Endocrine

Question 1

Differential for adrenal lesion

Answer 1

Question 2

MEN1

Answer 2

Rare

autosomal dominant heritable disorder

classically characterized by a predisposition to pituitary tumours, pancreatic neuroendocrine tumours and parathyroid hyperplasia (3Ps)

Note that the 3P’s don’t quite cut it

Also note that “pancreatic tumours” are actually entero-pancreatic and neuroendocrine

P.P.S note the presence of adrenal tumours (adenoma and carcinoma) – they CAN be functional but usually non functional adenomas

Parathyroids commonly multigland disease

Question 3

MEN2A

Answer 3

Autosomal dominant familial cancer syndrome characterised by the metachronous development of medullary thyroid cancer (MTC), phaeochromocytoma and primary hyperparathryoidism

(2P 1M)

RET mutation

Question 4

MEN2B

Answer 4

Medullary thyroid carcinomas

• Usually multifocal and more aggressive than in MEN-2A,

Pheochromocytomas

• However, unlike in MEN-2A, primary hyperparathyroidism is not present
• Accompanied by
  
  • Marfinoid body habitus with long axial skeletal features and hyperextensible joints
  • Neuromas (small benign nerve tumours – neuromas on the tongue and lips) neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract, and a marfanoid habitus,
  • Hirschsprung’s disease

– Due to RET mutations in codon 918

Question 5

Ways to remember MEN 1 vs 2A vs 2B

Answer 5

3 P’s, 2 P’s, 1 P 3 M’s

MEN1 tumour suppressor MEN2 RET

Easy to remember that MEN2 are medually (and therefore phaeo)

Easy to remember that pituitary and pancreatic are MEN1

Question 6

Adrenal lesion biochemistry

Answer 6

• Cushings (glucocorticoid excess)
  
  • Screening:
    
    • Low-dose (1 mg) overnight dexamethasone suppression test and midnight salivary cortisol may be required to confirm or exclude
  • Confirmatory:
    
    • 24-hour urinary free cortisol
  • ACTH level (independent vs dependent)
    
    • If high ACTH then do high dose dexamethasone
    • High dose (8mg) dexamethasone suppression test, if elevated at 8AM then ectopic production (not pituitary) of ACTH
• Conn’s (mineralocorticoid excess)
  
  • Hypertensive patients with elevated plasma aldosterone:renin activity ratio >20
  • Hypokalaemia is present in only half the patients with primary hyperaldosteronism
• Sex hormone
  
  • Serum DHEAS and 17-hydroxyprogesterone are measured to exclude adrenal androgen hypersecretion that occurs in some adrenocortical carcinomas or, when bilateral adrenal masses are present, congenital adrenal hyperplasia.
• Serum metanephrines

Question 7

Adrenal lesion imaging/localisation

Answer 7

• Imaging localisation
  
  • CT (thin slices)
    
    • Lipid rich low density/attenuation masses on unenhanced CT (<10 hounsfield units)
    • Rapid washout of contrasts (>50% at 10 minutes, >60% at 15 minutes)
    • Homogenous with regular outline, rounded, no extension into surrounding structures
    • <4cm in size have low malignant risk
  • MRI
    
    • Homogenous enhancement after gadolinium MRI is characteristic
  • PET
    
    • Low fluorodeoxyglucose uptake
• Invasive
  
  • Biopsy
    
    • Unhelpful at differentiating between adenoma and carcinoma and may precipitate a phaeochromocytoma crisis
    • Maybe for metastatic disease
  • Selective Venous sampling
    
    • Unilateral microadenoma vs bilateral hyperplasia

Question 8

What is adrenal washout on CT?

Answer 8

Question 9

Familial hypocalciuric hypercalcaemia

Answer 9

• Definition:
  
  • Benign inherited condition that causes hypercalcaemia, charactered by autosomal dominant inactivation mutation of the Calcium Sensing Receptor (CaSR)
• Incidence/epidemiology:
• Aetiology & risk factors:
• Pathophysiology:
  
  • Autosomal dominant with high penetrance
  • Inactivation of the CaSR in FHH make the parathyroid glands less sensitive to calcium  higher than normal serum calcium is needed to reduce PTH release
  • In the kidney this leads to calcium and magnesium reabsorption  high serum calcium, low urine calcium
• Clinical manifestations:
  
  • Heterozygote patients
    
    • Mild hypercalcaemia
    • Hypocalciuria
    • Normal PTH
    • High-normal serum magnesium
  • PTH can be elevated if concurrent vitamin D deficiency
  • Increased risk of pancreatitis
• Macroscopic features:
• Microscopic features:
• Investigations:
  
  • High serum calcium
  • Urinary calcium excretion is low (24 hours <200mg or 5mmol per day), can do a creatinine to calcium ratio
  • Magnesium
    
    • Reduced tubular resorption  low magnesium
  • PTH
    
    • Inappropriately normal or high
  • Note
    
    • When looking for FHH need to exclude the following conditions that can mask primary hyperparathyroidism
      
      • Vitamin D deficiency
      • Low calcium intake
      • Renal insufficiency
      • Thiazides and lithium
  • Genetic testing to confirm
• Treatment:
  
  • Not surgery!
  • Medical management with calcimimetics
• Prognosis:

Question 10

High calcium and face tumour?

Answer 10

Hyperparathyroidism – Jaw Tumour Syndrome : Autosominal dominant inherited mutation in the CDC73 gene, tumour suppressor

• Incidence/epidemiology:
• Aetiology & risk factors:
• Pathophysiology:
  
  • Hyperparathyroidism (late adolescence or early adulthood)
  • Benign tumours of the jaw called ossified fibromas
  • Renal cysts
  • Renal hamartomas
  • Wilms tumours
  • Benign or malignant uterine tumours
  • Parathyroid carcinoma

Question 11

Management of MEN1

Answer 11

• Consider each facet of the disease
• Primary hyperparathyroidism
  
  • Usually requires total parathyroidectomy + transcervical thymectomy
  • Lifelong supplements
  • If unable to undergo parathyroidectomy then medical management with calcimimetic drugs and bisphosphonates
  • Enteropancreatic tumours (see whole topic on this)
    
    • Gastrinoma
      
      • Most common
    • VIPomas
    • Insulinoma
    • Non functioning pancreatic tumours
      
      • Resection if over 2cm
  • Pituitary tumours (adenoma)
    
    • Prolactinoma
      
      • Dopamine agonists
    • GH secreting tumours
      
      • Surgery + external beam radiotherapy + somatostatin analogue
    • Non functioning tumours
      
      • Resection
  • Foregut carcinoids
    
    • Tumours in the thymus, lung and bronchus
  • Surveillance & Screening
    
    • Genetic testing to patients and first degree relatives
      
      • Multigland disease
      • Young or multifocal neuroendocrine tumours
    • Clinical, biochemical & radiological screening

Question 12

NF1

Answer 12

• Autosomal dominant NF1 gene mutation, chromosome 17
• NF1 codes for neurofibromin
• Benign
  
  • Neurofibromas cutaneous or subcutaneous
  • Malignant
    
    • CNS astrocytoma, gliomas
    • Sarcoma (including malignant peripheral nerve sheath tumours)
    • Rhabdomyosarcoma
    • GIST
    • Leukaemia
    • Phaeochromocytoma

Question 13

(a hereditary endocrine neoplasm condition)

SDH

Answer 13

• Definition:
  
  • Succinate dehydrogenase mutation
  • Hereditary autosomal dominant mutation in the succinate dehydrogenase tumour suppressor gene, associated with paragangliomas, phaeochromocytomas and GIST
  • Hereditary paraganglioma or hereditary phaeochromocytoma syndrome
• Incidence/epidemiology:
  
  • • Aetiology & risk factors:
  • Smoking is a strong risk factor for development of tumours
• Pathophysiology:
  
  • SDH (A, B, C, D) genes
    
    • A: Rare,
    • B: 80% tumour by age 50, most common paragangliomas, more likely malignant
    • C: Rare, paragangliomas, low chance malignancy
    • D: 90% tumour by age 50, malignant paragangliomas
  • Tumour suppressor gene
  • Autosomal dominant
  • Associated tumours
    
    • Paraganglioma
    • Phaeochromocytoma
    • GIST
    • Renal cancer
    • Thyroid cancer
• Clinical manifestations:
  
  • Paraganglioma
  • phaeochromocytoma
• Macroscopic features:
• Microscopic features:
• Investigations:
  
  • Lifelong surveillance
    
    • Age 10: metanephrines
    • CT intermittently
• Treatment:
  
  • Smoking cessation helps
• Prognosis:

SDH mutated GIST are less likely to respond to imatinib

Question 14

Von Hippel Lindau

Answer 14

• Definition:
  
  • Autosomal dominant familial disease characterized by the metachronous development of multiple benign and malignant tumours due to a VHL gene mutation
• Incidence/epidemiology:
  
  • 2.5:100,000
• Aetiology & risk factors:
  
  • Family history
  • Can be sporadic
• Pathophysiology:
  
  • VHL is a tumour suppressor gene that regulates hypoxia inducible factors that ultimately lead to angiogenesis (see cellular pathways doc for more details), also contributes to cell polarity/ECM/cell cycle regulation
  • 3 key tumours
    
    • Haemangioblastoma of CNS including retina
    • Renal clear cell carcinoma
    • Phaeochromocytoma
    • (also pancreatic cysts and tumours)
      
      • Cysts 70%
      • Serous cystadenomas 9%
      • Neuroendocrine tumours 9%
• Clinical manifestations:
  
  • 2 main endocrine presentations
    
    • Phaeochromocytoma
    • Pancreatic Islet cell tumour
      
      • Usually detected on surveillance
  • Hb can cause blindness
  • Deafness from inner ear tumour
• Macroscopic features:
  
  • Phaeochromocytoma in VHL is distinct to that of MEN2A
    
    • Thick capsule
    • Lots of angiogenesis
    • No background change of medullary hyperplasia
    • Similar presentation though, maybe less symptoms and more biochemical and incidental detection
    • Can also be multiple and extra adrenal
  • Pancreatic neuroendocrine tumours
    
    • Clinically silent
• Microscopic features:
• Investigations:
  
  • Diagnosis of phaeo (same pathway as normal)
    
    • The combination of elevated plasma normetanephrines and normal plasma metanephrines is highly suggestive of VHL-associated phaeochromocytoma.
  • Pancreatic tumours
    
    • In111 scintigraphy and EUS useful in differentiating between neuroendocrine tumours, cysts and cystadenomas
• Treatment:
  
  • Phaeochromocytoma
    
    • Same as normal
  • Pancreatic neuroendocrine tumours
    
    • Excision if
      
      • No metastatic disease
      • +2cm in HOP
      • +3cm in the rest
    • If smaller than monitor radiologically
• Prognosis:
  
  • (enlarge table)
  • In Denmark life expectancy 60-67 years, CNS and RCC killers
  • Plasma metanephrines from age 5 (annual) and MRI abdomen from age 15 (2 yearly)
  • Urinary cytology

Question 15

Branches of External Carotid Artery

Answer 15

• [branches of the external carotid: some anatomists like f*cking others prefer S & M]
  
  • S : superior thyroid artery.
  • A: ascending pharyngeal artery.
  • L: lingual artery.
  • F: facial artery.
  • O: occipital artery.
  • P: posterior auricular artery.
  • M: maxillary artery.
  • S: superficial temporal artery.

Question 16

Where is the external branch of the superior laryngeal nerve found at thyroidectomy?

