Endocrine Flashcards
What is the differential for an adrenal tumour?
- Adrenal primary
* Cortex
* Benign: Adrenocortical adenoma
* Malignant: Adrenocortical carcinoma
* Medulla (neuroendocrine)
* Benign: Phaeochromocytoma
* Note: extra-adrenal phaeochromocytoma = paraganglioma)
* 90% are benign, 10% malignant
* Note: Phaeo - cannot differentiate between benign vs. malignant on histology. Malignant if local invasion or DM, therefore need long-term follow up after resection !!!!
* Malignant: Neuroblastoma
* Haematological
* Lymphoma
* Mesenchymal
* Sarcoma (LS, FS, LMS, neurofibrosarcoma, angiosarcoma)- Metastases
- Lung, breast, RCC, ovary, melanoma, lymphoma
- Other
- Cyst
- Myolipoma
- Haemangioma
Primary tumours may be functioning or non-functioning
- Metastases
Describe the epidemiology, biological behaviour and risk factors for an adrenocortical carcinoma
Adrenocortical carcinoma
* Epidemiology
* I: Rare (1-2 / million / yr)
* A: Bimodal:
* Before age 5
* 40s-60s
* S: slight F>M (~2:1)
* G: 10-fold higher in children in Southern Brazil
* Aetiology
* Sporadic
* Genetic
* Li-Fraumeni (germline mutation p53) → breast cancer, soft tissue sarcoma, brain, ACC, leukaemia, lng cancer
* Beckwith Wiedmann Syndrome
* MEN1 →parathyroid, pituitary, pancreas, adrenal adenoma, ACC. Majority benign, non-functioning adenoma
* SBLA syndrome (germline TP53 mutation) → sarcoma, breast, lung, adrenal
* Biologic behaviour
* Often advanced stage at diagnosis
* P:
* 50-60% sufficiently functional to produce syndrome of hormone excess
* More likely to be functional than adenomas
* Cushing syndrome alone (45%)
* Mixed cushing and virilisation (25%)
* Virilisation alone (<10%)
* Feminisation <10%
* Hyperaldosteronism <10%
* Presence of virilisation suggests ACC rather than adenoma
* Often large, invasive lesions, many >20cm diameter, efface entire adrenal gland
* Invade adrenal vein, IVC, adjacent kidney, retroperitoneum
* N: Early (40%)
* M: Early: liver (60%), lungs (40%)
* Also retroperitoneal, IVC, bone
* Prognosis: 2yr OS 50%, 5yr OS 30%
* 2/3 have local recurrence within 5 years of surgery
Describe the epidemiology and pathology for pheochromocytoma. On IHC how is this differentiated from an adrenocortical carcinoma?
Pheochromocytoma
I: Rare
A: 40-50 years
G: M=F
Majority sporadic, 1/3 genetic syndromes (will present earlier and can be bilateral) MEN 2A/B, NF1, vHL
Presentation triad: Headaches, sweating and tachycardia
10% Tumour
-10% Inherited
-10% Bilateral
10% Malignant
-10% children
-10% outside the adrenal gland
Paraganglioma of the adrenal medulla
-Chromaffin cells, cam secrete chromogranin A in the serum
-Produce catecholamines: Adrenaline, noradrenaline or dopamine
Macro: In the adrenal medulla. Well circumscribed, unecapsulated lesion. Solid white-red/brown cut surface.
Micro: Large, polygonal cells with abundant cytoplasm. Variable nuclei. Usually low Ki 67. PASS score to assess for malignant potential (features such a mitoses per HPF, necrosis, spindling, high cellularity, Lvi, pleomorphism etc)
IHC: Chromagranin A, synaptophysin, S100, GATA 3.
Negative: Cytokeratin (AE1/3, CK 7, Ck20), MelanA, PAX 8
Describe the pathology for an adrenocortical carcinoma.
