Multiple endocrine neoplassia

MEN I

• Components:- (1) Classical lesions:- Endocrine tumors of parathyroid

gland, endocrine pancreas-duodenum complex, and anterior pituitary gland

(2) Other lesions:- foregut carcinoids (in the thymus, bronchial tree, and the stomach), adrenocortical hyperplasia; and non endocrine tumors, such as meningioma, ependymoma, eiomyoma, lipoma, facial angiofibroma, and collagenoma

Epidemiology

• Incidence Overall (postmortem studies) 0.25% Primary hyperparathyroidism 1–18% Gastrinomas 16 – 38

% Pituitary tumors <3 %• M:F = 1• Age 5 to 81 yr

Etiopathogenesis

• Familial:- Autosomal dominant with a high degree of penetrance

• Sporadic :- 8 to 14% of patients with MEN 1

• Mutations of the MEN-1 tumor suppressor gene on chromosome 11q13 encoding for ‘MENIN’ protein

• Resulting in DNA replication and repair.

Diagnosis

Genetic diagnosis

• Complete MEN-1 gene sequencing - best method and positive in 70% to 90% of typical MEN-1 cases.

• Multiplex ligation-dependent probe amplification (MLPA) assay –recent and for detection of large deletions occurring in 4% of MEN-1 cases

• Negative genetic testing cannot exclude the syndrome

• Candidate - index patients and first-degree relatives

• Offer at the earliest opportunity• Genetic counseling before testing

Surveillance and screening

• Recommended in presymptomatic gene carriers

• Started in first decade of life• By a combination of biochemical tests and

imaging studies

Primary HPT (pHPT)

• Primary HPT - Commonest (90%) and first detected endocrinopathy

• Often diagnosed around 20 years of age, and >95% before age of 40 years

Clinical features

• Decrease in bone mineral density, nephrolithiasis, fatigue, weakness, asthenia, depression, and typical concentration difficulty

Diagnosis

• Biochemical:- raised ionized or total-albumin corrected serum calcium and raised serum parathyroid hormone (PTH)

• Localisation:- Recommended in recurrent settings

MEN 1 v/s other causes of pHPT

• Mild hypercalcemia, severe is rare,• Earlier age at onset (20 to 25 yr vs. 55 yr), • Greater reduction in bone mineral density• Male/female ratio (1:1 vs. 1:3)

Pathology

• Asymmetric nodular hyperplasia resulting in multiple tumors.

• Most benign• Carcinoma rare (only 3 case reports)

Surgical management

• Challenge:- high recurrence rate • Issues:- Open bilateral neck exploration v/s minimally

invasive parathyroidectomy

Subtotal parathyroidectomy v/s total parathyroidectomy

Subtotal parathyroidectomy

• Surgery of choice as primary surgery• 3 to 3.5 gland removed• Remnant - smallest, most normal gland,

vascularity verification• Chance of persistent or recurrent

hypercalcemia - 40 to 60% within 10 to 12 yrs• Chance of hypocalcemia (requiring long-term

calcitriol) - 10 to 30%

Total parathyroidectomy

• Auto transplantation (forearm or subcutaneous fat on the thorax or abdomen)

• 10 fresh parathyroid pieces each 1 mm in size • High risk of hypoparathyroidism• Chance of recurrent hypercalcemia >50%• Required in presence of extensive disease or

in recurrence• For grafting - smallest, least diseased gland

Supernumary parathyroid tissue

• Cervical thymectomy + clearance of perithyroid fat

• Contribute for 15 % of recurrence

• Intraoperative PTH determination:- Requires special criteria to avoid false results, implying evaluation 20 minutes after glandular removal and that an end point value within the assay limits is reached

• Cryopreservation of parathyroid tissue:- recommended if facilities are available - risk for remnant ischemia and permanent hypoparathyroidism.

parathyroid tissue verification in resected specimens

• Needle biopsy aspiration with rapid PTH determination has replaced frozen sections

Re -Surgery

• Localization studies – 1. USG, 2. Sestamibi scintigraphy, 3. CECT, 4. PET with methionine tracer, 5. USG guided FNA with PTH measurement, 6. Selective venous sampling with rapid PTH

determination• Concordant results of two investigations are required

Endocrine Pancreatic and Duodenal Tumors

• Incidence - 30 to 80% in different series• Nonfunctioning (PPoma) 20 to 55 %• Gastrinoma – commonest (40%)• Multiple & Earlier age of onset