Answer 16

In close proximity to where the superior thyroid artery enters the superior pole of the thyroid

Question 17

Thyroid surgery

Jolls triangle

Answer 17

Jolls triangle – SLN at

risk insertion of sternothyroid, midline, STA

Question 18

Thyroid

Course and identification of the RLN

Answer 18

• Definition:
  
  • A branch of the vagus nerve
  • Supplies motor supply to the intrinsic muscles of the larynx but not the cricothyroid muscle
  • Injury
    
    • Unopposed adduction of the vocal cords
  • Course
    
    • Right:
      
      • Branch that arises from the right vagus nerve
      • it passes around the right subclavian artery
      • Travel back up in the tracheooesophageal groove
      • To enter into the larynx at the inferior border of the inferior constrictor
    • Left:
      
      • Branch that arises from the left vagus nerve
      • Passes from lateral to medial around the arch of aorta just adjacent to the ductus arteriosus
      • It travels up the tracheooesophageal groove
      • To enter into the larynx at the inferior border of the inferior constrictor muscle
  • Variation
    
    • Non recurrent laryngeal nerve, associated with arteria lusoria (abberant R subclavian off the aortic arch distal to L subclavian) where the R subclavian artery doesn’t come of the right brachiocephalic trunk, but directly off the arch of the aorta distal to the left subclavian artery, where it passes posterior to the oesophagus
    • The nerve in this situation, the nerve doesn’t travel in the inferior to superior orientation but from the lateral to medial directly off the vagus – in this situation it is at risk in thyroidectomy
  • Identification
    
    • The tubercle of zuckerkandel: has a close relationship to the RLN, the nerve is usually medial to the tubercle, therefore when rolling the thyroid medially, the nerve lies just behind the tubercle
    • The ITA: closely associated with the branches of the ITA
    • Berry’s ligament: condensation of the pretracheal fascia at the superiomedial aspect of the thyroid gland and trachea, the nerve can be incorporated into the ligament or closely adherent
    • Vasa-nervorum on its surface
    • Tracheo-oesophageal groove
  • Branches
    
    • Can branch before it enters the interior constrictor
    • Anterior branch = motor muscle of the larynx
    • Posterior branch = sensory suppy of the larynx

Question 19

Describe parathyroid glands

Answer 19

• Definition:
  
  • 4 endocrine glands in the neck that produce parathyroid hormone
  • 1x3x5mm
  • 2 on each side
  • 15% have super nummary glands (1:5 in MEN1), 1-3% have <4 glands
  • About the size of a split pea and weigh approximately 50mg each, light brown/tan and lobular in appearance, wobble if prodded by forceps, rich vascular
  • First discovered in Rhinos by Sir Richard Owen
• Embryology:
  
  • Superior pair derived from 4^th branchial pouch, migrate inferior at the 6^th week
  • Inferior pair derived from 3^rd branchial pouch
  • Inferior pair migrate down with the thymus and are more prone to ectopic location away from the thyroid
  • Endodermal in origin

• Surface anatomy:
  
  • Located behind the thyroid gland
  • 90% of patients have 4 glands
  • 90% are in close proximity to the thyroid and 10% are ectopic
• Surrounding structures and relations:
  
  • See parathyroidectomy –stepwise approach for exploring for an adenoma
  • Superior
    
    • Most common location:
      
      • Posterior to the coronal plane created by the RLN, posteromedial surface of the thyroid, generally posterior to but close to the tubercle of Zuckerkandle
      • Just superior ~1cm above the intersection of the RLN and the ITA
    • Ectopic locations:
      
      • High as the level of the thyroid cartilage and even at the level of the hyoid bone,
      • Usually if ectopic they are more likely to be retro-oesophageal
      • Within the carotid sheath
      • Intrathyroidal parathyroids are more likely to be superior glands
  • Inferior
    
    • Most common
      
      • Within the pretracheal sheath posterior to the inferior thyroid pole (60%)
      • Anterior and inferior to the junction of the RLN ITA intersection
    • Ectopic
      
      • Highly variable
      • From angle of mandible to the pericardium – check within the carotid sheath
  • Important anatomy include that relevant to thyroidectomy
    
    • RLN ascends in tracheoesophageal groove and enters inferior constrictor, close to ITA, beware non recurrent nerve
• Arterial supply:
  
  • Inferior thyroid artery (branch of the thyrocervical trunk off the subclavian) [STA off the ECA]
  • Blood supply comes to the gland from medial aspect – they come from the thyroid side of the gland – if doing a frozen section then sample from the lateral aspect so it doesn’t devascularise
  • Can see these coming vessels into the parathyroid
  • If devascularised then you can auto transplant them – chop up into fine pieces in saline – then use a blunt needle to embed them into the SCM (will take 4-6 weeks to start functioning)
• Venous drainage:
  
  • As per thyroid vein
• Innervation:
  
  • Sympathetic that run with the arteries to the cervical sympathetic ganglion
• Lymphatics:
  
  • Travels with artery
• Structure within the organ and cell types:
  
  • 4 cell types
  • Chief cells Parathyroid hormone
    
    • Polyhedral
    • Eosinophilic
    • Irregular anastomosing cords with extensive vascular supply
  • Oxyphil cells
    
    • Packed full of mitochondria ?function
  • Adipose – increases with age
  • Fibrovascular stroma
    
    • Carry the blood vessels and nerves, forms the capulse and the traebeculae that give it it’s lobulated appearance

Question 20

Describe the process of thyroxine production

Answer 20

Hypothalamus-Pituitary-Thryoid Axis

• Hypothalamus
  
  • Secretes thyrotropin releasing hormone (TRH)
  • TRH travels via the hypophyseal portal circulation to the anterior pituitary (hypophyseal meaning undergrowth – referring to the adenohypophysis which is the glandular undergrowth i.e. the anterior pituitary)
• Anterior pituitary
  
  • TRH triggers the release of Thyroid Stimulating Hormone (TSH)
  • TSH travels in the systemic circulation to the thyroid gland
• Thyroid
  
  • TSH binds to the thyroid releasing hormone receptor (TSH receptor)
  • Release of thyroid hormone into systemic circulation

Thyroxine production

• 5 step process which relies on iodine which is a trace element absorbed in the small intestine
• Iodine
  
  • Found in food (iodised table salt and enriched in bread), seafood, seaweed and some vegetables
  • Low iodine levels are predisposing factor to hypothyroidism, goitres, cretinism, myxoedema coma
• Synthesis of thyroglobulin:
  
  • Follicular cells produce this protein that doesn’t contain any iodine
  • Thyroglobulin is the precusor protein which is stored in the colloid
  • Produced in the rough ER, golgi apparatus pack it into vesicles, then pushed into the follicle lumen by exocytosis
• Uptake of iodine
  
  • Process is upregulated by protein kinase A phosphorylation (end result of TSH receptor binding by TSH)
  • Protein kinase A phosphorylation  increase in the sodium iodine symporter activity  iodide brought into the follicular cells
  • Iodide diffuses across the cell and is transported into the colloid
  • Protein kinase A phosphorylation activates the enzyme thyroid peroxidase (TPO)
• Creation and release of thyroxine
  
  • 5 step process
    
    • TPO has 3 functions to enact coupling the thyroglobulin and the iodide to create thyroxine (steps 1-3)
      
      • 1. Oxidation
           * Iodide to iodine by TPO
      • 2. Organofication
           * Linking of thyroglobulin to iodine by TPO
           * Creates two products
           
           • Monoiodotyrosine (MIT) – single tyrosine residue with iodine
           • Diiodotyrosine (DIT) – 2x tyrosine residues with iodine
           • The tyrosine amino acids come from the thyroglobulin
      • 3. Coupling reaction
           * TPO combines the iodinised tyrosine residues to make T3 (triiodothyronine – MIT + DIT) and T4 (tetra iodothyronine – 2x DIT)
      • 4. Storage
           * Newly created thyroid hormones, T3 and T4, are bound to thyroglobulin and stored in the follicle
      • 5. Release (from follicle to blood stream via the follicular cells)
           * Thyroid hormones are released back into the circulation
           * Thyrocytes (follicular cells), TG uptake by endocytosis, lysosome fuse with endosome containing iodinated thyroglobulin  proteolytic enzymes cleave off TG into T3, T4 and MIT and DIT, the MIT and DIT are put back into the follicles for future use
      • T3 and T4
        
        • Much more T4 than T3 is released
        • T3 is more active (potent)
        • Peripherally the T4 is deiodinated into T3 which activates it into the active form of the hormone
  • The whole process is a negative feedback process
    
    • Increased T3 T4 is sensed by the hypothalamus, to reduce the production and release of TRH, thus reducing production and release of T3 and T4 into the peripheral circulation

Question 21

Calcitonin

Answer 21

• Parafollicular cells (C cells) - neuroendocrine cells which secrete calcitonin. They are found adjacent to the thyroid follicles, in the connective tissue – these C cells are the site of medullary thyroid cancer
• Opposite effect of PTH i.e. lows calcium
  
  • Promotes deposition of Ca2+ into bones (inhibits osteoclasts and stimulates osteoblasts)
  • Inhibits Ca2+ reabsorption in the kidney (excreted in the urine)
  • Inhibits Ca2+ absorption by the intestines

Question 22

Vitamin D synthesis?

Answer 22

Question 23

Symptoms & signs of thyroid disease

Answer 23

Question 24

(table)

ConditionT3T4TSHCause

Answer 24

Question 25

Which is isotope used in thyroid

Answer 25

• Tc-99m pertechnetate or I123 = nuclear uptake scan

I131 = radioactive iodine

Question 26

Retrosternal mass differential

Answer 26

• Substernal goiter – 5 to 24 percent
• Neurogenic tumors (eg, ganglioneuromas in the posterior mediastinum) – 20 percent
• Thymoma – 18 percent
• Bronchogenic and pericardial cysts – 15 percent
• Lymphoma – 5 to 10 percent
• Teratoma (anterior mediastinum) – 8 percent

Question 27

Hashimoto’s

Answer 27

• Definition:
  
  • Chronic autoimmune thyroiditis
  • “Auto-immune lymphocytic thyroiditis”
• Incidence/epidemiology:
  
  • Most common cause of hypothyroidism (in iodine sufficient world)
• Aetiology & risk factors:
  
  • F>M 7:1
  • 40-60 years of age
  • Other autoimmune conditions
    
    • Diabetes
    • Coeliac
    • Addisons
    • Pernicious anaemia
    • Vitiligo
• Pathophysiology:
  
  • Autoimmune-mediated destruction of the thyroid gland involving apoptosis of thyroid epithelial cells
  • Antithyroid antibodies (anti-TPO, anti-thyroglobulin), infiltrate of the gland by lymphocytes with subsequent fibrosis and scarring
  • Combination of genetic and environmental factors
  • Link with Graves Disease
  • Initial hyperthyroidism followed by hypothyroidism
• Clinical manifestations:
  
  • Usually asymptomatic or hypothyroid symptoms
  • Gradual thyroid failure with or without (atrophic) goitre
  • Rarely have a tender goitre, doesn’t cause obstructive symptoms
  • Usually permanent except in children and post-partum
  • Signs & symptoms of hypothyroidism
    
    • Either due to low metabolic rate OR accumulation of matrix glycosaminoglycans in the interstitial spaces
    • Dermatological
      
      • Cool, pale, coarse dry skin
      • Brittle nails
      • Non pitting odema
      • Vitiligo
      • Alopecia
    • Eyes
      
      • Periorbital oedema
    • Haematological
      
      • Anaemia – normochromic normocytic
      • Pernicious anaemia 10% of patients (macrocytosis)
    • Cardiovascular system
      
      • Pericardial effusion
      • Bradycardia
      • Worsened heart failure
    • • Macroscopic features:
  • Local or diffuse process
• Microscopic features:
  
  • Lymphocytic infiltration of the thyroid with follicular destruction, plasma cells, and lymphoid nodules
• Investigations:
  
  • Bloods are diagnostic
    
    • Thyroid Function Tests
      
      • High TSH
      • Low free thyroxine (T4)
    • Auto antibodies
      
      • Anti TPO (thyroid peroxidase) and thyroglobulin
  • FNA if suspicious nodule
• Treatment:
  
  • Non operative/medical
    
    • Thyroxine therapy helps to replace T4 but also suppresses TSH secretion and helps reduce inflammation
    • Levothyroxine (synthetic T4) 100-125mcg/day, but need to monitor TSH 6 weekly until normal and a steady state
• Prognosis:

Question 28

Graves thyroiditis

Answer 28

• Definition:
  
  • Autoimmune cause of hyperthyroidism
• Incidence/epidemiology:
  
  • Most common cause of hyperthyroidism
    
    • Other common causes
      
      • Toxic multinodular goitre
      • Toxic adenoma
      • Early phase of thyroiditis
      • Drug induced (either thyroxine or iodine containing)
    • Other uncommon causes
      
      • TSH secreting pituitary tumour
      • Struma ovarii (rare ovarian tumour)
      • Choriocarcinoma
      • Factitious
• Aetiology & risk factors:
  