- Pathogenesis
* TP53 mutation
* LOH 11p15
Activating mutation CTNNB1 - Macroscopic appearance
* Large cortical mass invading adjacent structures
* Areas of necrosis and haemorrhage
* Cysts
* May be >20cm in size
* Variegated
* Poorly demarcated, no capsule- Microscopic appearance
- Adenomas recapitulate the layers of the adrenal cortex (GFR)
- Glomerulosa
- Fasiculata: clear
- Reticulata: pink
- More pink = bad
- Weiss criteria - adenoma vs. carcinoma if 3+ of the following (cannot distinguish on FNA) ⇒ but note, only definitive distinction is presence of local invasion or distant metastasis
- Capsular invasion
- Sinusoidal invasion
- Vascular invasion
- Clear cells <25%
- Diffuse architecture
- Mitoses
- Atypical mitoses
- High nuclear grade
- Necrosis
- Various growth patterns from differentiated architecture to sheets of anaplastic cells
- Grade –based on mitosis (20/hpf) and Ki67 10%
- Adenomas recapitulate the layers of the adrenal cortex (GFR)
- IHC
- Pos: Vimentin, Melanoma markers (Inhibin, melan-A / MART-1 ), NSE
+/- Synaptophysin
Neg: Chromogranin, S100 CEA, GATA3, CK7/CK20
- Pos: Vimentin, Melanoma markers (Inhibin, melan-A / MART-1 ), NSE
- Microscopic appearance
Describe the pathology for a paraganglioma and an adrenal adenoma
Paraganglioma =
* Neural crest neuroendocrine neoplasm
* extra-adrenal phaeochromocytoma –arise outside of adrenal, along the sympathetic chain: commonly retroperitoneum, chest, neck. Parasympathetic paraganglioma occur along vagus nerve (esp. carotid body)
* Genetics –inherited germline more common in phaeo
* RET, VHL, NF1…
* Production of noradenaline (normetanephrine) and dopamine (phaeo produce adrenaline and more episodic)
* Micro: epithelioid chief (polygonal cells with granual cytoplasm) cells in clusters/nests
Incidentaloma –4% of abdo scans. 80% are benign nonfunctional adenomas
Adrenal adenoma
* Majority are clinically silent and are usually incidental findings at autopsy or during abdominal imaging for an unrelated issue
* Functional tumours may cause Cushing syndrome, primary hyperaldosteronism or much less commonly, virilisation or feminisation tumours causing virilisation are more likely to be adrenocortical carcinomas
* Macroscopic appearance
* Well-circumscribed, unilateral, solitary, nodular lesion up to 2.5cm in size
* Fatty cut surface / Yellow to yellow-brown (lipid)
* Functional adenomas are associated with atrophy of the adjacent cortex (adjacent cortex in non-functioning adenomas is normal)
* Microscopic appearance
* Large cells, distinct cell borders
* Foamy cytoplasm, nuclear variation
* Variants: Oncocytic, myxoid,
* Can see necrosis and atypia in kids
* IHC: +ve a-inhibin, calretinin +/- synaptophysin
Describe MEN1 and MEN2
Adrenal tumours are a common component of MEN-1, but occur in later stages of disease
50% of people with MEN 2 will develop a pheochromocytoma
Multiple Neuroendocrine Neoplasia
MEN 1 (Mutation in MEN 1 gene)
* Tumours in multiple (>2 endocrine glands), usually benign
* Majority have parathyroid tumours (hyperplasia)
* Pancreatic neuroendocrine tumours (gasinoma, insulinoma, glucagonoma)
* Pituitary adenoma
* adrenal glands
* Women also risk of breast cancer
MEN 2 (Mutation in RET)
* MEN 2 A (95%)
○ Majority (>90% develop medullary thyroid carcinoma)
○ 50% adrenal pheochromocytoma
○ Parathyroid (less common then in people with MEN 1)
○ 90-100% Medullary thyroid carcinoma –50% by age 30
○ Association with skin condition lichen amyloidosis and Hirschsprung’s disease
* MEN 2B (5%)
○ Rare subtype of MEN 2
○ >98% develop medullary thyroid cancer, and much earlier i.e. childhood/young adult
○ 50% pheochromocytoma
○ 95% mucosal neuromas (benign nerve tumours of the tongue, lips, eyes or GI tract)
○ Curved spines, long limbs, thicker eyelids and lips (Marganoid habitus)
* Mutation in CDKN1 B causes MEN 4, which has similar features to MEN 1
* Risk reduction:
○ Thyroidectomy –by age 1, 5, 5-10 depending on MEN2 risk
○ Otherwise annual serum calcitonin and neck ultrasound from age 0,3,5
○ From age 11-16: Annual medical review and BP, annual fasting plasma fractionated metanephrine or 24 hour urine fractionated metanephrine, PTH and calcium
Describe cushings syndrome
Symptoms
Moon face , acne, buffalo hump, central adiposity, striae, easy bruising, poor wound healing, emotional and cognitive changes
Signs
Hypertension
Hyperglycaemia
Hyperlipidearmia
Osteoporosis
Screening
24 hour urinary cortisol (can be normal if sub clinical)
Low dose (1mg) dexamethasone suppression test
-1mg dex at 11pm and then serum cortisol measured ay 8am
-Cortisol levels should decrease after dex
-Abnormal resut: Adrenal tumour producing cortisol, pituitary tumour producing ACTH or ectopic tumour producing ACTH.
