MEN 2 SYNDROME

1. MEN II
Dr Ankita

2. • MEN II is a group of rare familial cancer
syndromes involving multiple endocrine
organs, most commonly thyroid, parathyroid
and adrenal glands.
• EPIDEMIOLOGY:
1 in 35,000 worldwide.
MEN IIA – 60-90% of MEN II families.
MEN IIB – 5% of MEN II families.

3. THROID
• Medullary Thyroid
Carcinoma
ADRENAL
• Pheochromocytoma
PARATHYROID
• Primary
Hyperparathyroidism
SKIN
• Cutaneous lichen
amyloidosis
GIT
• Hirschsprung
disease
MUSCULOSKELETAL
• Marfanoid Habitus
• Kyphoscoliosis
• Joint laxity
• Neuromas

4. • Autosomal dominant.
• Germline mutations in RET – proto-oncogene.
• RET (REarranged during Transfection) – located on chromosome 10q11.2
• RET encodes a receptor tyrosine kinase – with key roles in cell growth,
differentiation and survival.
• Ligands for RET – glial cell-line derived neurotrophic factor (GDNF) family.
• RET is expressed widely in neural-crest derived tissues – including thyroid C cells,
adrenal medulla, enteric nervous system and kidney.

5. Ligand (GDNF family) binds to
extra cellular region
Activation of Cysteine rich
region
Receptor Dimerization
Autophosphorylation of
intracellular Tyrosine residues
Activate multiple downstream
pathways of signal transduction

7. IIA
IIB
FMTC
MTC ,Pheochromocytoma,
Parathyroid hyperplasia or adenoma
MTC , Pheochromocytoma ,
Mucosal and gastrointestinal
neuromas ,Marfanoid features
MTC
MEN IIHallmark - MTC

8. MEN II A – “Sipple Syndrome”
• Gain-of-function mutations in the RET proto-oncogene.
• Classic MEN II A
• MEN IIA with Cutaneous Lichen Amyloidosis (CLA)
• MEN IIA with Hirschsprung disease (HD)
Pheochromocytoma – 40 – 50%Medullary carcinoma of
Thyroid – almost 100%
Parathyroid Hyperplasia – 10 – 20%

9. MEN IIA – MEDULLARY CARCINOMA OF THYROID
• Occur in almost 100% patients of MEN IIA.
• Usually multifocal
• Virtually always associated with C-cell hyperplasia in the adjacent thyroid.
• Usually clinically aggressive.
• Elevated Calcitonin.
• Younger patients, may arise during first decade of life.

10. Medullary Carcinoma of Thyroid
• Neuroendocrine neoplasms derived from the parafollicular cells, or C
– cells.
• Account for 5% of thyroid neoplasms.
• 70% - Sporadic. 30% - associated with MEN Syndrome.
• In some instances, the tumor cells elaborate other polypeptide
hormones, such as serotonin, ACTH, and vasoactive intestinal peptide
(VIP).

11. CLINICAL COURSE
• Mass in neck.
• Painless, or
• Associated with dysphagia or hoarseness.
• Metastasis
• Up to 75% of patients have nodal metastasis, mostly involving central
compartment, ipsilateral and contralateral jugulocarotid chains
• 10% have distant metastasis
• may have severe diarrhea and flushing

12. DIAGNOSIS
• Thyroid nodule – cold on scanning
• Elevated Calcitonin
• diagnosis and postoperative follow-up of patients for residual, recurrent or
metastatic disease.
• Carcinoembryonic Antigen
• useful biomarker, especially for presurgical assessment of tumor load and in
calcitonin-negative tumors.
• Family history – genetic testing for RET mutations.

13. GROSS
• Familial cases – B/L & Multicentric
• Firm, pale, gray to tan and infiltrative.
• Larger lesions often contain areas of
necrosis and hemorrhage and may
extend through the capsule of the
thyroid.

14. MICROSCOPY
• Composed of polygonal to spindle-shaped cells
• May form nests, trabeculae, and even follicles.
• Small, more anaplastic cells are present in some
tumors.
• Abundant amphophilic to clear cytoplasm.
• Nuclear cytoplasm is coarsely clumped (salt &
pepper appearance) with inconspicuous nucleoli.
• Acellular amyloid deposits, derived from altered
calcitonin polypeptides, are present in the
adjacent stroma.
• Multicentric C-cell hyperplasia in the surrounding
thyroid parenchyma - peculiar features of familial
medullary cancers.
• Asymptomatic carriers - C-cell hyperplasia or
small (<1 cm) “micromedullary” carcinomas.
Histology demonstrates abundant
deposition of amyloid, visible here as
homogeneous extracellular material,
derived from calcitonin molecules secreted
by the neoplastic cells.

