1. MULTIPLE ENDOCRINE NEOPLASIA
Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

2. MULTIPLE ENDOCRINE NEOPLASIA
Multiple endocrine neoplasia (MEN) syndromes consist of rare, autosomal dominant mutations in genes that regulate cell growth.
Classification recognizes:
Type I & type II MEN
Type II divided into the
Type IIA
Type IIB
Menin protein:
Produced by the MENIN gene, is a tumor suppressor.
Loss of this protein allows tumors to arise.
Ret protein:
Produced by the RET gene
proto-oncogene, can be
constitutively activated,
causing abnormal cell
proliferation

6. MULTIPLE ENDOCRINE NEOPLASIA
Type 1 MEN is hyperfunctioning following tumors:
All 4 parathyroid glands
Pancreatic islets
gastrinoma
insulinoma
glucagonoma
vasoactive intestinal peptide tumor (VIPoma)
pancreatic polypeptide–producing tumor (PPoma)
Anterior pituitary
prolactinoma,
somatotropinoma,
corticotropinoma
nonfunctioning tumors

7. MULTIPLE ENDOCRINE NEOPLASIA
Type 2A MEN is defined by:
Thyroid carcinoma (100%)
Pheochromocytoma (50%)
Hyperparathyroidism (20%)
Familial MTC is hereditary MTC without other associated endocrinopathies
Type 2A MEN (Sipple syndrome) accounts for most cases of type 2 MEN.
Type 2 MEN affects about 1 in 40,000 individuals
C-cell hyperplasia develops early in life and can be viewed as the precursor lesion for MTC, which often arises multifocally and bilaterally.
Less than 25% of patients with type 2A MEN develop hyperparathyroidism
Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation.

8. Type 2B MEN is defined by: MTC Pheochromocytoma.
MULTIPLE ENDOCRINE NEOPLASIA
Type 2B MEN is defined by:
MTC
Pheochromocytoma.
Associated abnormalities include:
Mucosal neuromas
Medullated corneal nerve fibers
Marfanoid habitus
MTC is relatively aggressive and frequently occurs in childhood
Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and, often, bilateral involvement

9. Etiology Type 2 MEN Type 1 MEN
The RET gene is responsible for type 2 MEN proto-oncogene, located on band 10q11.2
RET leads to hyperplasia of target cells in vivo and tumor development
Type 1 MEN
The MENIN gene responsible for type 1 MEN has been localized to chromosome band 11q13;
It produces a nuclear protein called menin, a tumor suppressor.

10. Clinical presentation
Type 1 MEN
Hyperparathyroidism is most common initial clinical manifestation of type 1 multiple endocrine neoplasia (MEN).
Some patients may manifest findings of ZES before they have hyperparathyroidism.
Symptoms of gastrinoma may become clinically apparent either with abdominal pain and diarrhea or with complications such as ulcer perforation or bleeding.
Type 2A MEN
All patients develop MTC on the basis of C-cell hyperplasia.
About 50% of patients with MTC manifest pheochromocytomas (usually late in life), and 20% of patients have hyperparathyroidism.
Type 2B MEN
Pheochromocytomas occur earlier than in patients with type 2A MEN.

11. Clinical presentation MEN Type 1
Pancreatic endocrine tumors
These occur in about 70% of patients with MEN1.
60% of tumors are gastrinomas and produce ZES
PU account for most of the MEN1 morbidity and mortality
About 30% are insulinomas.
VIPoma (vasoactive intestinal peptide and pancreatic polypeptide-secreting tumor)
Duodenal microgastrinoma is very common and probably accounts for almost half of all MEN1-associated gastrinomas.
They are usually multiple, with up to 15 separate tumors.

12. They tend to be more aggressive than sporadic cases.
Clinical presentation MEN Type 1
Pituitary adenomas
Present by screening in 30% of patients, but is found at post-mortem in 50%.
Unlike the pancreas and parathyroid, there does not appear to be diffuse pituitary hyperplasia.
Prolactinoma producing hyperprolactinaemia occurs in about 30% of cases.
They tend to be more aggressive than sporadic cases.
Acromegaly, due to excessive human growth hormone (hGH) occurs in about 30%.
Adrenocorticotrophic hormone(ACTH) may produce Cushing's syndrome but other functioning tumors are rare.