?Can cortsiol secretion be suppressed with dex
-Dex binds to same receptor as cortsiol
-Reduces ACTH in normal people. Therefore taking dex should reduce ACTH and cortsiol
-Low dose test to distinguish if there is too much ACTH
Adrenal tumour producing cortisol
No change in cortsiol, ACTH low
Pituitary tumour producing ACTH
No change in cortisol, but will decrease on high dose test
Ectopic ACTH
No change in cortisol, ACTH high
Diagnostic
High dose dexamethasone suppression test.
-Not usually needed for adrenal tumour producing cortsiol, but can be used to distinguish pituitary producing too much ACTH vs ectopic ACTH
Cortisol measured morning, 8mg dex at 11pm and cortsiol and ACTH measured 8am the next day
-Pituitary tumour producing ACTH
ACTH suppressed, Decrease in cortisol
Ectopic ACTH
No decrease in cortsiol, ACTH remains high
Describe the medical management for hypercortisolism, hypocortisolism, aldosterone insufficiency, hypogonadism, virilisation.
Medical Treatments of hormone excess
Patients can have adrenal insufficiency e.g surgery or miotane or excess cortisol by persistent tumour
* Hypercortisolism ○ Miotane in ACC or Cushings disease, steroidgenesis inhibitor often first line ○ ketoconazole 200-400mg TDS or metyrapone * Hypocortisolism ○ Patients treated with miotane can have steroidogenesis inhibited by mitotane ○ Close monitoring for hyperkalaemia for patients using miotane ○ Hydrocortisone replacement * Aldosterone Insufficiency ○ Miotane can eventually cause aldosterone deficiency ○ Aldosterone insufficiency: postural hypotension, hyponatremia or hyperkalemia and diagnosed with elevated plasma renin activity ○ Fludrocortisone * Hypogonadism ○ Miotane can also lead to hypogonidsm in med § Testosterone replacement therapy * Virilisation –bicalutamide or finasteride
Describe the symptoms, signs and work up for Conns syndrome, primary hyperaldosteronism, pheochromocytoma, adrenocortical carcinoma and adrenal metastasis.
Describe the adjuvant radiotherapy technique for adrenocortical carcinoma.