  • Family history
  • 2-4^th decade of life
  • Female 4:1
  • Hepatitis C on interferon
  • Stress
  • Smoking
  • Post partum
• Pathophysiology:
  
  • Auto antibodies stimulate the TSH receptor signalling growth
  • Eye disease (cross reactivity)
    
    • TSHR antibodies activate fibroblasts, lymphocytes and adipocytes
    • EOM, connective tissue and fat all increase in volume due to inflammation and acculumation of GAG glycosaminoglycans (mucopolysaccarides deposition)
    • Cornea loses its protection from the eyelid
• Clinical manifestations:
  
  • “Moderate to severe hyperthyroidism, new opthalmopathy and diffuse goitre”
    
    • Signs
      
      • Graves ophthalmopathy (20% of patients)
        
        • 3 subtypes
          
          • Ocular myopathy
            
            • Fibrosis of the EOM
            • Diplopia
            • Exophthalmos
          • Congestive ophthalmopathy
            
            • Periorbital oedema
            • Conjunctival injection
            • Exopthalmos
          • Chronic eyelid lad
            
            • Inability to completely oppose the eye lids
            • Lag and retraction of the eyelid
            • Corneal ulceration
        • Lid retraction
        • Lid lag
        • Exophthalmos
        • Keratopathy
        • Opthalmoplegia from EOM paralysis
        • Compressive optic neuropathy
• Macroscopic features:
• Microscopic features:
• Investigations:
  
  • TFT
    
    • High T3-4 and low TSH
  • Common to have (70%) LFT dysfunction mild
  • Autoantibodies
    
    • Thyroglobulin AB (usually Hashimotos but can be in Graves – note these can effect thyroglobulin monitoring for tumour marker after thyroidectomy)
    • Thyroid peroxidase (usually Hashimotos but can be in Graves)
    • Thyrotropin or TSH receptor antibodies (typical in Graves)
  • USS
    
    • Hypervascularity (thyroid inferno on doppler)
    • Diffuse swelling
    • Hyperechoic heterogenous echotexture
  • Radioactive iodine uptake scan (diffuse uptake)
• Treatment:
  
  • Non operative/medical
    
    • Graves opthalmopathy
      
      • Referral to ophthalmologist – may need eyelid surgery
      • Return patient to euthyroid status but not radioactive iodine
      • Smoking cessation
      • Corneal lubrication topical
      • Mild bed head elevation
      • Glasses during the day to protect from wind/dirt
      • Night shields for eyes
      • NSAIDS
      • Selenium
      • Steroids
      • If severe may need IV dexamethasone or plasma phoresies and orbital decompression, radiation treatment to the retroorbital tissues
    • Symptomatic & definitive
      
      • Symptomatic
        
        • B blocker (propranolol) or calcium channel blocker
        • Potassium iodide
          
          • Lugol’s iodine [potassium iodide with iodine water]
          • 10 days, 5-6 drops tds (or potassium iodide 60mg tds)
      • Definitive
        
        • 3 options for Graves Disease
        • Need to consider pregnancy and Graves opthalmopathy
        • Antithyroid drugs (ATD) include carbimazole or propylthiouracil
          
          • Carbimazole
            
            • 5mg tablets, 12-18 months, aim to stop treatment, 50:50 chance of remission
            • Side effect:
              
              • Agranulocytosis (fever, malaise, pharyngitis)
              • Teratogenic affects
          • Propylthiouracil (PTU)
            
            • Indication:
              
              • 1&3^rd trimester
              • Thyroid storm
              • If carbimazole is ineffective
            • Side effect:
              
              • Hepatic necrosis
            • Interferes with the synthesis of thyroxine by inhibiting TPO (coupling of iodine and tyrosine), PTU also inhibits conversion of T4 to T3
        • Radioactive iodine
          
          • I131 molecule, given as small dose, absorbed into the blood stream from the GI tract, the thyroid is the only tissue in the body that takes up iodine, it is concentrated within the gland, so the radiation is localised to the gland
          • Can take up to 6 months to work and may need second dose to be effective
          • Contraindications:
            
            • Graves eye disease – can worsen in 15% of patients
            • Pregnancy or breast feeding for 12 months after treatment
            • Need radioactive precautions for a few days
          • Side effects:
            
            • Hypothyroidism (80%)
• Operative
  
  • Total thyroidectomy
    
    • Indications
      
      • Failed medical therapy
      • Anatomical reasons (possible cancer or nodules, tracheal compression)
      • Urgency of treatment – quickest way to return to euthyroid
      • Contraindications to anti thyroid drugs (major reactions)
      • Contraindications to RAI (Pregnancy), second trimester pregnancy
      • Thyroid eye disease
      • Patient preference
      • Significant risk of recurrence with subtotal options
• Prognosis:

Question 29

Thyroid storm

Answer 29

• Treatment:
  
  • Medications per NG if needed
    
    • Glucocorticoids
    • Potassium Iodide
    • B blockade
      
      • Propranolol
    • Thioamide
    • Cholestyramine
      
      • Bile-salt sequestrants bind thyroid hormones in the intestine and thereby increase their fecal excretion.
  • ICU care
  • Cooling
  • Empiric antibiotics
  • Treat underlying thyroid condition; radioactive iodine or thyroidectomy
• Prognosis
  
  • Mortality 20%

Answer 30

• TIRADS (ACR Thyroid Imaging, Reporting and Data System)
  
  • 1. Composition
       * 0 = cystic or spongiform
       * 1 = mixed (solid & cystic)
       * 2 = solid (or nearly completely solid)
       
       • 2. Echogenicity
            * 0 = anechoic
            * 1 = iso/hyperechoic
            * 2 = hypoechoic
            * 3 = very hypoechoic
            * 3. Shape
            
            • 0 = wider than tall
            • 3 = taller than wide
              * 4. Margin
            • 0 = smooth/ill defined
            • 2 = lobulated/irregular
            • 3 = extrathyroidal extension
              * 5. Echogenic foci
            • 0 = none or large comet tail artifact
            • 1 = macrocalcifications (can be associated with medullary)
            • 2 = peripheral rim calcification (eggshell, can be seen in malignancy)
            • 3 = punctate echogenic foci (microcalcifications) (psammoma bodies)
              * Total
            • 0 = TIRADS 1 = Benign
            • 2 = TIRADS 2 = Not suspicious
            • 3 = TIRADS 3 = Mildly suspicious
            • 4-6 = TIRADS 4 = Moderately suspicious
            • 7+ = TIRADS 5 = Highly suspicious
  • Remember
    
    • Cancer is more hypoechoic (solid component – obviously a hypoechoic cyst is good)
    • Hyperechoic is good
    • Intact rim calcification is ok, invasion through rim is bad, internal microcalcification bad

Question 31

ATA nodule USS patterns and risk of malignancy

Answer 31

Question 32

Bethesda score for thyroid FNA

Answer 32

1: Non diagnostic

• Need 3+ clusters with 20+ cells in each
• 1-4% risk of malignancy

2: Benign

• 0-3% risk of malignancy
• Should we the most common category
• Colloid, hyperplastic adenoma, thyroiditis
• Repeat USS 12 months

3: Atypia of undetermined significance, follicular lesion of undetermined significance

• 5-15% risk of malignancy (should be a minor of results overall)
• Close follow up at 3 months with FNA or if other high risk features maybe repeat sooner or diagnostic hemithyroidectomy

4: Follicular neoplasm or suspicion of follicular neoplasm

• 20-30% risk of malignancy
• Is there capsular invasion or vascular invasion – can only tell on histology
• Typically management is diagnostic hemithyroidectomy

5: Suspicious for malignancy

• 60-75% risk of malignancy
• Usually papillary thyroid cancer
• Nuclear inclusions/grooves, orphan Annie eyes, psammoma bodies
• Surgical option depends on size, lateral neck involvement

6: Malignant
* 97-99% risk of malignancy

Question 33

Risk factors for thyroid cancer

Answer 33

Female more common (but also nodules more common)

Age

• Red flags for cancer (Win Meyer Rochow)
  
  • Male
  • Extremes of age (<20 or >50 years)
  • Symptoms local invasion (dysphagia, hoarseness)
  • Radiation to the H&N or background radiation
  • Familial cancer

Ionizing radiation

Dietary iodine deficiency (follicular)

Previous long term thyroid inflammation (Hashimotos)

Family history

• Thyroid cancer
• Medullary cancer (20%) MEN 2A and 2B RET
• FAP APC
• Cowdens PTEN (uterine, breast, hamartomas)
• Carney complex type one (benign adrenal adenomas)
• Thyroid cancers of any types (genes not yet recognized yet)

Question 34

Pathophysiology of differentiated thyroid cancer

Answer 34

• Differentiated
  
  • 85% papillary, 10% follicular
  • Arise from follicular thyroid/epithelial cells
  • Produce thyroglobulin
  • Take up iodine
  • Differentiated have low mutation rate – usually one particular driver mutation

Papillary

• Spread via
  
  • Lymphatic (30%)
  • Extra thyroid direct extension
  • 1% Lung most common distant metastasis followed by bone
    
    • Genetic mutations
      
      • BRAF (2/3s), RAS, RET/PTC most common
      • Poorly differentiated ones have acquired a further TERT or Tp53 mutation

Follicular

• Spread via
  
  • Haematogenous; dissemination to lung, bone, liver
• Genetic mutations
  
  • RAS
  • Pi3K
  • PTEN
  • PAX8

Question 35

Pathophysiology of non differentiated thyroid cancers

Answer 35

• De-differentiated
  
  • 1-5%
  • Anaplastic (arise from follicular cells)
  • De novo or de differentiation of well differentiated cancer
  • Invasive of local vessels and RLN nerve
  • Early metastasis to lung, bone and brain

Medullary

• 5%
• C cells – parafollicular
• Don’t take up iodine
• Neuroendocrine tumour – neuroectodermal origin
• Produces calcitonin
• RET oncogene mutation = 25% familial and 75% sporadic – associated MEN2A/B
• Tubercle of Zuckerkandel most common site?
• Spread via
  
  • Lymphatics
• Metastasis to lymphatics, liver, bone, brain, adrenals

Hurthle cell

• 5%
• Similar in some ways to differentiated
  
  • But doesn’t take up iodine as much
• Spread
  
  • Lymphatic

Lymphoma

• Rare
• Arise from the thyroid stroma

Metastasis to the thyroid

• Renal cell (48.1 %)
• Colorectal (10.4 %)
• Lung (8.3 %)
• Breast cancer (7.8 %)
• Sarcomas (4.0 %)
• Melanoma (rare)

Question 36

Clinical manifestations of thyroid cancers

Answer 36

Papillary

• Most found incidentally
• Dysphagia or stridor due to mass effect
• Hoarseness direct invasion RLN
• Lymph adenopathy 30% Lymph node metastasis common [papillary more common than follicular, thus remember that it has the more common modality of metastasis]

Follicular

• Slow growing mass
• Regional lymph nodes rarely involved

Anaplastic

• Rapid neck swelling
• Local compression or invasive symptoms

Medullary

• Diarrhoea
• Vasoactive
• Neck mass

Question 37

microscopic findings in follicular thyroid cancer

Answer 37

• No orphan annie (papillary)
• Extracapsular or vascular invasion (carcinoma)
• Uniform follicles
• Subtypes
  
  • Can be minimally to widely invasive
  • Minimally = solid tumour with thick capsule and some invasion
  • Widely = Infiltration of the capsule and adjacent thyroid tissue and blood vessels
  • Hurthle cell tumour, encapsulated tumour containing >75% oncocytic cells which are pink granular eosinophilia cells due to high amount of mitochondria, can be benign or malignant (1/3) with increasing risk with size (>3cm) and age, can spread lymphatically

Question 38

Microscopic findings in papillary thyroid cancer

Answer 38

• 10+ histological subtypes
  
  • Microcarcinoma – indolent (<1cm than size, usually incidental, usually hemithyroidectomy is enough)
  • Encapsulated variant, but with local invasion
  • Infiltrated subtype, sometimes mistaken for Hashimotos
  • Follicular variant
  • Insular Poor differentiated poor prognosis
    
    • Orphan Annie eye nuclei – dispersed chromatin & pale nuclei, nuclear groove
    • Branching papillae, fibrovascular stalk
    • Psammaoma bodies – calcified structures in the core of the papillae