13. Diagnosis MEN type 1
Screening of first- and second-degree relatives type 1 (MEN1)
Diagnosis of MEN1 depends on high level of suspicion in patients with multiple
Facial angiofibromas,
Collagenomas, and lipomas
Features of hyperparathyroidism
High gastric acid secretion.
Investigations include:
Hormone hypersecretion
Imaging studies for the presence of tumors.
DNA testing is available and identifies a mutation in about 80% of patients with familial MEN1.
Mutation analysis may be used to confirm the clinical diagnosis,
Screen asymptomatic family members.
Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in a family is known

14. Imaging features MEN Syndrome
Radiographic views of the hands in a patient with type 1 (MEN1) and primary hyperparathyroidism.
These images show subperiosteal bone resorption along the radial aspects of the middle phalanges.

15. Imaging features Type 1 MEN Syndrome
CT scan of the pancreas in a patient with type 1 (MEN1) and a gastrinoma. Image shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.

16. Imaging features Type 1 MEN Syndrome
CTscan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma.
The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S)

17. 6x5x5 cm adrenal mass arising from right adrenal
Imaging features Type 1 MEN Syndrome
6x5x5 cm adrenal mass arising from right adrenal

18. Screening tests MEN type 1
Screening tests are:
Serum calcium,
Gasting gastrin,
Prolactin.
Sensitive markers of pancreatic disease are basal and test-meal stimulated pancreatic polypeptide and gastrin, and basal insulin and proinsulin.
80% of affected individuals will have been identified by the 5th decade.
Screening of sporadic pancreatic endocrine tumors for evidence of MEN1 is probably justified, especially for gastrinomas or insulinomas.
There is little evidence to support screening in those with sporadic pituitary tumors.

19. Management Surgical Skin tumors may be removed
The surgical approach to pancreatic endocrine tumors in MEN1 is controversial:
Surgical cure is best achieved by removing the pancreas and duodenum with adjacent lymph nodes. There is still a high rate of recurrence but the overall mortality remains low
Pituitary tumors: Same as for sporadic pituitary tumors.
Parathyroidectomy, subtotal or complete, is practiced for MEN1 but long-term follow-up reveals a high rate of recurrence in MEN1.
The treatment of metastatic disease is the same as in sporadic cases.

20. Prognosis MEN type 1
The average age of death in individuals with multiple endocrine neoplasia type 1 (MEN1) is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.
Pancreatic endocrine tumors, particularly gastrinomas, become malignant in about 50% of patients with MEN1.
Untreated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.
Pancreatic endocrine tumors associated with MEN1 are less malignant than sporadic tumors and carry a better prognosis, with a median survival of 15 years compared to 5 years for patients with sporadic tumors.
This may reflect more indolent disease or earlier diagnosis.

21. Clinical presentation MEN Type 2A
Patients may present with symptoms related to:
Medullary thyroid carcinoma
Hyperparathyroidism
Pheochromocytoma.
Virtually all patients have MCT symptoms may include:
hypertension
episodic sweating
diarrhoea
pruritic skin lesions
lump in the neck(which may cause compressive symptoms).

22. Clinical presentation MEN Type 2A
25% of MEN Type 2A have Hperparathyroidism and associated hypercalcemia may lead to:
Polyuria
Polydipsia
Constipation
Memory problems
Depression,
Nephrolithiasis
Cutaneous lichen amyloidosis in multiple endocrine neoplasia type 2A (MEN2A) presents with multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.

23. Clinical presentation MEN Type 2B
Patients may present with symptoms related to:
Medullary thyroid carcinoma
Pheochromocytoma.
Neuromas usually predate MTC and pheochromocytoma.
Almost all patients have a Marfan's-like habitus.
Neuromas appear as:
Glistening bumps around the lips, tongue, and mouth.
Bumps on the eyelids, which are often thickened
Involvement of peripheral motor and sensory nerves can cause a peroneal muscular atrophy (Charcot-Marie-Tooth syndrome)
Intestinal ganglioneuromatosis affects about 75% of cases.
Delayed puberty is a common feature.