Adjuvant Adrenocorticotroph carcinoma
* Simulation
* Position: Supine, arms above head,
* Support: Knee support, ankle stocks
* Tattoos midline and lateral
* 4DCT from above diaphragm to sacrum, 2mm slices
* IV contrast
* Fuse pre-op MRI / CT
* Technique
* Beam type: Photons
* Energy: 6MV
* 3DCRT/IMRT
* Presribed to PTV
* Dose
* Adjuvant: 50Gy/25#, boost macroscopic disease to 54Gy/25#
* Systemic therapy
* Mitotane can be started with or after RT majority received with RT in Michigan study
* QA
* Weekly treatment review, hx, ex
* Volumes
* GTV: Macroscopic disease as seen on imaging or marked by surgical clips (should be none if R0 or R1)
* CTV HD: GTV + 5mm clipped to anatomical boundaries
* CTV LD: Tumour bed + regional LNs (adjacent bilateral PA LN basin) defined using pre-op imaging, operative reports, surgical clips and simulation CT
* Cranial: Diaphragm curs / apex
* Caudal: Aortic crest (covering renal hilum)
* Dorsal: Diaphragm / parts of thoracic wall if infiltration
* Medial: Para-aortic / paracaval nodes
* Lateral: as far as pre-op extension with margins
* PTV = CTV + 10mm
* Target verification
* Daily kV imaging, bone match, review soft tissue
* OARs
* Spinal cord: max ≤45Gy
* Contralateral kidney: V6Gy<30%
* Combined kidney: V20Gy < 50%
* Liver: Mean <28Gy (risk RILD < 5%)
* Small bowel: ALARA. No hotspots
* Lung: V20Gy <20%
* Heart
* Mean < 20Gy
* V30Gy < 46%
* V40Gy < 35%
* Toxicity
* Acute
* Lethargy
* Radiation dermatitis
* Nausea / vomiting
* Diarrhoea
* Anorexia
* Abdominal pain
* Gastritis
* Subacute
* Radiation pneumonitis
* Late
* Impaired kidney function
* Radiation induced liver idsease
* Budd-Chiari syndrome
* Enteric strictures, ulceration, adhesions
* Lung fibrosis
* Cardiac disease
* Secondary malignancy
* Follow up
* First 2 years: Every 3 months - hx, ex (BP), CT
* Then 6 monthly to year 5
Describe the management of adrenal cortical carcinomas.
Adrenal cortical carcinoma
* Aggressive
* Can be functional
*
* Neoadjuvant chemo under on clinical trial
* Surgery often more extensive involving en-bloc resection of nodes, kidney, liver, spleen, pancreas
○ Specialised centre, avoid tumour spill or incomplete resection
○ Functional tumour –hormone (glucocorticoid) replacement postoperatively
○ IVC extension or tumour thrombus not a contraindication, but requires cardiac input with cardio-pulmonary bypass
○ Suspicious LN should also be resected
* Adjuvant therapy (limited evidence, lack of prospective randomised trials)
○ Low risk: no adjuvant treatment
○ High risk features: Spillage, positive margins and mitotic rate (Ki 67 or MIB-1 staining), tumour > 8cm or vascular invasion
▪ Adj Miotane for 3-5 years
* reduces the steroids produced by the adrenal cortex –needs cortisone replacement
* Improved DFS and OS in german/italian retrospective review: stage 1-2 pts, RFS 3.5years vs 2 years
▪ RT
* Previously thought to be radioresistant, however may be achievable for better control with modern RT techniques
* Retrospective study in Germany found RT + Mitotane improved local control but not OS. LC 12% vs 80%
* Michigan retrosepctive cohort: 60% vs 5% -updated –improved LC, RFS, OS
○ 50Gy/25 + boost to 54Gy
○ Ideally start <12 weeks postop
○ Pattern of failure identified in the aorto-caval region, should be included in volumes
○ Very high risk KI67>20%, extensive vascular invasion/IVC thrombus
§ Chemo: Cisplatin or carboplatin and etoposide + mitotane
○ Radionuclides § I-131 Recurrent disease: ○ Surgery with adjuvant mitotane § RFA § SBRT ○ Trial –immuno, ○ Mitotane monothereapy (for small low grade disease) ○ Chemo+mitotane
Describe the management of pheochromocytoma
Pheochromocytoma
* Surgical resection is mainstay of treatment
* Requires cardiac monitoring and hypertensive crisis monitoring intra-operatively
○ Combine alpha and beta blockers
* Minimally invasive adrenalectomy can be safely performed in ?90% of patients
* In bilateral tumours, cortical sparing adrenal-ectomy may be considered to prevent permanent glucocorticoid deficiency
Describe the epidemiology and risk factors for thyroid cancers.
