Multiple Endocrine Neoplasia Flashcards
1
Q
What is Multiple Endocrine Neoplasia?
A
- Hereditary cancer syndromes
- Rare autosomal dominant disorders very occasionally sporadic
- Characterised by tumours or hyperplasia in 2 or more endocrine glands
2
Q
What are the MEN classifications?
A
MEN-1
MEN-2
- MEN-2A
- MEN-2B
- Familial Medullary Thyroid Cancer
3
Q
What are differences between MEN and sporadic Endocrine Tumours?
A
- Involve a collection of endocrine malignancies
- Spectrum of clinical presentation
- Tumours occur in more than 1 endocrine gland and multiple tumours may be seen in one gland
- Family screening is required
4
Q
What are genetic defects in MEN?
A
- MEN 1 – Inherited mutation causing inactivation of a tumour suppressor gene – MENIN – on the long arm of CHS11 leads to unregulated growth.
- MEN 2 – Mutation on CHS 10 causing activation of the RET proto-oncogene, activates tyrosine kinase receptor causing unregulated growth.
5
Q
What are the organs affected by MEN1, MEN2A, and MEN2B?
A
MEN1
- Pituitary
- Parathyroid
- Pancreatic Islets
MEN2A
- Medullary Thyroid Carcinoma
- Parathyroid
- Phaechromocytoma
MEN2A
- Medullary Thyroid Carcinoma
- Marfanoid Habitus
- Phaechromocytoma
6
Q
What is MEN-1?
A
- Parathyroid glands
- Pancreatic Islet Cell –neuroendocrine
- Pituitary Adenomas – anterior pituitary
- Others – adrenocortical, thyroid, foregutcarcinoids
- Non-Endocrine features: Lipomas, Angiofibromas, Collagenomas
Combinations of approx 20 diff endo/non-endo tumours. Decreased life expectancy
7
Q
What is a Lipoma, Angiofibromas, and Collagenomas?
A
- Lipoma: A lipoma is a benign tumor composed of adipose tissue (body fat).
- Angiofibroma: Angiofibromas are small, reddish brown or even flesh-colored, smooth, shiny, 0.1- to 0.3 cm papules present over the sides of the nose and the medial portions of the cheeks.[1] They contain fibrous tissue.
- Collagenoma: Type of Connective tissue nevus, is an rare condition in which the cells in the deeper layers of the skin experience an excess of collagen.
8
Q
What is the Epidemiology?
A
- Prevalence is 0.25% of the population (1:35,000)
- Variable penetrance
- Variable clinical manifestations
- Typically manifests after the 1st decade
- Symptoms occur in the 3rd decade in women and the 4th in men
9
Q
What is Classification for diagnosis of MEN?
A
- Clinical Diagnosis: A patient with 2 or more MEN1- Associated tumours
- Familial Diagnosis: A patient with MEN1 – associated tumour and a first degree relative with MEN1
- Genetic Diagnosis: An individual with MEN1 mutation with no clinical manifestations
10
Q
What is Hyperparathyroidism in MEN1?
A
- Most common feature of MEN1.
- Penetrance nearly 100%, occurs early in life
- Affects all four glands
- Clinical features: Polydipsia, Polyuria
- Diagnosis: Inappropriately raised PTH for raised calcium, sestamibi scan.
11
Q
How is Screening and Treatment for Hyperparathyroidism conducted in MEN1?
A
- Screening: Annual Ca and PTH
- Treatment: Parathyroidectomy (total or partial)
12
Q
What is the differences between non-MEN1 HPT and MEN1 HPT?
A
- Hypercalcaemia is mild
- Earlier onset – 25 years vs 55 years
- Greater loss of bone mineral density
- Equal M:F
13
Q
Describe Enteropancreatic Neuroendocrine tumours in MEN1?
A
Second most common manifestation – 60%
- Gastrinoma>Insulinoma>VIPoma>Glucagonoma
- Multicentric
- Varied size and progression
- Sometimes co-secretory, Sometimes non-secretory
14
Q
What are Gastrinomas?
A
Commonest cause of morbidity and mortality
High propensity to metastasize. Hyperparathyroidism in MEN1 exacerbates ZES
Clinical manifestations: ulcer, diarrhoea and steatorrhoea
Diagnosis: Plasma gastrin >114pmol/L, Localisation by somatostatin receptor scintigraphy
15
Q
How are Gastrinomas treated?
A
Treatment:
- Surgery
- PPI’s
- H2 histamine receptor antagonists
- Chemotherapy
16
Q
How insulinomas treated?
A
Affect 20-30% patients, 10% insulin and gastrin. Usually solitary, benign and symptomatic. Occurs in the pancreas
- Symptoms: Those of hypoglycaemia
- Diagnosis: Unsuppressed insulin with hypoglycaemia and raised C-PEP, low βOHB often use 72 hour fast
- Localisation not easy: CT, venous sampling
- Treatment: Surgery, Diazoxide, Somatostatin analogues
17
Q
How is screening and treatment for Enteropancreatic Neuroendocrine tumours?
A
Screening:
- Biochemical: Annual fasting gut hormones and glucose
- Imaging: Annual MRI/CT/endoscopic US
Treatment:
- Surgery: Controversial
- Biotherapy: PPIs, H2 histamine receptor antagonists, Targeted radionuclide therapy or chemotherapy
18
Q
What are Pituitary Tumours in MEN1?