24. MULTIPLE ENDOCRINE NEOPLASIA
Mucosal neuromas

25. Diagnosis of multiple endocrine neoplasia type 2
Screening for pheochromocytoma is 24 hours urine for elevated catecholamines and catecholamine metabolites, especially vanillyl-mandelic acid (VMA).
Clinical suspicion or elevated urinary catecholamine values demand an abdominal MRI scan. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas.
Thyroid tumours can be investigated initially by ultrasound and fine-needle aspiration.

26. Diagnosis of multiple endocrine neoplasia type 2
Medullary thyroid carcinoma (MTC) is suspected with an elevated plasma calcitonin concentration.
This is a specific and sensitive marker. In provocative testing, calcitonin concentration is measured before and 2 and 5 minutes after intravenous administration of calcium.
Parathyroid abnormalities are diagnosed when there are simultaneously elevated serum calcium and parathyroid hormone levels with an elevated urinary calcium to creatinine ratio.

27. Screening for multiple endocrine neoplasia type 2
The two types of molecular
diagnosis for MEN2 are: Mutation and
Linkage analysis
of the RET proto-oncogene
(chromosomal locus 10q11)
Genetic linkage analysis has 98-99% predictive accuracy
Screening for early detection of thyroid, parathyroid and adrenal disease, reduces both morbidity and mortality in MEN2:
Recurrence of medullary thyroid carcinoma (MTC) should be monitored with
Calcitonin
Carcinoembryonic antigen (CEA)
False-positive and false-negative results have been reported

28. Management MEN type 2 General principles
Identify individuals with germline RET-disease-causing mutations associated with MEN2 before symptoms develop.
Reduce morbidity and mortality in the highest-risk
Prophylactic thyroidectomy
Screening for MTC
Phaeochromocytoma screening and parathyroid disease before symptoms develop.
Counseling of patients with MEN
The treatment for adrenal medullary hyperplasia or phaeochromocytoma is bilateral adrenalectomy.
Total thyroidectomy for patients as young as 3 years for MEN2A if they contain the genetic mutation.
Hyperparathyroidism: subtotal parathyroidectomy is advised, along with cervical thymectomy because of the increased risk of supernumerary parathyroid glands.

29. Management MEN type 2B
In MEN 2B, thyroidectomy with lymph node clearance should be performed at the earliest possible age.
MTC is biologically aggressive in these patients and has been reported as early as 15/12 age.
Patients with the genetic mutation for MEN2B, total thyroidectomy is recommended in infancy.
Patients not identified by screening, thyroidectomy should still be performed.
Prognosis
Patients with MEN2B tend to do worse than those with MEN2A
It is particularly poor in MEN2B who present with clinically apparent MTC.
Their 10-year survival is about 50%, and death from metastatic disease in the mid-twenties is common

30. Medullary Thyroid carcinoma
Initial thyroid lesion in MEN2 is C-cell hyperplasia, which has been found as early as the age of 3 years in MEN2A and may be present at birth in MEN2B.
Over the subsequent 5 to 10 years microscopic MTC develops and finally gross tumors become apparent.
MTC typically presents as a neck mass or neck pain at about age 15 to 20 years.
More than 50% already have cervical lymph node metastases.
Inherited MTC accounts for 25% of cases in association with MEN types 2A and 2B, but non-MEN familial MTC also occurs.
It may present with a thyroid lump. Diarrhoea may also occur.
Metastases may occur, to the lung, liver and bone.
Paraneoplastic syndromes are rare but may include Cushing's or carcinoid syndrome.

31. Pheochromocytoma Phaeochromocytoma occurs in 50% of MEN2.
In patients with MEN2 are usually found in the adrenals
About 70% are bilateral, almost all are benign.
They produce excessive adrenaline secretion leading to tachycardia, palpitations, hypertension and headache.
Investigations include plasma concentrations of free metanephrines, and imaging CT or MRI
Positron emission tomography (PET) is also used for diagnosis.
Treatment surgical, laparoscopic surgery is increasingly used.
Overall, half of the patients with malignant pheochromocytomas remain alive for five years.

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