Incidence (Australian statistics)
- 3154 cases annually
- 9th most common cancer
Female predominance (2.5:1)
Median age of diagnosis = 55 years
- Papillary tend to be younger
- Follicular tend to be older
Subtypes
- Papillary (85%)
- Follicular (10%) including Hurthle Cell
- Anaplastic (<5%)
- Medullary (<5%)
Aetiology
1) Ionising radiation a. Nuclear accidents (Hiroshima bomb, Chernobyl) b. Therapeutic radiation (EBRT or previous I-131) 2) Familial/genetic cause a. RET (MEN2) --> medullary (also get parathyroid and phaeo) 1. Risk reducing thyroidectomy between 1-10 years old b. PTEN (Cowden's) --> papillary c. APC (FAP) --> papillary 3) Insufficient dietary iodine
Describe the 2024 classification of thyroid tumours
WHO 2024 update
Follicular neoplasms divided into benign, low risk and maligant
Invasive follicular variant of papillary thyroid cancer now its own cancer.
Grading –for differentiated and medullary
Differentitated: high grade = necrosis, mitosis/2mm
Medullary: necrosis, mitosis per 2mm2, Ki67 >5%
New subtypes for follicular, oncocytic, invasive follicular variant papillary
Minimally invasice (capsule
Encapsulated angioinvasive = >4 foci
Widely invasive (rare more likely to be PDTC, Differentiated high grade HGTC)
New tumour: high grade follicular cell derived nonanaplastic thyroid carcinoma
Presents as >5cm Thyroid nodule, cold on iodine, hot on PET. 20-50% metastatic
Gross capsule infiltration and extrathyroid invasion. +- encapsulation
2 subtypes:
Differentiated High grade thryroid cancer –new
Any papillary or Follicular cell carcinoma with high grade features , Often from papillary
Retains follicular or papillary architecure
Has mitosis, necrosis (focal, comedo, extensive),
But KI67 not used
Poorly differentiated thyroid carcinoma (worse than differentiated) Turin criteria invasion, architecture (solid, insular, trabecular), = no colloid production lacks conventional nuclear atypia (papillary thyroid) and 3 mitosti/2mm@ +_ necrosis +- convoluted nuclei (raisin like nuclei) IHC: variable thyroglobulin (loss), TTF1 pos, PAX 8 pos, cytokeratin pos, neuroendocrine neg
New category –thyroid tumours of uncertain histogenesis.
PDTC
Anaplastic – now includes SCC. BRAF V600E is targetable by drugs.
2023 Bethesda for FNAp
Describe the pathology for papillary thyroid cancer.
Describe the pathology for thyroid follicular adenoma
Describe the pathology for follicular thyroid cancer.
Describe the pathology for thyroid hurthle cells cancer
Describe the pathology for anaplastic thyroid cancer
Describe the pathology for medullary thyroid cancer
Describe the work up for thyroid cancer
- Serum
○ TSH and T4 (rarely impacted with thyroid cancer)
§ TSH more concerning if hypothyroid -> refer for I-123 or 99mTc if appropriate
§ Hyperfunctioning nodules are rarely malignant. Cold nodules are usually cancerous.
○ Baseline thyroglobulin (papillary or follicular)
○ Baseline CEA and calcitonin (medullary)
○ Calcium level- Imaging
○ Minimum of US thyroid + neck
§ Suspicious appearance: size >1cm, solid, hypoechoic, microcalcifications, increased vascularity, infiltrative margins, taller rather than wider
§ Generally only nodules >1 cm need Ix
○ Consider CT Neck and Chest +/- WBBS (if metastasis is suspected)
§ Carefully consider use of iodinated contrast (will preclude whole body radioiodine imaging or RAI for 2 months)
§ Historically, used to encourage CT without contrast. This is no longer the case. Per NCCN 2.2024, “Use of iodinated contrast is required for optimal cervical imaging using CT. Potential delay in RAI will not cause harm.”
- Imaging
- FDG-PET may be useful for anaplastic carcinoma
○ inverse relationship with radioactive iodine avidity therefore may be useful for staging.
§ All anaplastic thyroid Ca are PET avid; not all papillary thyroid Ca are PET avid
§ Not avid in well diff - Biopsy:
○ Non diagnostic – repeat
§ If partially cystic observation or surgery is reasonable, but if solid surgery is recommended
○ If diagnostic or suspicious PTC – Surgery
○ Indeterminate – follicular or hurthle cell harbour 20-30% malignancy, while follicular lesion of undetermined significance have a 5-10% risk. Molecular markers (BRAF, RAS, E=RET, PAX8, galectin 3 may be used)
§ If follicular – order i-123 if not done, if concordant hyperfuctioning nodule and TSH low normal – observe. If not – lobectomy/thyroidectomy
§ If Hurthle cell – lobectomy or thyroidectomy
§ Benign – observe
○ If nodules are being observed repeat USS 6-18m. If stable, stretch out, if increase in size repeat FNA - Radionucleide scan- I-123 (only γ radiation, good for scans not therapy).