15. • Electron microscopy - numbers of
membrane-bound electron-dense granules
within the cytoplasm of the neoplastic
cells.
• Special stains and IHC:
• Calcitonin positive
• Chromogranin and synaptophysin
positive
• Carcinoembryonic antigen (CEA)
positive in tumor
• Congo red positive in amyloid material
(polarizes: birefringence apple-green)
• TTF-1 usually positive
• Thyroglobulin negative Immunohistochemical stain for calcitonin
is positive in a medullary thyroid
carcinoma with spindled morphology.

16. MEN IIA - PHEOCHROMOCYTOMA
• 40-50%
• Gain-of-function mutation in RET gene.
• Bilateral
• May arise in extra adrenal sites

17. PHEOCHROMOCYTOMA
• Pheochromocytomas are neoplasms composed of chromaffin cells,
which synthesize and release catecholamines and in some instances
peptide hormones.
• They are a rare cause of surgically correctable hypertension.
• And hence, it is important to recognize these tumors.
• Familial cases – present at a younger age and often harbour bilateral
disease as compared to the sporadic form.

18. • Pheochromocytomas have been associated with a “rule of 10s”.
• 10% of pheochromocytomas are extra-adrenal, occurring in sites such
as the organs of Zuckerkandl and the carotid body (designated as
Paragangliomas).
• 10% of sporadic adrenal pheochromocytomas are bilateral (50% -
familial syndromes).
• 10% of adrenal pheochromocytomas are biologically malignant (20-
40% in paragangliomas).
• 10% of adrenal pheochromocytomas are not associated with
hypertension.

19. • 25% individuals harbour a germline mutation in one of atleast six
known genes.
• The affected gene fall into two broad classes:
• Other familial cases are associated with germline mutation in genes
encoding succinate dehydrogenase complex (SDHB, SDHC & SDHD).
Enhance the growth factor receptor
pathway signalling
• RET – MEN IIA, IIB
• NF1 - Neurofibromatosis
Increase the activity of the
transcription factor HIF-1α
von Hippel-Lindau Syndrome.

20. CLINICAL COURSE
• 90% of patients - hypertension.
• 2/3rd - paroxysmal episodes,
• which are described as an abrupt, precipitous
elevation in blood pressure,
• associated with tachycardia, palpitations,
headache, sweating, tremor, and a sense of
apprehension.
• may also be associated with pain in the
abdomen or chest, nausea, and vomiting.
• be precipitated by emotional stress, exercise,
changes in posture.

21. • More commonly, patients demonstrate chronic, sustained elevation in blood
pressure.
• Patients with urinary bladder paragangliomas occasionally precipitate a
paroxysm during micturition.
• The elevations of blood pressure are induced by the sudden release of
catecholamines that may acutely precipitate congestive heart failure, pulmonary
edema, myocardial infarction, ventricular fibrillation, and cerebrovascular
accidents.
• Cardiac complications – catecholamine cardiomyopathy or catecholamine-
induced myocardial instability and ventricular arrhythmias.

22. GROSS MORPHOLOGY
• Variable size and weight (from few grams to almost
4000g).
• Round to oval, sharply circumscribed mass that is often
encapsulated.
• The larger tumors are well demarcated by either
connective tissue or compressed cortical or medullary
tissue.
• Richly vascularized fibrous trabeculae within the tumor
produce a lobular pattern.
• In many tumors, remnants of the adrenal gland can be
seen, stretched over the surface or attached at one pole.
• Cut surfaces
• Smaller pheochromocytomas are yellow tan.
• Larger lesions tend to be hemorrhagic, necrotic, and
cystic and typically efface the adrenal gland.
The tumor is enclosed within an
attenuated cortex and
demonstrates areas of
hemorrhage. The comma-shaped
residual adrenal is seen below.

23. MICROSCOPY
• Variable histological pattern.
• The tumors are composed of polygonal to spindle-
shaped chromaffin cells or chief cells, surrounded by
supporting sustentacular cells – creating small nests or
alveoli (zellballen pattern).
• Rich vascular network.
• The cytoplasm has a finely granular appearance, best
demonstrated with silver stains, due to the presence of
granules containing catecholamines.
• The nuclei are usually round to ovoid, with a stippled
“salt and pepper” chromatin that is characteristic of
neuroendocrine tumors.
Photomicrograph of pheochromocytoma,
demonstrating characteristic nests of cells with
abundant cytoplasm.

24. • There is no histologic feature that reliably predicts clinical behavior.
• Several histologic features, such as numbers of mitoses, confluent tumor
necrosis, and spindle cell morphology, have been associated with an aggressive
behavior and increased risk of metastasis, but these are not entirely reliable.
• Tumors with “benign” histologic features may metastasize, while bizarrely
pleomorphic tumors may remain confined to the adrenal gland.
• Therefore, the definitive diagnosis of malignancy in pheochromocytomas is
based exclusively on the presence of metastases. These may involve regional
lymph nodes as well as more distant sites, including liver, lung, and bone.