Question 39

Microscopic appearance medullary thyroid cancer

Answer 39

• Large amounts of amyloid (homogenous extracellular material) from the calcitonin molecules – congo red
• Stain for chromogranin, calcitonin an CEA, wont stain for thyroglobulin
• Single discohesive cancer cells

Question 40

Preoperative investigations for thyroid cancer

Answer 40

Labs

• Calcitonin and CEA for medullary (not thyroglobulin)
• TSH
• Phaeochromocytoma work up for medullary, prior to surgery
  
  • If family history of cancers, or sudden unexplained death
  • Plasma metanephrines
  • Calcium, PTH and Vitamin D levels (due to MEN2A hyperparathyroidism)
  • Refer for RET mutation testing

CT

• Indications:
  
  • Extensive lymphadenopathy
  • Suggestion of extra thyroid infiltration/invasion
• Contrast
  
  • Iodine based contrast is OK, it washouts out in a few weeks

USS (ATA) + FNA – Bethesda classification (as above)

• Papillary
  
  • Can be diagnosed on FNA
• Follicular
  
  • Can’t be distinguished from adenomas on FNA
• Anaplastic
  
  • Need to exclude another rapid growing mass such as lymphoma

Nuclear

• Differentiated
  
  • Tc99
  • I123 (I131 is radioactive treatment)
• DOTATE PET
  
  • Medullary
• Undifferentiated
  
  • FDG
    
    • 60% risk of malignancy if PET avid

Question 41

Non operative management in thyroid cancer

Answer 41

Active surveillance

• Indication
  
  • Micropapillary (<1cm)
  • No aggressive disease (high grade), distant disease or lymph nodes
  • Not located adjacent the RLN or trachea
  • High surgical risk due to comorbidities
  • Short life expectancy

Radioactive iodine

• Differentiated cancers only
• Need to have high TSH when being given so that it is taken up – give artificial TSH called thyrogen, or stop thyroxine beforehand
• Take a stimulated thyroglobulin level at the time of the ablation, also post treatment uptake scan done to check for residual tissue
• Contraindications
  
  • Pregnancy and breastfeeding 12 months
• Side effects
  
  • Salivary gland dysfunction, dry mouth or inflammation of the glands
• 2 indications:
  
  • Adjuvant to improve disease free survival for those without known residual disease
  • Treatment for residual or recurrent disease (previous total thyroidectomy)
• Adjuvant treatment depends on risk stratification (2009 not 2015 which has continuum)
  
  • Low
    
    • Small
    • Unifocal
    • No/minimal nodal disease
    • 1 month post operative thyroglobulin <1
  • Intermediate
    
    • Aggressive histology (extrathyroidal invasion)
    • Vascular invasion
    • Nodal involvement
    • 1 month post operative thyroglobulin 1-10
  • High
    
    • Gross extrathyroidal extension
    • R1 resection
    • +4cm
    • Extensive vascular invasion
    • Large lymph nodes >3cm or extranodal extension
    • Distant metastatic disease
    • 1 month post-operative thyroglobulin >10

Thyroid suppression with thyroxine

• Differentiated cancers express TSH receptor, by suppressing TSH then decreased risk of recurrence
• Give a dose of thyroxine that keeps TSH at <0.1 in high risk patients, 0.1-0.5 for intermediate patients
• Indications
  
  • High risk and intermediate risk patients based on ATA guidelines (see above in RAI)
• Complications
  
  • Arrythmias particularly AF
  • Osteoporosis
• Due to complications need to adjust based on response to treatment after 5-10 years of treatment
  
  • 3 risk differing groups:
    
    • If suppressed thyroglobulin or negative uptake scan
    • If negative uptake scan but TG not <0.1
    • If residual disease on uptake scan
• Monitoring with serum thyroglobulin, clinical examination, USS/PET/CT
• Radioactive iodine resistant disease
  
  •  tyrosine kinase inhibitors (Lenvatinib- multiple targets VEGF + RET)
• Medullary metastatic disease
  
  • Vandetanib and cabozanixib
• Anaplastic
  
  • Radiotherapy

Question 42

Operative management in thyroid cancer

Answer 42

Condensed version of management

• Differentiated = N status, then T status, then high risk features
• Medullary = N status and calcitonin levels
• Anaplastic = depends on PET scan, minimally morbid resectability and BRAF

Lobectomy

• Indications
  
  • Micropapillary cancer if not for active surveillance
  • Follicular neoplasm ?adenoma
  • T1-2 differentiated cancer if no high risk features
  • WMR lecture, his cut off is T1 (i.e.<2cm); note iflobectomy
    
    1. Might have multifocal disease
    2. Residual thyroid will take up RAI if given
    3. Make thyroglobulin surveillance difficult

Total thyroidectomy

• Straight up for
  
  • T2 or N1
• Prophylactic in
  
  • High risk features
    
    • Radiation exposure as a child or H&N radiation
    • Family history
    • Posterior or adjacent the trachea
    • Aggressive cytology
    • Extra thyroid spread
    • Multifocal
• Completion TT
  
  • Just under half of lobectomy will need TT
  • R1 resection, local extension, vascular invasion, >4cm
  • Higher risk of RLN injury, hypocalcaemia

Lymph node management

• Generally leave lymph nodes alone unless high risk (prophylactic/prognostic) or involved (therapeutic)
• High risk
  
  • Same as above
  • >4cm or invading surrounding structures
    
    • Benefits of prophylactic CND
      
      • Improved accurate staging
      • May indicate RAI if involved
      • Not much increase in the morbidity compared to TT alone
      • Reduce the need for re-operative surgery
      • Lower the post operative thyroglobulin levels
      • Against prophylactic CND
        
        • Most are micrometastatic – unclear survival benefit
        • No level 1 evidence
        • RAI is being used less, but upstaging might be unnecessarily be causing us to over treat
      • Central compartment lymph node dissection - prophylactic
        
        • Comprehensive compartment orientated removal of the prelaryngeal, pretracheal and paratracheal lymph node basin
          
          • All fat from between the carotid sheaths, level VI
        • Complications
          
          • RLN injury
          • Hypocalcaemia and hypoparathyroidism
      • Lateral compartment lymph node dissection
        
        • Remove involved compartment and adjacent station nodes, plus central compartment
    • Special considerations in anaplastic cancer

Question 43

TNM staging thyroid cancer

Answer 43

T

• T1 <2cm
  
  • T1a <1cm
  • T1b 1-2cm
• T2 2-4cm
• T3 >4cm or into strap muscles
  
  • T3a >4cm but limited to thyroid
  • T3b into strap muscles (any size)
• T4 into surrounding tissues beyond strap muscles
  
  • T4a invasion into surround tissues including RLNx
  • T4b invasion into prevertebral fascia, carotid, mediastinal vessels

N

• N1a Level VI orVII
• N1b I-V or retropharyngeal

Differentiated AJCC 8^th edition staging

• Because the prognosis is so good for young people the staging is age based
• <55 TxNxM0 = stage 1, TxNxM1 = stage 2
• >55
  
  • Stage 1: T1-2N0M0
  • Stage 2: T1-3 N1
  • Stage 3: T4a NxM0
  • Stage 4a: T4b NxM0
  • Stage 4b: TxNx M1

Question 44

What operation will you do for a patient with medullary thyroid cancer?

Answer 44

Exclude phaeo with serum metanephrines

They will get a total thyroidectomy

Lymphadenectomy depends on calcitonin levels and staging

Question 45

Work up for anaplastic thyroid cancer management

Answer 45

Cross sectional imaging including FDG PET CT

Bronchoscopy and endoscopy for aerodigestive involvement

MDT review with Pall care

?Resectable with minimal morbidity?

If not then BRAF testing for darafenib

If wild type then consider RTx or palliative chemo

Question 46

Follow up post thyroid surgery and management of recurrence

Answer 46

• Differentiated
  
  • Post operative appointment (wound, TFT, Thyroglobulin 6-8 weeks post op)
  • 6 month assessment (TSH, T4, TG and TG antibody levels)
  • 1 year, repeat blood tests and thyroid & neck ultrasound + clinical examination to detect any recurrence or nodal disease – FNA and TG washings of the node
  • If TG or TG antibodies rising then do ultrasound, if US normal then need whole body RAI uptake scan or PET scan
    
    • Medullary
      
      • Monitoring calcitonin and CEA levels, ultrasound of the neck and cervical LNs
      • If calcitonin low – monitor
      • If calcitonin rising or doubles in <6 months
        
        • USS neck
        • CT neck, chest, abdo, pelvis
        • PET scan
    • Recurrence (differentiated)
      
      • Local, lymph nodes or distant disease
      • Need biopsy to confirm the diagnosis
      • Staging
        
        • RAI scan or PET scan
      • Local nodal disease
        
        • Compartment resection
      • Distant
        
        • Multimodality
          
          • Surgery
          • RAI
          • Targeted RTx
          • Thermal ablation
          • Targeted therapies
            
            • Tyrosine kinase inhibitors for radioactive resistant disease
          • Systemic chemotherapy not traditionally used due to poor response
        • Can still have good prognosis
          
          • Age
          • Number and distribution of lesions

Question 47

Thyroid lymphoma

Answer 47

• Definition:
  
  • Lymphocyte malignancy involving the thyroid gland
• Incidence
  
  • Accounts for 1-5% of all thyroid neoplasms
  • Elderly females
  • Previous Hashimotos thyroiditis
• Classification & Aetiology
  
  • May arise as part of a generalized lymphoma
  • May develop in pts with chronic lymphocytic thyroiditis (Hashimotos’s)
• Pathogenesis
  
  • “Pseudocystic” mass
  • Most are non-Hodgkin’s B cell type, diffuse large B cell, marginal zone lymphoma or mixed type
• Clinical Manifestation
  
  • May present with a rapidly (day on day – inpatient work up) enlarging mass +/- stridor / dysphagia
• Investigation
  
  • FNA +/- core biopsy / open Bx – if Dx unclear from FNA
  • stage with LDH, CT, BM aspirate
    
    • Staging
      
      • 1: just within the thyroid
      • 2: thyroid and regional lymph nodes
      • 3: both sides of the diaphragm
      • 4: disseminated
• Management
  
  • [WMR lecture; admit as inpatient, if airway threatened then intubate, get biopsy, treat with chemo]
  • R CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus the monoclonal antibody rituximab (Rituxan)
  • Surgery used to alleviate Sx of obstruction, or for pts who don’t respond
  • ?if confined to the thyroid alone, can be treated with lobectomy with subsequent
  • chemo-radiation (otherwise chemo-radiation alone)
  • but NB Surgery + chemorads vs chemorads alone = same survival stage for stage
• Prognosis:
  
  • Overall 5-yr survival ≈50%
  • Pts with extrathryoidal disease have lower survival rates

Question 48

spell them

Signs and symptoms of postoperative hypocalcaemia

Answer 48

Numbness and tingling in distal extremities and perioral, tongue

Chvostek sign

• Tap over the facial nerve  muscle contraction

Trousseau sign

• BP cuff to inflate the cuff above systolic  after a few minutes carpopedal spasm (tetany of the wrist and fingers)

Tetany and trismus

Laryngospasm

Arrythmias, QTc prolongation

Chest pain

Seizures

Question 49

Management of post operative hypocalcaemia

Answer 49

Post operative calcium, PTH and ECG if symptomatic

Depends if

• Symptomatic
• PTH level then Ca2+ level

Asymptomatic

• PTH >2.0
  
  • Ca >2.1
    
    • No action
  • Ca <2.1
    
    • Calcitabs (500mg) PO x2 TDS
    • Repeat bloods within 5 days
• PTH <2
  
  • Ca >2.1
    
    • Calcitabs (500mg) PO x1 TDS
    • Calcitriol (0.5mcg) PO 1x daily
    • Repeat bloods within 5 days
  • Ca <2.1
    
    • Calcitabs (500mg) PO x2 TDS
    • Calcitriol (0.5mcg) PO x2 daily
    • Remain inpatient

Symptomatic

• Mild-moderate
  
  • Caltrate 1-2 tablets PRN 30 minutes x2 then seek help
  • Calcitriol to increase the GIT ability to absorb the calcium (can normally only absorb 5 tablets)
• Severe
  
  • IV replacement
    
    • Calcium gluconate (10ml 10% = 2.2mmol calcium)
      