○ Incidence of malignancy in thyroid nodule 5%
○ 20% cold nodules are malignant
○ Hot nodules usually adenoma and rarely malignant
○ Note: I-123 is given for imaging and i-131 for treatment ->no special radioactivity precautions to be taken with 123
Limitation of FNA in follicular thyroid adenoma vs carcinoma
- FNA cannot be used to differentiate Follicular adenoma (benign ) from follicular carcinoma (malignant) as it required the architecture and capsule examination to determine this. Hence if a FNA showed suspicious follicular neoplasm, the next step is thyroidectomy
- Hurthel cell can also not be diagnosed with FNA alone
Describe the advantages and disadvantages of FNA for thyroid nodules.
Describe the staging for thyroid cancer
Describe the difference between iodine 123 and iodine 131.
Describe the management of differentiated thyroid cancers
Surgery
- Thyroidectomy is the primary treatment modality
○ Total thyroidectomy vs hemi-thyroidectomy (controversial)
§ Unilateral hemithyroidectomy can be considered if primary is <1cm (T1a)
§ Benefits of total thyroidectomy (regardless of size):
□ Reduce risk of future second primary
□ Use of thyroglobulin in surveillance
□ Use of radioiodine imaging or therapeutic I-131
- Extent of neck dissection is controversial ○ Typically include adjacent central level VI nodes as routine (for high risk patients) § Elective nodal dissection further to this is not recommended ○ If node positive (cN1), ipsilateral modified radical neck dissection is required - Medullary thyroid carcinoma is the exception ○ Always have upfront total thyroidectomy + level VI dissection ○ Bilateral modified neck dissection if any nodal suspicion of nodal involvement
Radioactive Iodine (I-131)
- Papillary and follicular only (follicular-cell derived)
○ Note uptake is reduced in Hurthle Cell
- Absolutely indicated if: ○ Extrathyroidal extension ○ Bulky primary disease (>4cm) ○ Burden of nodal disease (>5 LN) ○ Large vessel vascular invasion ○ High residual thyroglobulin post-op ○ Gross residual disease (unresectable) - Consider if multiple intermediate risk factors: ○ Detectable post-op thyroglobulin ○ Moderate size of primary (1-4cm) ○ Microscopic positive margins (R1) ○ LVI (small vessel) ○ Low-volume nodal metastases ○ Multifocality - Rationale ○ Remnant ablation --> assists with use of Tg and radioiodine imaging in surveillance ○ Adjuvant ○ Metastatic
TSH Suppression
- Papillary and follicular only (follicular-cell derived)
- TSH suppression is required for papillary/follicular carcinomas: ○ All patients receiving a partial thyroidectomy ○ Patients with residual disease ○ Patients at high-risk of disease recurrence - Thyroxine is given to keep TSH < 0.1 - Must occur after post-operative whole body iodine imaging +/- therapeutic I-131 ○ TSH stimulation is important for this
Describe the procedure for iodine 131 administration and the associated safety precautions.
- Procedure
○ Prepare patient prior to whole body iodine scan (aim to increase cellular uptake of iodine)
§ TSH stimulation must be done prior to iodine scan.
§ TSH stimulation via thyroid hormone withdrawal or by using recombinant TSH.
§ Advantages of recombinant TSH: Fewer side effects and shorter period of elevated TSH and therefore a theoretical lower risk of tumor progression.
§ Recombinant TSH approved for f/u iodide scans and for the I-131 tx of low-risk patients.
§ Iodide transporters are also present in salivary glands and GIT.