Risk of Metastatic

• Presence of a clinical syndrome of hormone excess (up to 50% risk)

• Size > 3 cm• 25–40% of patients with pNET >4 cm develop

hepatic metastases, and 50–70% of patients with tumors 2–3 cm in size have lymph node metastases

Gastrinoma

• Age of onset after 30 years• Microadenoma, Multiple & deep mucosal• Gastrinoma triangle• Pancreatic Gastrinoma – large & early liver metastases concomitant nonfunctioning NET

• Clinical Features - ZES• Biochemical Diagnosis:- Increased fasting

serum gastrin concentration in association with increased basal acid output (gastric pH <2) and if needed iv provocative tests with either Secretin (2 U/kg) or calcium infusion (4 mg Ca/kg/h for 3 h)

Localization

• Ultrasonography, Endoscopic USG, CT, MRI, Selective abdominal angiography or Somatostatin-receptor scintigraphy

• The combined use of intraarterial calcium injections with hepatic venous gastrin sampling

Failure of localization

• In MEN1, ZES does not develop in the absence of primary hyperparathyroidism, and hypergastrinemia has also been reported to be associated with hypercalcemia

Treatment

• Surgical:- (1) Controversial role (2) Indication - size > 2 cm, symptomatic (3) C/I - Liver metastases (4) Duodenectomy or Limited resection (5) Whipples most effective but less

preferred (cure rate > 65%)

Limited resection v/s Whipples

• Best cure rate with Whipples – 65%• Excellent survival with limited resection – 52%

and 100% at 15 yr in patients with and without metastases, respectively

Non surgical treatment PPI – Backbone UGIE Surveillance – ulcer, carcinoid

Treatment of metastatic Gastrinoma

• Chemo - Streptozotocin and 5-FU• Somatostatin analogs - octreotide or

lanreotide• Hepatic artery embolization• Administration of human leukocyte interferon• Removal of all resectable tumor

Insulinoma

• Incidence 10 to 30% of pNET• Affected age group – younger than 40 yr• Usually single & >5 mm in diameter but

concomitant other pNET may exist• Hypoglycemic symptoms• 72 hours fasting test – diagnostic

• Preoperative localization – EUS, MRI, CT or celiac axis angiography, selective intraarterial stimulation with hepatic venous sampling, and intraoperative direct pancreatic USG

• Surgery - Enucleation – commonly performed, • Other options:- Distal pancreatectomy or partial

pancreatectomy, or excision of all the macroscopic pancreatic tumors with enucleation of nodules in the remaining pancreas

• Monitoring the insulin/glucose ratio during surgery

• Metastatic disease - Streptozotocin, 5-FU and Doxorubicin or hepatic artery embolization

Nonfunctioning pNET

• Commonest pNET• Malignant pNET - commonest cause of death

in MEN1• Worse prognosis than functioning tumors• Indication of surgery – size >1 cm &

symptomatic

Target therapy

• Sunitinib & Everolimus are of proven benefit (increase survival) in advanced pNET but these studies don’t specify MEN 1 status, so probably advanced MEN 1 patients may get benefitted from these drugs.

Pituitary tumors

• Incidence - 15 to 50%• Age of onset - 5 yr of age to as late as the

ninth decade, and the mean - 38.0+/-15.3 yr• F > M• Macroadenoma – 85%• 1/3 – invasive histology – locally aggressive

but not carcinoma

• 60% secrete prolactin, 25% secrete GH, 5% secrete ACTH and remainder nonfunctioning

• Treatment :- medical therapy (bromocriptine or cabergoline for prolactinoma; or octreotide or lanreotide for somatotrophinoma) or selective transsphenoidal adenomectomy with radiotherapy reserved for residual or unresectable

Carcinoid tumors

• Overall incidence <3 %• Bronchial, Thymic and Gastric• Thymic – aggressive course – increased risk of

death – median time to death 9.5 years• Most – no Carcinoid syndrome• No hormonal or biochemical abnormality –

chromogranin ‘A’ absent• Imaging - CT, MRI, SRS – not a routine• Treatment - surgery

Adrenocortical tumors

• Incidence of asymptomatic tumors - 20–73%• <10% have hormonal hypersecretion• Risk of carcinoma - >4 cm in size, atypical or

suspicious radiological features in 1–4 cm sized, show significant measurable growth over a 6-month interval and with hyperandrogenemia

• Treatment – surgical