Multiple endocrine neoplasia Type 1

Abhilash

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)

• Other neoplasms

– Adrenocortical tumors

– Thyroid tumors.

– Visceral and cutaneous lipomas.

– Meningiomoas.

– Facial angiofibromas

– Collagenomas

– Thymic, gastric and bronchial carcinoids.

• 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.

Epidemiology

• Incidence 1 in 30,000.

• M:F=1:1

• No racial or ethnic predilection.

• Diagnosis before 10 years of age is rare.

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.

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

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.

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

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.

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

Insulinomas

• 10% MEN1 patients

• Usually occur in third decade.

• Single or multiple macroadenomas.

• Benign.

• May present with hypoglycemia responsive to glucose.

Glucogonomas

• Rare.

• Usually as single macroadenoma>3cm.

• Skin rash(necrolytic migratory erythema), venous thrombosis, anemia, diarrhea, anorexia, weight loss, stomatitis, hyperglycemia, hyperglucogonemia.

VIPomas

• Rare.

• WDHA syndrome.

• Watery diarrhea, hypokalemia, achlorhydria.

PP omas

• Secrete pancreatic polypeptide.

• No clinical significance.

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.

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.

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.

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

Collagenomas and facial angiofibromas

• Collagenomas >70 % cases – multiple, skin coloured cutaneous nodules. Asymptomatic.

• Multiple facial angiofibromas – 40-90% MEN1.

• Benign tumors. Acneiform papules.

LIPOMAS

• 20-30% MEN1 cases

CNS

• Meningiomas – 8%

• Ependymomas – 1%

Diagnosis

• Biochemical abnormalities with clinical features in age <40 years can be suggestive of MEN1.

• Mutational analysis of MEN1 gene

Parathyroid tumors.

• Serum PTH.

• Serum Calcium.

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

Gastrinomas

• Elevated serum fasting gastrin.

• Increased basal gastric acid secretion.

• Secretin stimulated gastrin test.

Insulinomas

• 72 hour fasting protocol.

• Fasting hypoglycemia reversed with glucose with high insulin, elevated C peptide levels and proinsulin levels.

Prolactinomas

• MRI

• Fasting prolactin levels 20 fold than upper limit of normal is diagnostic.

• 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

Management.

• Surgery is the mainstay for treatment.

• Medications to control hormone secretion.

• Chemotherapy and radiation have minimal role.

Parathyroid tumors

• Indications for surgery

– Symptomatic PHPT.

– Hypercalciuria, hypercalcemia and presence of gastrinoma.

• Recurrence more common than in sporadic cases.

• 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.

• Rapid intraoperative PTH assays to ensure no ectopic or supernumerary glands.

• Alternatively total parathyroidectomy followed by life long treatment with VitD analogues.

• Calcimimetics – calcium sensing receptor agonists. – reduce PTH release and parathyroid hyperplasia.

• Cinacalcet- in patients with recurrence or unfit for operation.

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.

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.

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.

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

Adrenocortical tumors

• No consensus.

• Larger tumors – surgical removal – due to higher malignant potential.

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.