§ Withdraw thyroxine (50% for 4 weeks, then withdraw in the 1 week prior). Aim TSH 30
□ Or Thyrogen injections in two days prior to procedure
§ Low iodine diet for 2 weeks prior to scan
§ No CT scans within 2 months of scan
○ First perform I-123 or I-131 whole body radioiodine scan
§ If no uptake, then no role for therapeutic I-131
○ Administration of radioactive I-131
§ Low-risk adjuvant (remnant ablation)
□ No LN or DM, R0, no local invasion, no aggressive histology, no vascualr invasion, no uptake I 131 outside surgical bed
□ Suppress TSH with thyroxine, RAI 30mCi to ablate remnant
§ High-risk adjuvant
□ Microinvasion, LN, I-131 uptake outside thyroid bed or aggressive histology
□ 75-100mCi
§ Known residual/metastatic disease = 150-200mCi
○ Must have a further whole body radioiodine scan post-treatment to assess uptake (<1 week after)
○ Need permanent thyroid replacement
Describe the management for Medullary thyroid cancer
- Cure only with complete resection of primary and regional disease
- All pt with MTC should be offered germline RET testing. Consider prophylactic complete thyroidectomy if pos.
Surgery:
○ Ensure to have preop levels of Calcitonin and CEA to assess residual disease postop
○ Do CT chest if Node + or If Calcitonin >400pg/ml
* Need total thyroidectomy and level 6 neck dissection due to high risk of bilateral+ multifocal disease and nodal involvement
* If high suspicion for nodal involvement, then bilateral level 2-4 LND.
○ If pos, then sample mediastinal and jugular nodes, then dissect if positive
* Post op Ix:
○ TFT (TSH, T3,T4), calcium and CEA+ calcitonin
* Thyroxine for replacement. NOT for TSH suppression (C-cells do not respond to TSH)
* Calcium CEA and calcitonin to check for residual disease. ~ Can take some time to nadir ~6months
▪ If normal –> observation
▪ If high (>100pg/ml)–> then repeat CT+MRI neck ,chest, liver. PET/CT dotatate and WBBS indicated if very high calcitonin.
* If no disease detected, close surveillance
* If local recurrence, assess if resectable. If unresectable, then PORT
Adjuvant RT
* PORT reduces the LR in high risk patients (e.g. nodal involvement, ETE, or R1+).
○ Those with extrathyroidal extension or involved nodes are at greatest risk.
○ Doses of at least 60 Gy given with IMRT are more effective.
○ Radiotherapy should start within 6–8 weeks of surgery.
* Indications:
○ Unresectable Residual disease
○ Macro + Microscopic residual disease
○ Metastatic disease -> painful bone mets
○ Consider if margin negative with extension extrathyroid extension AND residual calcitonin without distant mets at post-op check AND optimal surgery is performed
○ Should NOT be used to treat persistent calcitonin levels in absence of gross or microscopic positive margins
○ Evidence:
* SEER data shows NO improvement in OS. 5 year LR PFS 87%
* Slight improvement in local DFS reported with EBRT in select pts with extrathyroid invasion or extensive locoregional nodes (Brierley, Thyroid 1996, MTC: analyses of survival and prognostic factors and role of RT in local control). 2019 Systematic review by Rowell showed LR reduction by 38%
Describe the management of anaplastic thyroid cancer.
Management depends on the presence of BRAF mutation.
BRAFV600E MUTATTION
Stage IVA
- Thyroidectomy should be considered
○ Only long-term survivors have had resection
○ 2017 MA showed that mOS for surgical pt were better than non-surgical
- **Neck dissection only if positive nodes
- Total thyroidectomy recommended as ATC often coexist with DTC.
○ this would allow RAI for the DTC if present.
- Adjuvant Concurrent chemoradiotherapy should be given
○ 66Gy/33F to the operative bed (with concurrent doxorubicin)
Stage IVB
- Neoadjuvant dabrafenib+trametinib to improve the chance of complete tumour resection
- Resectable:
○ If resectable after NA dabra/trametinib, then proceed with complete resection, followed by chemoRT as per above (RT+Adj CRT improve OS >2yrs)
- Unresectable:
○ IF unresectable after NA dabra/trametinib, then ChemoRT, clinical trials or supportive care
- Note: IF no NA dabra/trametinib were given before surgery, then ensure refer to experienced surgeon
BRAFV600E WT
Stage IVA- as above
- Thyroidectomy should be considered
○ Only long-term survivors have had resection
○ 2017 MA showed that mOS for surgical pt were better than non-surgical
- **Neck dissection only if positive nodes
- Total thyroidectomy recommended as ATC often coexist with DTC.