      • Bolus 20mL calcium gluconate 10% (4.4mmol) in 100ml NS over 20 minutes
      • Infusion 100mL calcium gluconate 10% (22mmol) with 900mL NS at 50ml/hr (1.1mmol an hour)
      • Extravasation causes severe tissue necrosis
  • Blood test every 3 hours
  • Monitored bed

The main difference between cholecalciferol and calcitriol is that cholecalciferol is a type of vitamin D that is made by the skin when exposed to sunlight whereas calcitriol is the active form of vitamin D that occurs in the kidney

Question 50

Definition of hyperparathyroidism

Answer 50

• A condition whereby there is parathyroid overproduction
• Can be classified as primary, secondary or tertiary
  
  • Primary hyperparathyroidism:
    the autonomous, spontaneous overproduction of PTH
    
    • 85% adenoma [single or multiple]
    • 15% hyperplasia [all abnormal in secondary, more likely hyperplasia in familial]
    • <1% carcinoma
  • Secondary hyperparathyroidism: overactivity of the PTH glands due to hyperplasia in response to a chronic depression in serum calcium (seen in chronic renal failure and vitamin D deficiency)
  • Tertiary hyperparathyroidism: autonomous overproduction of PTH as a progression of secondary hyperplasia despite normalisation of renal failure
  • Don’t mention [Quaternary: Once the underlying problem has been resolved but hyperparathyroidism persists (despite surgery renal transplant)- note sometimes tertiary/quaternary lumped together]

Question 51

Pathophysiology/pathogenesis of hyperparathyroidism

Answer 51

• Primary hyperparathryoidism
  
  • Adenoma 85%
    
    • Sporadic
      
      • The somatic PRAD1 rearrangement upregulates cyclin D1 in sporadic adenomas
      • MEN1
        
        • MEN1 gene (chromosome 11q13)
        • Tumour suppressor gene, codes for menin
        • Multiglandular, ectopic, and supernumerary disease
  • Hyperplasia 10% (2+ gland)
    
    • MEN2A [not B]
      
      • RET mutation (chromosome 10q11.2)
      • Protooncogene
  • Carcinoma <1%
    
    • RET protooncogene
    • CDC73 tumour suppressor gene
• Secondary
  
  • Multiple asymmetrical gland hyperplasia
  • 1. Renal Disease
       * Hypocalcaemia due to reduced reabsorption of urinary calcium
       * Decreased phosphate excretion→high phosphate
       * Loss of renal parenchyma→reduced alpha 1 hydroxylase→ decreased activated vitamin D→ reduced intestinal absorption of calcium
  • 2. Malabsorption
  • 3. Vitamin D deficiency
  • 4. Lithium use

Parathyroid cancer

• Sporadic
  
  • Neck radiation
• Gene mutation (CDC 73)
  
  • RET
  • Hyperparathyroidism Jaw Tumour Syndrome (HPT JT)
    
    • Tumour suppressor gene
    • Associated with mandible/maxilla tumours, uterine and renal cancer

Question 52

Clinical manifestations of parathyroid disease

Answer 52

Primary hyperparathyroidism

• Incidental
• Hypercalcemia
  
  • Bones: Osteoporosis/fractures, bone pain
  • Stones: Renal stones
  • Groans: Depression
  • Moans: Pancreatitis; constipation
  • Neck lump
  • Renal
    
    • Nephrocalcinosis
    • Calciphylaxis
    • Renal impairment
  • Osteitis fibrosa cystica
  • Other
    
    • Multiple adenomas: pituitary, pancreas, adrenals, thyroid
    • Limbus keratopathy
    • Increased joint flexibility
    • Strong nails and pseudoclubbing
    • Absence of lamina dura
    • Calcium deposition in bloods vessels, HTN, heart failure

Parathyroid cancer

• Nearly always functioning
• Extremes of hypercalcaemia
• Very high PTH
• Neck lump
• Hoarse voice (RLN)

Question 53

Macro/micro appearance of parathyroid disease

Answer 53

• Macroscopic features:
  
  • Adenoma (usually single)
    
    • ovoid, soft, reddish brown tumours, usually a little darker than the normal gland
  • Carcinoma
    
    • Gray white irregular mass sometimes >10g >2cm
• Microscopic features:
  
  • Hyperplasia: increased number of chief cells, cells with more abundant, clear cytoplasm “water-clear cells” in a diffuse or multinodular arrangement, decreased fat cells/fat depleted
  • Adenoma:
    
    • Fairly uniformed polygonal chief cells with small, centrally placed nuclei.
    • A few nests of larger oxyphil cells.
    • Rim of compressed normal tissue.
    • Common to find pleomorphic nuclei
    • Lack of fat
  • Carcinoma
    
    • Uniform and resemble somewhat normal parathyroid cells
    • Nuclear atypia should not be the defining feature as you can see this in adenomas
    • Cells form nodular or trabecular pattern with a dense fibrous capsule, invasion of surrounding structures
    • Parafibromin staining (as 70% are related to parafibromin)

Question 54

Investigations for hyper parathyroidism

Answer 54

• Concepts
  
  • The work-up of parathyroid hyperparathyroidism (like any endocrine surgical condition) depends on confirming the biochemical abnormality and then performing imaging studies to localize the tumour
  • Also, need to work up the thyroid gland lesions because you will come across them in the procedure
  • Exclude 3 mimic conditions and concurrent phaeo:
    
    • FHH (familial hypocalciuria hypercalcaemia)
    • Parathyroid related hormone (small cell or other cancer – paraneoplastic syndrome)
    • Lytic bone lesions
• History
  
  • Symptoms of hypercalcaemia or local symptoms
  • Symptoms of underlying malignancy
  • Symptoms of endocrine disorder
  • Medications
    
    • Lithium
    • Thiazides
    • Vitamin D
  • Family history
    
    • Familial hypocaliuric hypercalcaemia
    • Endocrine diseases
  • Previous neck surgery
  • Previous H&N radiotherapy
• Exam
  
  • General
    
    • Body habitus
    • Voice
    • Thyrotoxicosis?
  • Neck
    
    • Masses
    • Scar
    • LNs
• Bloods
  
  • 1. Intact PTH (low = other cancer)(high or inappropriately normal will be PHPT)
  • 2. PTHrp?
  • 3. Vitamin D
  • Serum calcium (+/- ionized calcium)
  • Serum albumin
  • Creatinine, urea
  • Phosphate and magnesium
    
    • Expect low serum phosphate unless renal failure
    • Secreting phosphorus and absorbing chloride (anion exchange)
  • Serum metanephrines to exclude a phaechromocytoma that can occur in conjugation with hyperparathyroidism in patients with multiple endocrine neoplasia 1 and 2A
• 24 hour urinary calcium with calcium/creatinine ratio
  
  • Consider Familial hypocalcuric hypercalcaemia
    
    • Autosomal dominant – abnormalities in the calcium sensing receptor (CASR) gene
    • Abnormal calcium-sensing receptors expressed on parathyroid and renal cells  reduced sensitivity to calcium levels  mild hypercalcemia with normal/slightly elevated PTH levels + normal phosphate levels
    • A urinary calcium level is normal/elevated in patients with PHPT but low/low normal in those with FHH
    • Patients with FHH will not benefit from surgical intervention
    • Excluded by measuring the 24hr urinary calcium/creatinine ratio (<0.01)
  • Renal failure
• Imaging:
  
  • Localisation & complications
  • Detect complications of pHPT
    
    • Abdominal imaging for asymptomatic patients (as nephrocalcinosis is an indication for surgery)
    • DEXA
  • Secondary hyperparathyroidism  patients with secondary HPT do not undergo localisation studies as they will always have a 4-gland bilateral exploration of their neck
  • 99mTc Sestamibi scan (early & delayed) and high resolution ultrasound (If these scans are concordant, then removing the identified gland will lead to a cure in 95-98% of patients), 4D CT third line, 4 gland exploration next up
  • Modalities
    
    • Non invasive
      
      • USS Neck and renal tract*
        
        • 80% sensitivity
        • Parathyroids are posterior to the thyroid gland, homogenous, hypoechoic and white hyperechoic rim, hypervascular with a solitary pedicle
        • Also look at thyroid for nodules that need management at same time
        • Stones and calcinephrosis
      • Multiphase CT (4D)
        
        • Tripe phase (Non-con, arterial, delayed)
        • The 4^th dimension is time.. which is stupid because all multiphase scans have time as a 4^th dimension
        • Thin slices through the neck
        • Adenoma
          
          • Hyperenhancing on the arterial and washed out in the delayed in comparison to the thyroid
      • MRI
        
        • MRI is infrequently utilised in initial workup because of lower spatial resolution and artifacts. Adenomas can show variable signal intensity on MRI. Reported signal characteristics
        • T1
          
          • typically intermediate to low signal
          • subacute haemorrhage can cause high signal intensity
          • fibrosis or old haemorrhage can cause low signal intensity
        • T2
          
          • typically hyperintense
          • subacute haemorrhage can cause high signal intensity
          • fibrosis or old haemorrhage can cause low signal intensity
          • Since most lesions demonstrate high T2 signal intensity, the addition of contrast for MRI does not significantly increase detection.
      • SPECT
        
        • Single Proton Emission Computerized Tomography = Sestamibi-single photon emission computed tomography (SPECT or MIBI-SPECT) combined sestamibi and low dose CT, resolution not as good as a CT normally
      • Sestamibi*
        
        • Nuclear medicine scan
        • Radioisotope technetium-99m bound to six (sesta=6) methoxyisobutylisonitrile (MIBI) ligands (as opposed to Tc99 bound to sulphur colloid used in SLNBx)
          
          • Taken up by both thyroid and parathyroid, but retained for longer in the parathyroid gland
        • A second image is obtained after a washout time (approximately 2 hours), and mitochondria in the oxyphil cells of the abnormal glands retaining the 99mTc are seen with the gamma camera
• Invasive
  
  • Selective angiography
    
    • ITA blush
    • Risky
      
      • Selective venous sampling
        
        • Comparing the iliac vein PTH to various neck veins (STV, ITV, thymic vein, vertebral vein)
  • Intraoperative
    
    • USS
    • Methylene blue localization
    • Gamma probe localisation
      
      • Tc-99 m sestamibi isotope on the day of surgery
      • Containing more than 20% of background radioactivity in a patient with a positive sestamibi scan is consistent with the finding of a solitary parathyroid adenoma
    • Intraoperative parathyroid levels
      
      • Drop of more than 50% after 10 minutes and into the normal range
  • Is this a MEN problem (1 or 2A, not 2B)?
    
    • Genetic counseling should be performed for patients younger than 40 years with pHPT and multigland disease (MGD) and considered for those with a family history or syndromic manifestations

Question 55

Non operative management of hypercalcaemia

Answer 55

• Depends on severity and underlying cause
• Mild
  
  • No treatment needed
  • Oral hydration
  • Treat underlying cause
  • Avoid
    
    • Thiazides/lithium
    • Prolonged bed rest
    • Vitamin D supplements
    • High calcium diet
• >3.5 or symptomatic
  
  • Rehydration 300ml/hr normal saline for a litre then 100ml hour
  • IV bisphosphonate
  • Calcitonin
  • Steroids in granulomatous disease, sarcoid, lymphoma
  • Dialysis
  • Calcimimetic (cinacalcet)

Question 56

When is surgery indicated for patients with elevated parathyroid levels

Answer 56

Everyone except;

• Another cause i.e. FHH, vitamin D deficiency
• Those not fit for surgery
• Asymptomatic with no end organ effects with either
  
  • Life expectancy <10 years, or
  • Normal calcium (can offer parathyroidectomy) particularly if lives remotely or age <50

Question 57

What is hungry bone syndrome?