A
- Apparent in 30-50% patients
Clinical presentation depends on hormone secreted
- 60% prolactin
- 25% growth hormone
- 5% ACTH
- 10% non-functioning
Sometimes the secretion is ectopic e.g.due to carcinoid tumours.
Adrenal lesions are common (20-40%) but usually non-functioning and do not require treatment.
19
Q
What are presentations, investigations and management of Pituitary Tumours?
A
- Presentation, investigation and management are as non-MEN pituitary tumours however more frequent in women, more invasive and therefore aggressive and frequent co-secretory
- Screening: Annual Prolactin and IGF-1, MRI 3-5 yrs
- Treatment: Dopamine agonists for Prolactin, ocreotide/lanreotide for GH, transphenoidal surgery
20
Q
Describe Foregut Carcinoid in MEN1?
A
- Occur in 10% MEN1 patients, more freq than in the general population.
- Sporadic carcinoid predominantly mid and hindgut. MEN1 predominantly foregut.
- Usually non-functional
- Bronchial carcinoids mainly in women and thymic in men.
- Thymic are agrressive and therefore screening of these patients is recommended.
- Gastric carcinoid usually found incidentally.
21
Q
How are foreut carcinoid screened, diagnosed and monitored?
A
- 5HIAA and chromogranin A unhelpful in diagnosis
- CT/MRI chest every 1-2years
- Gastroscopic examination and biopsy every 3 years if there is evidence of hypergastrinaemia
- If disease is advanced – surgery and radio+chemo
- Thymic tumours are aggressive and always require surgery
22
Q
How is MEN1 screened?
A
Biochemical screening
- Calcium, prolactin, gastrin and chromogranin A
- Rarely develops <5 or >70 years, 95% by 40.
Genetic screening
- MEN1 germline mutation testing in patients and first degree relatives
- No mutation identified in 10-20%
- No genotype-phenotype correlation
- >300 mutations reported, usually family specific
23
Q
What are syndromes in MEN2?
A
- Medullary Cell Carcinoma
- Phaeochromocytoma
- Parathyroid tumours (MEN 2A)
- Marfanoid habitus, mucosal neuromas and skeletal abnormalities (MEN 2B)
24
Q
What are features of Marfanoid Habitus?
A
- Pes Cavus
- Mucosal Neuromas
- Slender body
- Long limbs
- Decreased Upper: lower body ratio
- Pectus Excavatum
- Arachnodactyly
- Dilation of aorta
25
What is present in all patients when MEN2 is diagnosed?
* Medullary thyroid carcinoma is present in all patients at diagnosis.
26
What is the epidemiology surrounding MEN 2A?
* **The most common type of MEN2 (80-90%)**
* Prevalence is 1:40,000
* Phaeos in 50%, usually bilateral, peak 40yrs
* Parathyroid adenomas 25%
27
What are the 2 variants in MEN 2A?
* Cutaneous Lichen amyloidosis
* Hirschsprung’s disease
28
What is the epidemiology surrounding MEN 2B?
* Prevalence 1:1,000,000, 5% MEN2
* Patients have some aspects of marfanoid habitus, hallmark mucosal neuromas
* MTC: Early onset (12M), aggressive, prophylatic removal if have mutation
* Phaeochromacytomas occur earlier than in type 2A
29
What is a Medullary cell thyroid carcinoma?
* In parafollicular C-cells of thyroid, secrete calcitonin
* Multifocal, involves both lobes. Amyloid deposition occurs in the gland
* In the general population 70-80% MTC is sporadic and the remainder inherited. Least aggressive in FMTC and most aggressive in MEN2 B.
* Hyperplasia progresses to malignant change
* Earliest case in 2A is 3 yrs of age. In 2B may be present from birth
30
What are clinical features of Medullary Cell Thyroid Carcinoma?
* Thyroid nodule or goitre
* Diarrhoea
* Flushing.
31
How is a Medullary Thyroid Carcinoma diagnosed?
**Biochemical**
* Calcitonin \>200ng/ml + pentagastrin stimulation
* Carcinoembryonic antigen (CEA)
**Genetic testing for RET germ line mutation**
* 95% patients have gene identified
* Good genotype:phenotype correlation (unlike MEN1) normal RET analysis excludes the disease
* Can be carried out at birth or in utero
**Imaging**
* Ultrasound most commonly used- cheap
* If mets MRI, CT, Sestamibi, Scintigraphy
**FNA cytology**
* Used on thyroid nodules to exclude malignancy
32
How is Medullary Thyroid Carcinoma treated?
* Surgical resection at the hyperplasia stage
* Suppression with thyroxine
* Follow up with calcitonin and CEA measurement
33
What is the epidemiology of Phaeochromacytoma?
* Bilateral in 70%
* Rarely extra-adrenal or malignant
* Often asymptomatic
34
How is Phaeochromocytoma diagnosed and treated?
* Diagnosis - plasma or urine metanephrines
* Localisation – CT, MRI, Scintigraphy
* Treatment – surgery after α and β blockade
35
How does Parathyroid disease present in MEN2?
* Seen in 25-30% MEN2A patients
* Majority hyperplasia only – picked up during MTC surgery.
* Often asymptomatic and no abnormal biochemistry although hypercalciuria may occur
* Not all glands are involved
36
How is MEN2 screened?
* RET gene mutation analysis to identify carriers
* MTC screening annually age 3-40yrs in MEN2A and FMTC, thyroidectomy \<6M in MEN2B
* Phaeo every 2 years from 5 years of age
* HPT every 2 years from 10 years of age in MEN2A
* Patients should be monitored for recurrence