25. • ELECTRON MICROSCOPY - variable
numbers of membrane-bound, electron-
dense secretory granules.
• IHC
• Chromogranin positive
• Synaptophysin positive
• Tyrosine hydroxylase positive
• S-100 protein: immunoreactivity of
sustentacular cells surrounding
Zellballen
• HMB-45 may show focal or faint
positivity
• Ki-67 may be helpful to assess
proliferative
Synaptophysin S-100

26. LABORATORY DIAGNOSIS
• Based on demonstration of increased urinary excretion of free
catecholamines and their metabolites, such as vanillylmandelic acid
and metanephrines.

27. MEN IIA – CUTANEOUS LICHEN AMYLOIDOSIS
• Aka Lichen Planus amyloidosis.
• Presents with pruritic, pigmented, scaly papules.
• Sites – extensor surfaces of extremities and
interscapular region.
• Histology – Amyloid deposition in papillary dermis.
• May develop prior to diagnosis of medullary
carcinoma of thyroid.

28. MEN IIA – HIRSCHSPRUNG DISEASE
• Congenital aganglionic megacolon.
• 1 in 5000 live births.
• Results when the normal migration of neural crest cells from cecum to
rectum is arrested prematurely or when the ganglion cells undergo
premature death. This produces a distal intestinal segment that lacks
both the Meissner submucosal and the Auerbach myenteric plexus
(“aganglionosis”).
• Loss-of-function mutation in RET gene.
• Diagnosis of Hirschsprung disease requires documenting the absence
of ganglion cells within the affected segment.
• IHC - acetylcholinesterase.

29. MEN IIB
• Germline mutation – point substitution in RET affects a critical region of
the tyrosine kinase domain and leads to constitutive activation of RET in
the absence of ligand.
• Medullary thyroid carcinoma, pheochromocytoma BUT NOT PRIMARY
HYPERPARATHYROIDISM.
• In addition, MEN-2B is accompanied by neuromas or ganglioneuromas
involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal
tract, and a marfanoid habitus, with long axial skeletal features and
hyperextensible joints.

30. FAMILIAL MEDULLARY THYROID CANCER
• There is a strong predisposition to medullary thyroid cancer but not
the other clinical manifestations of MEN-2A or MEN-2B.
• A substantial majority of cases of medullary thyroid cancer are
sporadic, but as many as 20% may be familial.
• Familial medullary thyroid cancers develop at an older age than those
occurring in the full-blown MEN-2 syndrome and follow a more
indolent course.

31. MANAGEMENT of MEN 2
• HISTORY
• A detailed history of the associated conditions in the patient and the family
members.
• PHYSICAL EXAMINATION
• Finding – pigmented papules in interscapular region (CLA),
- decreased upper to lower body ratio (marfanoid habitus),
- joint hyperlaxity
- red papules (mucosal neuromas).

32. • BIOCHEMICAL TESTING
• Serum Calcitonin
• Parathyroid hormone
• Plasma free metanephrines
• Urinary catecholamine levels.
• RADIOLOGICAL TESTING
• Cold nodule – thyroid (USG neck)
• Localisation of pheochromocytoma on MRI or CT.
• GENETIC TESTING
• MEN-1 or RET gene
• Screening : 1st degree relative of the patient
- Patients with CLA
- Families whose infants or children have MEN IIB or Hisrchsprung disease.

33. • Diagnosis via screening of at-risk family members in MEN-2A is
important because medullary thyroid carcinoma is a life-threatening
disease.
• Now, routine genetic testing identifies RET mutation carriers earlier
and more reliably in MEN-2; all individuals carrying germline RET
mutations are advised to undergo prophylactic thyroidectomy to
prevent the inevitable development of medullary carcinomas.

34. SURVELLIANCE
MEDULLARY
CARCINOMA THYROID
• An annual physical
examination
• Neck ultrasound
• Serum Calcitonin
concentration
PHEOCHROMOCYTOMA
• Plasma metanephrine
• Or, 24-hr Urinary
metanephrines
• If +ve – CT or MRI
HYPERPARATHYROIDISM
• Serum Calcium
• If elevated, Serum PTH
Children with high-risk mutations
– 3 yrs of age.
Children with moderate-risk – 5
yrs of age.
Children with high risk category –
11 yrs
Children with moderate risk
category – 16 yrs of age
Children with high risk category –
11 yrs
Children with moderate risk
category – 16 yrs of age

35. • Previously considered a part of MEN 1.
• Germline mutations in CDKN1B, as a result of decrease in expression of p27 tumor suppressor gene.
• Patients present with
• Hyperparathyroidism (30-74 yrs)
• Neuroendocrine tumors – pituitary adenoma, small-cell neuroendocrine cervical carcinoma,
adrenal masses, bronchial carcinoid, papillary thyroid carcinoma, gastric carcinoid and
pancreatoenteric masses.
• Nonneuroendocrine tumors – angiomyolipoma, schwannoma, meningioma, liver hemangioma,
prostate cancer, breast cancer, lipoma and uterine fibroid).
• Genetic testing should be done in patients with family history of known mutation and patients negative
for MEN 1 genetic testing.
MEN 4

36. THANK YOU