Answer 57

• After either parathyroidectomy OR thyroidectomy for graves
• Strict protocol requiring calcium infusions
• High bone turnover during secondary hyperparathyroidism, but when the PTH levels drop the turnover stops and suddenly the bone sucks up magnesium, calcium and phosphate
• Symptoms
  
  • Severe hypocalcaemia
  • Hypophosphatemia
  • Hypomagnesaemia
    
    • IV calcium, magnesium replacement

Question 58

Causes of hypercalcaemia

Answer 58

Question 59

Investigation pathway for hypercalcaemia

Answer 59

Question 59

Investigation pathway for hypercalcaemia

Answer 59

Question 60

Parathyroid hunting

Answer 60

• Identify and remove abnormal parathyroid
  
  • Superior Parathyroid
    
    • Most upper PT are posterior to upper pole (The 3 landmarks to aid location are):
      
      • Inferior cornu of the thyroid cartilage
      • RLN
      • The most cranial branch of the inferior thyroid artery
      • Posterior to thyroid at junction of upper 1/3 & lower 2/3
      • Abnormal P IV glands tend to migrate posteroinferiorly, beside or behind the oesophagus
      • Location of the inferior thyroid vascular pedicle and gentle traction can aid localisation
      • If not found inspect the perithyroid visceral sheath, particularly the posterior aspect of the upper pole and thyroid capsule.
      • Identify and preserve the inferior thyroid vessels and RLN.
      • If still not found move on, search for P III.
    • Inferior parathyroid
      
      • Most lower PT are anterior & inferior to thyroid pole ie. RLN & ITA
      • Rarely posterior, the more inferior the more anterior they tend to lie.
      • There is symmetry of position in 60% of cases.
      • Search from the inferior thyroid artery to the inferior thyroid pole
      • Often they are found within the thymic sheath (may need to incise or mobilise the thymus)
      • Carotid sheath
      • Undescended – look high
      • If a gland is not found search for it should be abandoned in case a normal gland is devascularised. Move to the other side.
    • When to stop looking
      
      • STOP = when found one abnormal gland** + **another 2 look normal
      • 50% drop in PTH intraoperatively @ 10 minutes
    • When to go hunting
      
      • Exploration should be pursued in 3 circumstances:
        
        • <4 found and none are pathological (a likely adenoma remains to be found).
        • If <4 glands found and at least 2 are pathological (multiglandular disease, likely others affected).
        • All four glands found and none are pathological (ectopic supernumerary gland).

Question 61

Describe the adrenal glands

Answer 61

• Definition:
  
  • The adrenals are paired glands that lie on top of the kidneys bilaterally
  • Composed of two quite different components embryologically and functionally
    
    • The outer cortex - derived from the intermediate mesoderm - acts as an endocrine organ producing corticosteroids & androgens
    • The inner medulla – derived from the ectodermal neural crest – acts as part of the autonomic nervous system producing catecholamines & dopamine

(think pituitary – anterior/posterior)

• Embryology:
  
  • Cortex is derived in situ from the intermediate mesoderm along with the gonads and kidney
  • Medulla is derived by migration of cells from the neural crest and is ectodermal in origin
  • Adrenals at birth are large but regress as cortex shrinks,
• Surface anatomy:
  
  • Just lateral to the vertebrae with the 12^th rib overlying the inferior portion
• Surrounding structures and relations:
  
  • Within Gretoas fascia but have their own capsule
  • Left
    
    • Short fat crescentric
    • Overlying the left renal hilum on the medial aspect of the kidney
    • Medial: aorta
    • Posterior: lies on the left crus of the diaphragm and front of left kidney (same as right)
    • Anterior:
      
      • Superior part has the lesser sac and stomach bed
      • Inferior part has the body of the pancreas and the splenic vessels
  • Right
    
    • Tall skinny triangular
    • Surmounts the right kidney (not enough room to be medial due to the proximity of the IVC)
    • Posterior: lies on the right crus of diaphragm and the front of the right kidney
    • Medial: IVC
    • Anterior:
      
      • Bare area of the liver
      • Below the liver it is covered by the peritoneum of the hepatorenal (Morrisons) pouch
• Arterial supply:
  
  • 3x
    
    • Inferior phrenic
    • Aorta
    • Adrenal (off renal)
• Venous drainage:
  
  • Single vein
    
    • Right is only a few millimietres and direct into the IVC
    • Left is longer and enters the left renal vein
  • The cortex drains through the medulla, important as glucocorticoid hormones (from cortex) activate PNMT a medullary enzyme involved in catecholamine synthesis
• Innervation:
  
  • Cortical control is not neural but by ACTH from the anterior pituitary
  • Medulla - myelinated preganglionic sympathetic fibres from the splanchnic nerves via the coeliac plexus (T5-9), the fibres synapse directly with medullary cells
• Lymphatics:
  
  • Para aortic
• Structure within the organ and cell types:
  
  • Contained within Greotas fascia but with some fat and connective tissue separating it from the kidney
  • The adrenal gland has an outer yellow cortex completely enclosing a much thinner grey medulla
  • Cortex
    
    • Products (salt, sugar, sex – the deeper you go the sweeter it gets)
      
      • Aldosterone
      • Cortisol
      • Androgens
    • Three layers or zones (GFR)
      
      • Zona glomerulosa (with small columnar cells, minimal cytoplasm, clusters of cells)
      • Zona fasciculata (largest layer, parallel rows of pale-staining vacuolated cells)
      • Zona reticularis (a network of smaller, branching cords and darker-staining cells).
  • Medulla (15% of volume)
    
    • Vascular spaces and eosinophilic phaeochromocytes - larger cells
    • Products
      
      • Catecholamines adrenaline (epinephrine) (80%) and noradrenaline (norepinephrine) (20%)
      • Dopamine
    • Many of the medullary cells exhibit the chromaffin reaction: they contain fine cytoplasmic granules (the catecholamine precursors) which are coloured brown by chromium salts (hence chromaffin cells)
• Relevance to operations:

Question 62

Describe RAAS physiology

Answer 62

Question 63

Describe the hypothalamic pituitary adrenal axis

Answer 63

Question 64

In medulla what enzyme converts noradrenaline to adrenaline

Answer 64

PNMT

Question 65

table

Differential for adrenal lesion

Answer 65

• Benign vs Malignant (primary vs secondary)
• Functional vs non-functional
• Sporadic vs hereditary

Question 66

Work up for adrenal lesion

Answer 66

• Investigations:
  
  • Is it malignant? is it functional?
  • History
    
    • Past medical history of malignant disease
    • Family history of endocrine disease
    • Previous imaging that can be compared to
    • Symptoms
      
      • Malignancy
        
        • Weight loss
      • Mass
        
        • Acute pain (from haemorrhage)
        • Back pain
      • Functional
        
        • Cushing’s
          
          • Easy bruising
          • Fatigue
          • Weight gain
          • Leg swelling
          • Mood swings
          • Mental fogginess
        • Primary aldosteronism
          
          • Muscle cramps
          • Weakness
          • Paraesthesia
        • Sex hormone excess
          
          • Infertility
        • Phaechromocytoma
          
          • Episodic spells of dizziness
          • Palpitations
          • Headache
          • Diaphoresis
          • Tremor
          • Anxiety
  • Examination
    
    • Signs of hormone excess such as
      
      • Cushings
        
        • Moon face
        • Weight gain with buffalo hump
        • Central obesity and thin extremites
        • Skin changes (thin with easy bruising, acne, purple striations)
        • High BP
        • Abnormal hair growth
        • New diabetes
        • Osteoporosis
        • Proximal myopathy
        • Cessation of menses
        • Breast and impotence in men
      • Primary hyperaldosteronism
        
        • Resistant hypertension
        • Hypokalaemia
        • Acidosis
        • Hypernatremia
      • Sex hormone excess
        
        • Hirsutism
        • Acne
        • Gynaecomastia
        • Male pattern baldness
      • Phaeochromocytoma
        
        • Hypertension
        • Orthostatic hypotension
        • Retinopathy
        • Congestive cardiac failure
        • High BGL
  • Biochemistry
    
    • Cushings (glucocorticoid excess)
      
      • Screening:
        
        • Low-dose (1 mg) overnight dexamethasone suppression test and midnight salivary cortisol may be required to confirm or exclude
      • Confirmatory:
        
        • 24-hour urinary free cortisol
      • ACTH level (independent vs dependent)
        
        • If high ACTH then do high dose dexamethasone
        • High dose (8mg) dexamethasone suppression test, if elevated at 8AM then ectopic production (not pituitary) of ACTH
    • Conn’s (mineralocorticoid excess)
      
      • Hypertensive patients with elevated plasma aldosterone:renin activity ratio >20
      • Hypokalaemia is present in only half the patients with primary hyperaldosteronism
    • Sex hormone
      
      • Serum DHEAS and 17-hydroxyprogesterone are measured to exclude adrenal androgen hypersecretion that occurs in some adrenocortical carcinomas or, when bilateral adrenal masses are present, congenital adrenal hyperplasia.
    • Serum metanephrines
  • Imaging localisation
    
    • CT (thin slices)
      
      • Lipid rich low density/attenuation masses on unenhanced CT (<10 hounsfield units)
      • Rapid washout of contrasts (<50% at 10 minutes, <60% at 15 minutes)
      • Homogenous with regular outline, rounded, no extension into surrounding structures
      • <4cm in size have low malignant risk
    • MRI
      
      • Homogenous enhancement after gadolinium MRI is characteristic
    • PET
      
      • Low fluorodeoxyglucose uptake
  • Invasive
    
    • Biopsy
      
      • Unhelpful at differentiating between adenoma and carcinoma and may precipitate a phaeochromocytoma crisis
      • Maybe for metastatic disease
    • Selective Venous sampling
      
      • Unilateral microadenoma vs bilateral hyperplasia
• Treatment:
  
  • Non operative (<2% of <4cm lesions suspected will harbour carcinoma)
    
    • If benign appearing then repeat imaging in 6-12 months plus repeat functional studies
    • Benign cyst or myelolipoma convincingly diagnosed on imaging, can observe despite size >4cm
      
      • Myeloplipoma
        
        • Benign tumour composed of mature fat and interspersed hematopoietic elements that resemble bone marrow
  • Operative
    
    • Indications for adrenalectomy
      
      • Size: +4cm
        
        • 25% of tumours >6cm will be carcinoma therefore require adrenalectomy
      • Suspicious for malignancy on imaging
      • Functional
        
        • If functional consider perioperative steroids
    • Approach
      
      • Open vs lap
      • Transperitoneal vs retroperitoneal

Question 67

Risk factors and pathophysiology of adrenocortical carcinoma

Answer 67

• Aetiology & risk factors:
  
  • Most sporadic
  • Southern Brazilian children
  • Genetic conditions
    
    • MEN1
    • Li Fraumeni syndrome p53 (breast, osteosarcoma and brain tumour)
    • Beckwith widemann syndrome (IGF-2 gene, exophthalmos, macroglossia, nephromegly)
    • APC FAP
    • Lynch syndrome
  • Congenital adrenal hyperplasia
• Pathophysiology:
  
  • Retinoblastoma gene and p53
  • Most are functional (+60%)
  • 40% present with metastasis
  • Common to produce sex hormones as the 21-hydroxylase is defective (thus shunting away from the corticosteroid pathway)

Question 68

Clinical manifestations of ACC

Answer 68

• Incidental/asymptomatic
• Functional
  
  • Cushings syndrome (most common), primary hyperaldosteronism (minority), virilisation or femination
  • Mass effect
    
    • Abdominal or back discomfort
  • Necrosis of large lesions can cause fevers
  • Children usually have virilization and uncommon to have isolated cushings

Question 69

Macroscopic and microscopic appearance ACC

Answer 69

• Macroscopic features:
  
  • Unencapsulated; large (200 g, 20 cm)
  • 90% are larger than 6cm
  • Variegated cut surface due to haemorrhage, cysts, necrosis
  • Often soft, friable intratumoral nodules; often invasion of major veins
  • Tend to invade adrenal vein, vena cava, adjacent kidney and retroperitoneum; may cause thromboemboli
  • Metastases to liver (60%), regional lymph nodes (40%), lungs (40%), peritoneal and pleural surfaces, bone, skin (anaplastic tumors) or retroperitoneum
• Microscopic features:
  
  • For diagnosis need to demonstrate either metastasis or local invasiveness (bit like follicular carcinoma)
  • Ki-67 (>5%) and the Modified Weiss criteria can be used for recurrence risk calculation

Question 70

What is adrenal washout on CT?