○ this would allow RAI for the DTC if present.
- Adjuvant Concurrent chemoradiotherapy should be given
○ 66Gy/33F to the operative bed (with concurrent doxorubicin)
Stave IVB resectable
- Surgery with extension of resection depending on the degree of soft tissue involvement.
○ either total thyroidectomy, lobectomy with wide margins or enblock resection
- Adjuvant ChemoRT followed complete resection
Stage IVB unresectable
- Targeted therapy, chemoRT, or BSC depending on the clinical setting
Surgery (only for M0)
- Total thyroidectomy should be considered
○ Only long-term survivors have had resection, improves overall survival
EBRT
- Concurrent chemoradiotherapy should be given adjuvantly
○ 66Gy/33F to the operative bed (with concurrent doxorubicin)
- If not suitable for surgery, should have definitive chemoradiotherapy ○ 70Gy/35F with concurrent doxorubicin ○ 60Gy/40F BD with concurrent doxorubicin
If unresectable neoadjuvant TKI
then palliative RT is appropriate
○ 50Gy/20F OR 30Gy/10F
Metastatic disease is incurable.
Describe the evidence for EBRT in differentiated thyroid and anaplastic thyroid cancer
Differentiated Thyroid (Role of EBRT)
- Primarily retrospective data
Macroscopic Disease
- Hong Kong data (2002)
○ 842 patients with 124 having macroscopic residual
○ EBRT resulted in improved LRC at 10 years (56% vs 24%)
- MSKCC data (2014)
○ 66 patients with macroscopic residual disease
○ EBRT resulted in LRC at three years of 77%
Microscopic Disease
- Systematic Review (2016)
○ 5114 patients in 16 papers
○ EBRT improved LRC (92% vs 75%)
§ Benefit isolated to >45yo
Anaplastic
* MSKCC Anaplastic Thyroid Carcinoma [Fan Cancer ‘19]: Retro. ≥ 60 Gy.
TBL: This retrospective analysis of over 100 patients treated at MSKCC indicates radiation doses ≥60 Gy improve not only local control but also overall survival, supporting more aggressive radiation regimens as a crucial component of any trimodal treatment regimen.
○ 104 pts. 1984-2017. Curative intent or PORT. 30% metastatic. MFU 6 mo.
§ CCRT in 95% (mostly doxorubicin, less commonly paclitaxel ± pazopanib).
○ 1y OS 34%. 1y LPFS 74%.
○ On MVA, RT ≥ 60 Gy was associated with improved LPFS and OS.
- Subbiah [JCO ‘18]: Phase II. Dabrafenib (BRAF inhibitor) + Trametinib (MEK inhibitor).
The first regimen to demonstrate robust clinical activity in BRAF V600E-mutated ATC, leading to its FDA approval for locally advanced or metastatic ATC pts with BRAF V600E mutation and with no satisfactory locoregional treatment options.
§ 16 ATC patients.
§ ORR 69%. MDOR, MPFS and MOS were Not Reached.
§ After 12 mo. since Tx, 80% pts were alive which is remarkable relative to the historical rate of 20% - 40% for this clinical population.
§ Common G3+ toxicity consisted of anemia (13%), diarrhea (6%), hyperglycemia (6%), fatigue (6%).
Describe the prognosis and follow up for thyroid cancer.
Follow-Up
Papillary and Follicular Carcinoma
- Clinical review every six months for two years ○ TSH, thyroglobulin + anti-Tg Ab every six months ○ US neck every twelve months - Clinical review every twelve months thereafter - If low risk and no suspicion of recurrence ○ Continue TSH suppression with blood tests - If high-risk ○ Withdraw TSH suppression prior to blood tests ○ If rising test numbers, consider whole body iodine scan
Medullary Carcinoma
- Clinical review every six months for two years ○ CEA + calcitonin - Clinical review every twelve months thereafter - No need for routine imaging ○ If serum markers rising, consider FDG or DOTA PET
