
endoscopic surveillance and gastrectomy once
macrolesions are visible.
• Somatostatin analogues – reduce tumor size and
reduce gastrin secretion in MEN1.