Answer 70

• CT adrenal
  
  • Protocol
    
    • Non con – measure the hounsfield units
    • Contrast
      
      • Arterial
      • Portal venous
      • Delayed
        
        • Washout (not that specific)
          
          • Absolute (compared to non contrast) washout
            
            • >60% likely benign
            • <60% likely a cancer
          • Relative washout
            
            • >40% likely benign
            • <40% likely a cancer
        • Fine slices through the adrenals
      • Other suspicious features for malignancy
        
        • Typically over 5cm, >6cm risk is +25%
        • Heterogenous lesion
        • Haemorrhage
        • Invasion
        • Irregular margins on unenhanced CT
        • Denser that adenoma (attenuation >10 Hounsfield)

Question 71

Treatment of adrenocortical carcinoma

Answer 71

• Patient and tumour factors
  
  • Tumour
    
    • Localised vs metastatic
    • If localised
      
      • Principles
        
        • R0 resection
        • En bloc resection of any involved adjacent organs
        • IVC involvement can be resected and thrombectomy
        • Open procedure – unacceptable local recurrence rate laparoscopic
      • If metastatic
        
        • Systemic treatment
        • Localised treatment including debulking, RFA, TACE
        • Radiotherapy
  • Non operative
    
    • Medical therapy with mitotane (1,1-dichloro-2-( o -chlorophenyl)-2-( p - chlorophenyl)ethane) is used in advanced ACC
      
      • Mitotane, originally used as an insecticide, is a lipophilic agent concentrated in the adrenal cortex, where it induces necrosis by mitochondrial degeneration. Tumour response occurs at a therapeutic range of 14–20 mg/L in up to one-third of patients, though gastrointestinal and neurological side-effects are common and adrenaline sufficiency may occur.
      • Cytotoxic to the adrenal, reduces steroid hypersecretion by tumour cells – leads to adrenal insufficiency (requiring adrenal replacement)
  • Operative
    
    • Open is recommended approach – don’t want to violate tumour capsule
    • Transabdominal or thoracoabdominal
    • En-bloc resection of the perinephric fat, regional lymph nodes and adjacent organs including kidney, pancreas, liver or spleen maybe required to achieve complete resection
• Prognosis:
  
  • 85% will have local or distant recurrence
  • 2 year survival is 50%
  • 5 year survival is 20%
  • TNM
    
    • T1 :<5cm, no invasion
    • T2: >5cm, no invasion
    • T3: any size, local invasion
    • T4: any size, invading adjacent organs
    • N1: node positive
    • M1: distant metastasis

Question 72

Phaeochromocytoma (definition, pathophys, clinical manifestations)

Answer 72

Rule of 10’s - outdated :(

• 10% of sporadic phaeochromocytoma are bilateral
• 10% are extra adrenal
  
  • “Paraganglioma”
  • Bifurcation of the aorta
  • These secrete noradrenaline not adrenaline (cause there isn’t the PNMT enzyme)
  • 10% familial
  • 10% are malignant
  • 10% are NON functional
  • 10% in children

Defintion

• Neoplasms composed of chromaffin cells, which synthesize and release catecholamines and in some instances peptide hormones
• Phaeochromocytoma and extra-adrenal paraganglioma are tumours derived from catecholamine-producing chromaffin cells of neural crest origin arising in either the adrenal medulla (phaeochromocytoma) or extra-adrenal autonomic ganglia (paraganglioma)

Pathophysiology

• Most are sporadic
  
  • 1/3 of these carry a germline mutation
    
    • RET (sporadic MEN2)
    • VHL
    • NF1
    • SDH (succinate dehydrogenase)
• In pregnancy the gravid uterus compresses the tumour
• Larger and extra adrenal lesions are more likely to be malignant

Clinical manifestation

• Paroxysmal excessive secretion of catecholamines
  
  • Symptoms
    
    • Headache
    • Palpitations
    • Sweating
    • Pallor
    • Nausea
    • Weight loss
    • Fatigue
    • Anxiety
    • Often provoked by postural change, exercise, anxiety
    • Commonly associated with diabetes
    • Crisis may cause sudden multiorgan failure, stroke, death
  • 5% of adrenal incidentalomas are phaeochromocytomas

Question 73

Phaechromocytoma macro/micro appearance

Answer 73

Macroscopic features:

• The majority of extra adrenal paragangliomas occur in the abdomen, either from the sympathetic ganglia in the organ of Zuckerkandl (around the bifurcation of the aorta), around the renal hilum or at less frequent sites bladder, mediastinum
• In contrast to sympathetic paragangliomas, parasympathetic paragangliomas arise more commonly in the head and neck

Microscopic features:

• Phaeochromocytoma of the Adrenal gland Scoring Scale (PASS) have been devised in order to predict malignancy
• Ki67 proliferation index may be elevated in malignant phaeochromocytoma
• A zellballen is a small nest of chromaffin cells or chief cells with pale eosinophilic staining. Zellballen are separated into groups by segmenting bands of fibrovascular stroma, and are surrounded by supporting sustentacular cells. A zellballen pattern is diagnostic for paraganglioma or pheochromocytoma. Zellballen is German for “ball of cells”.

Question 74

Investigations for phaeochromocytoma

Answer 74

• Biochemical
  
  • 1. Free plasma metanephrines (if higher pretest probability – screening test)
       * These are the inactive metabolites of adrenaline and noradrenaline
       * 2. Urinary 24hr metanephrines (if lower pretest probability – confirmatory test)
• Imaging
  
  • Functional localisation studies should accompany cross-sectional imaging prior to surgery for phaeochromocytoma
  • CT adrenal
    
    • 85-94% sensitive
    • Homogenous mass, if internal haemorrhage may be heterogenous
    • High hounsfield unit of 40-50 on non contrast
    • Don’t washout
  • MRI
    
    • Appears same intensity as liver on T1
    • High signal on T2 due to high vascularity
    • Good for children and pregnancy and thorax
    • Delayed washout, at 10 minutes less than 50%
  • Functional
    
    • Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate (gallium Ga-68 DOTATATE)-positron emission tomography (Ga-68 DOTATATE PET) is proving to be more sensitive in some patients than I-123, CT/MRI, or
    • Iodine-131 or 123-metaiodobenzylguanidine (MIBG) scintigraphy – good for localisation
    • FDG-PET for detection of phaeochromocytoma, ACC and metastatic disease are all hot, but can help localise the a phaeochromocytoma
• Avoid, selective venous sampling and biopsy
• Genetic testing
  
  • If young <50
  • Multiple
  • Extra adrenal
  • Family history
  • Malignant
  • Screen PTH, calcium, vitamin D, urinary cytology for RCC, fundoscopy and thyroid USS

Question 75

Treatment of phaeochromocytoma

Answer 75

• The first priority is alpha blockade
  
  • (prazocin – selective alpha or phenoxybenzamine), then everything is elective
  • Dry/stuffy nose
• Then beta block
• Depends if resectable or not
  
  • Metastatic disease/non resectable
    
    • Symptom relief can be achieved by tumour debulking
    • Inhibition of catecholamine synthesis, and α- and β-adrenergic receptor blockade
    • External beam radiotherapy, chemotherapy, radiofrequency ablation and transcatheter arterial embolisation may have a role
    • Therapeutic doses of [131 I]MIBG can produce symptomatic and hormonal improvement as well as tumour regression or stabilisation
  • Resectable
    
    • Procedure
      
      • Lap over open (if <6cm)
      • Consider bilateral adrenalectomy in MEN2, VHL
      • May need to do subtotal adrenalectomy if bilateral
      • Don’t remove them intraoperatively if found by co incidence
  • Perioperative care
    
    • Alpha adrenergic blockade (phenoxybenzamine)
    • Fluid resuscitation (as they are volume deplete, and can eat salt)
    • After alpha blockade then introduce Beta blockade (unopposed alpha blockade causes hypertensive episode and pulmonary oedema)
    • The period of preoperative blockade allows intravascular volume expansion to occur and cardiomyopathy secondary to chronic hypertension to resolve
    • Arterial and venous lines
    • Avoid handling the tumour
    • Intravenous administration medication for
      
      • Hypertensive episodes
        
        • IV magnesium
        • The short-acting vasodilator sodium nitroprusside
        • Calcium channel blocker nicardipine
        • α-adrenergic receptor anatagonist phentolamine
      • Tachycardia and arrhythmia
        
        • B blocker
      • Hypotension may occur post operatively thus needing HDU
      • Consider steroid stress dosing
    • Monitor BGL because the lipolytic, glycolytic and glycogenolytic affects of the catecholamines has been removed
    • Pregnancy
      
      • Alpha adrenergic blockade, elective caesarean in third trimester
      • Vaginal delivery contraindicated
      • Early adrenalectomy post partum or in second trimester
• Prognosis:
  
  • Follow-up fractionated urinary metanephrines are measured and repeated annually for life to exclude recurrence or further new disease

Question 76

Cushings syndrome

Answer 76

• Definition:
  
  • Constellation of signs and symptoms attributable to chronically inappropriately elevated glucocorticoids levels
• Incidence/epidemiology:
  
  • True incidence unknown 0.1-1 per 100,000
• Aetiology & risk factors:
  
  • ACTH dependent
    
    • Pituitary adenoma (65% of endogenous)
    • Ectopic adenoma or carcinoma (small cell lung)
  • ACTH independent
    
    • Adrenal tumour
      
      • Adenoma 90%
      • Carcinoma 10%
    • Drugs
    • Bilateral adrenal hyperplasia
• Clinical manifestations:

( see table)

• Investigations:
  
  • Exclude medication related
  • Biochemical diagnosis
    
    • 1. Screening test = Hypercortisolaemia
         * Late night salivary cortisol
         * 1mg overnight dexamethasone suppression test
         
         • 2x 0.5mg tablets, take the 1mg at 11pm, then have cortisol levels taken at 8AM
         • If elevated cortisol despite dexamethasone then it is positive do urine
    • 2. Confirmatory test
         * 24hr urinary free cortisol
    • 3. ACTH level (independent vs dependent)
  • Imaging - adrenal
    
    • CT (triple phase adrenal)
      
      • Benign
        
        • Size <3.5cm
        • <10 Hounsfield units
        • If >10 but washout >60% in 15 minutes
      • Malignant
        
        • Size >3.5
        • Local invasion, heterogenous
        • Multiple different hormones especially virilizing
        • Measure DHEA
        • >10 Hounsfield units and washout >60% at 15 minutes
    • MRI scan
      
      • Low fat content
      • High enhancement and long washout with gadolinium
  • Investigation on ACTH dependent
    
    • High dose dexamethasone test (most pituitary sources will be suppressed)
    • Inferior petrosal sinus catheterization
    • Imaging
      
      • MRI brain
      • CT chest (bronchial carcinoid)
• Treatment:
  
  • Operative
    
    • Surgery mainstay for all
    • Bilateral adrenalectomy for failed pituitary surgery or if no source of the ectopic ACTH is found
    • Localised tumour then laparoscopic approach
    • Beware complications (wound infection, skin injury, fractures, hypoglycaemia, adrenal insufficiency)

Question 77

Congenital adrenal hyperplasia

Answer 77

• A group of syndromes, typically autosomal recessive.
• An inherited enzyme deficiency that blocks one of many enzymes involved in steroid synthesis.
• The most common 21-hydroxylase (90%).
• Failure of the negative-feedback loop leads to ACTH excess and adrenal cortical overstimulation hyperplasia → build up of steroid precursors → excess of adrenal androgens.
• The high levels of androgens causing virilisation (ambiguous genitalia in females).
• Associated with urinary salt wasting, diarrhoea, hypovolaemia, hyponatraemia and hyperkalaemia.
• Most can be managed by diagnosis and replacement of the missing steroid hormone.

Not great quasimneumonic:

A = aldosterone (hypertension, hypokalaemia)

T = testosterone (virilisation)

Before you have sex your blood pressure goes up

Replace the 1 with a up arrow

21 Hydroxylase deficiency

17a Hydroxylase deficiency

11b Hydroxylase deficiency

Question 78

Primary hyperaldosteronism

Answer 78

Conns syndrome

“Over the past 60 years, three facts have become clear:

First, primary aldosteronism (PA) is more common than previously thought, and it affects between 5 and 10 percent of all patients with hypertension.

Second, most patients with PA are normokalemic.

Third, PA has more than one cause, and most patients with PA have bilateral idiopathic hyperaldosteronism (IHA).”

Definition:

• Autonomous adrenal cortical tissue secreting excessive aldosterone

Incidence/epidemiology:

• 5% of hypertensive patients

Pathophysiology:

• Most commonly caused by a single benign adenoma
  
  • Adenoma (60%).
  • Bilateral (micronodular) adrenal hyperplasia (40%)
• Less commonly
  
  • Aldosterone producing adrenocorticocarcinoma
• Glucocorticoid remediable hyperaldosteronism (dexamethasone suppressible <1%, familial)
• Aldosterone is the final common product of the hydroxylase enzyme pathway pregnenolone → progesterone→ corticosterone → aldosterone.
• Aldosterone controls reabsorption of Na+ in the DCT via Na+/K+ and H+ pumps. Followed by H2O and so volume.

Clinical manifestations:

• Typically found on investigation of resistant HTN or hypokalaemia.
• Incidentaloma
• Symptoms of hypokalaemia
  
  • Cramps
  • Muscle weakness
  • Palpitations
  • Polyuria

Investigations:

• Screening tests
  
  • Blood pressure
  • Potassium level
  • Ratio renin:aldosterone (>30 indicates primary) has a 90% sensitivity.
    
    • Must stop ACEI and all diuretics (frusemide, spironolactone).
    • Early on K⁺ will be normal in primary hyperaldosteronism
• Confirmatory test
  
  • Admission for a saline/sodium loading (Demonstrate raised aldosterone despite salt and H₂O overload with 5g salt PO for 5/7 prior, then 2-3L of IV N/S in 4-6/24, then measure renin: aldosterone level
  • Fludrocortisone suppression test
    
    • Good if on multiple antihypertensive
    • 5 day admission required
    • 0.1-0.2mg 6 hourly Fludrocortisone plus sodium chloride and potassium – should suppress aldosterone levels
• Localisation:
  
  • CT – 3mm adrenal cuts, MRI.
  • Adrenal venous sampling
    
    • Helps to avoid removing an adrenal due to a lesion that isn’t functional, may be difficult to lateralize if hyperplasia and not gross
    • Adenoma producing lesion typically very small – and a lesion seen might be not responsible for the Conn’s
    • Invasive, sample the venous blood from the adrenal glands
    • If >35-40 then AVS needed
    • This is important to know for the exam

Treatment:

• Post diagnosis correct BP and K+.
• Plan lap adrenalectomy if:
  
  • Patient <40 years.
  • Mass >1cm.
  • Normal contralateral gland.
• IF not: selective venous sampling (aldosterone, cortisol, renin) via an IVC catheter may identify a dominant gland or bilateral disease.
  
  • Fludrocortisone suppression test may be helpful.
  • Patients with glucocorticoid-remediable hyperaldosteronism should be treated with steroids.
  • Spironolactone

Prognosis

• At best ⅔ of patients are cured by surgery, the majority will experience a benefit from reduced medication requirements

Question 79

Adrenal insufficiency

Answer 79

• Definition:
  
  • Inadequate production &/or release of corticosteroids
• Aetiology & risk factors:
  
  • Primary adrenal insufficiency
    
    • Autoimmune (Addison’s Disease)
    • Tuberculosis
    • Bilateral adrenal haemorrhage, infection or neoplasm
      
      • Waterhouse-Fredrickson syndrome (meningococcal)
      • Heparin induce thrombocytopaenia
  • Secondary adrenal insufficiency
  • Tertiary adrenal insufficiency
    
    • Exogenous steroid use
    • Anything effecting hypothalamus
• Pathophysiology:
  
  • Stress - both mineralocorticoid and glucocorticoid deficiency can participate in the development of adrenal crisis.
  • The physiologic basis for this is the ability of aldosterone or synthetic mineralocorticoid to promote sodium retention as well as to enhance vasoconstrictor responses of the vasculature
  • Glucocorticoid deficiency can contribute to hypotension by causing decreased vascular responsiveness to angiotensin II and norepinephrine, decreased synthesis of renin substrate, and increased prostacyclin production
• Clinical manifestations:
  
  • Chronic
    
    • Fatigue
    • Weakness
    • Weight loss
    • Electrolyte imbalance (low sodium, high potassium, anaemia, hypoglycaemia)
    • Skin pigmentation
  • Acute
    
    • Acute illness/stress response precipitant
    • Same as above +
    • Abdominal pain
    • Fevers (do assume fever is secondary to infection)
    • Confusion-coma
    • Hypotension tachycardia
  • Addisonian crisis
  • Refractory shock/hypotension
    
    • Unresponsive to inotropes
• Investigations:
  
  • Biochemistry
    
    • 8AM serum cortisol and ACTH
    • ACTH stimulation test
    • Renin aldosterone levels
  • Abdominal CT
• Treatment:
  
  • Treat before making diagnosis
  • Hydrocortisone
  • Perioperative (stress dosing)
    
    • None if 5mg/day for upto 3 weeks
    • Intermediate (between these two groups) do 8am fasting cortisol level (24hrs since steroid dose)
    • If >20mg/day for 3 weeks
      
      • Minor surgery - just take regular dose
      • Moderate surgery - 50mg IV before induction then 25mg TDS for 24 hrs
      • Major surgery - 100mg IV before induction then 50mg TDS for 24 hrs. Then taper by half per day to maintenance level

Question 80

Non operative therapies for pancreatic neuroendocrine tumours

Answer 80

Unresectable metastatic disease

• Long acting somatostatin analogues
• Ablation
• Embolisation
• Chemotherapy
• TKI (sumatinib)
• MTOR inhibitors (everolimus)
• Interferon alpha
• Somatostatin analogues (octreotide)
• Peptide receptor radionuclide therapy – radioactive somatostatin analogues (Lutetium 177 dotatate)

Question 80

Non operative therapies for pancreatic neuroendocrine tumours

Answer 80

Unresectable metastatic disease

• Long acting somatostatin analogues
• Ablation
• Embolisation
• Chemotherapy
• TKI (sumatinib)
• MTOR inhibitors (everolimus)
• Interferon alpha
• Somatostatin analogues (octreotide)
• Peptide receptor radionuclide therapy – radioactive somatostatin analogues (Lutetium 177 dotatate)

Question 81

Indication for adrenalectomy

Answer 81

>4cm

Suspicious features

Functional

Question 82

Cushingoid mneumonic

Answer 82

Cushingoid

Cataracts

Ulcers

Striae and skin thinning

Hypertension and hirsutism

Immunosuppression and infections

Necrosis of femoral heads

Glucose elevation

Osteoporosis and obesity

Impaired wound healing

Depression and mood changes

Question 83

Origin Facts Manifestations Diagnosis Medical Surgery

Insulinoma

Answer 83

Cell origin

Beta

Facts

Most common

0.1 per 100,000

90% Benign

F>M

>99% pancreatic

10% multiple

10% familial

Manifestations

Cherry red or brown lesion

Hypoglycaemia

Weight gain

Whipples triad:

Fasting

Low sugar <5

Symptomatic (Neuroglycopaenic + ANS activation)

Better with IV glucose

Diagnosis:

Fasting BGL <3

High insulin >3

High C peptide

High proinsulin

50% too small for standard imaging

EUS then

Ca arteriography

IOUS

Octreotide scan doesn’t work

Medication management

High carb diet

2nd line diazoxide (inhibits insulin release)

Octreotide (30% respond)

mTOR inhibitors

Surgical management

Intraoperatively check for multiple pancreatic lesions, kocherisation + opening the lesser sac

Enucleation or oncological resection if malignant

Question 84

Origin Facts Manifestations Diagnosis Medical Surgical

Gastrinoma

Answer 84

Cell origin:

G cells

Facts:

60-90% malignant and 40% with liver metastases

⅔ in duodenal wall

80% in gastrinoma triangle [Juncs of Neck-body/CD-CBD /D2-D3]

1:4 MEN1

Sporadic = larger/solitary

Manifestations:

ZES

Epigastric pain

Diarrhoea

Oesophagitis

Duodenal or jejunal ulceration

Diagnosis:

Fasting gastrin level >100 (PPI false positive)

If <1000 then do a secretin test

Gastric pH <2

Endoscopy

CT/MRI/somatostatin receptor scintigraphy

EUS 2^nd line

ASVS 3^rd line

IOUS

Medical management:

High dose PPI (beware low B12 and Mg)

MEN1 might have only medical management (small & multifocal ++), sort out the parathyroid

Mets: octreotide, resection, embolisation, transplant

Surgical management:

Duodenotomy to check for occult gastrinoma are nearly always in the duo

Formal resection + peritumoral lymph nodes

Question 85

Origin Facts Manifestations Diagnosis Medical Surgical

Glucagonoma

Answer 85

Cell origin:

Alpha cells

Facts:

90% malignant

F>M

Body and tail of pancreas

Manifestations:

4 D’s

Diarrhoea

DVT

Dermatitis

Diabetes

Weight loss

Necrolytic migratory erythema (NME) - blistering rash in groins, leg and anogenital

Diagnosis:

High glucagon levels

Mild-moderate DM

Medical management:

Octreotide

Thromboprophylaxis

IV amino acid infusion (deficiency causes NME)

Surgical management:

Distal pancreatectomy + LN dissection +/- splenectomy +/- cholecystectomy - not enucleation

Question 86

Origin Facts Manifestations Diagnosis Medical Surgical

VIPoma

Answer 86

Cell of origin:

D2 cells of the pancreas

Facts:

50% malignant

Rare

Usually solitary

Distal pancreas

Can be extrapancreatic (adrenal, retroperitoneal or mediastinum)

Manifestations:

“WDHA syndrome” - pancreatic cholera

Watery diarrhoea 5L per day!

Hypokalaemic achlorydia

Diagnosis:

High VIP levels

Low potassium

Metabolic acidosis

Medical management:

Octreotide

Correct electrolytes

Surgical management:

Oncological resection

Cholecystectomy

Question 87

Origin Facts Manifestations Diagnosis Medical Surgical

Somatostatinoma

Answer 87

Cell origin:

D cells

Facts:

Extremely rare

Found in either HOP or D2

Decreases hormone secretion

70% malignant

Manifestations:

Diarrhoea

Steatorrhea

Malabsorption

DM

Cholecystitis

Diagnosis:

High somatostatin levels

Medical:

Octreotide (somatostatin receptor analogues)

Surgical:

Oncological resection + cholecystectomy

Question 88

Origin Facts Manifestations Diagnosis Medical Surgical

Carcinoid

Answer 88

Cell of origin:

Enterochromaffin cells - EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion.

Facts:

NET of mid gut

Small

80% are APUDomas

Amine Precursor Uptake – for high uptake of amine precursors including 5-hydroxytryptophan (5-HTP) and dihydroxyphenylalanine (DOPA).

Decarboxylase – for high content of the enzyme amino acid decarboxylase (for conversion of precursors to amines).)

Manifestations:

Asymptomatic

Carcinoid syndrome

• face neck flushing
• Diarrhoea
• Bronchospasm
• Right heart valve disease

Diagnosis:

Blood chromogranin A

Urine 24 hours 5 HIAA

Echo

Medical management:
Octreotide

Liver mets: resect/embolise/ablation

Pre-Op Carcinoid Syndrome: ECHO / Octeotride Infusion / Betablockers / Antihistaminics and Hydrocortisone infusion to avoid Carcinoid Crisis (bronchoconstriction – fever – arrhythmia – shock – flushing)

Surgical

Resect

Adjuvant

Question 89

Name two eponyms used to identify the EBSLN

Answer 89

• Space of Reeve: avascular plane between upper pole of thyroid and cricothyroid muscle
• Joll’s triangle superior insertion of strap muscles, upper pole of thyroid (lateral) and midline trachea (medial)

Question 90

Name three eponyms used to identify the RLNx at thyroidectomy

Answer 90

• Tubercle of zuckerkandle; nerve lies posteriomedial to this projection
• Ligament of Berry; the nerve lies lateral to this
• Simons triangle; common carotid lateral, oesophagus medial, interior thyroid artery superior

Question 91

What is associated with a R non RLN?

Answer 91

• Non recurrent laryngeal nerve, associated with arteria lusoria (abberant R subclavian off the aortic arch distal to L subclavian) where the R subclavian artery doesn’t come of the right brachiocephalic trunk, but directly off the arch of the aorta distal to the left subclavian artery, where it passes posterior to the oesophagus
• The nerve in this situation, the nerve doesn’t travel in the inferior to superior orientation but from the lateral to medial directly off the vagus – in this situation it is at risk in thyroidectomy

Question 92

Where does the RLN enter the larynx?

Answer 92

• To enter into the larynx at the inferior border of the inferior constrictor (cricopharngeus)