Thyroid Flashcards
Broad epidemiology of thyroid cancer in general
- 1% of all malignancies; 95% of endocrinology malignancies
- F>M (2.5: 1)
- PTC and FTC 40-50 y/o; MTC and ATC 60 y/o
- Increasing incidence due to increasing recognition of thyroid nodules on surveillance
Broad aetiology of thyroid malignancies:
Relate genetics to specific subtypes
- Sporadic
- Ionising radiation (H&N RT, atomic bomb survivors)
- Low iodine (FTC and ATC only)
- Family history of thyroid cancer
- Genetic syndrome
o PTC/ FTC: Cowden (PTEN gene), Gardners (APC gene)
o MTC a/w MEN 2A and MEN 2B (RET proto-oncogene mutation)
2 broad categories of thyroid ca?
- Differentiated thyroid carcinoma (DTC) – papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC),
Medullary thyroid carcinoma (MTC) - Undifferentiated/ anaplastic thyroid carcinoma (ATC)
Basic epidemiology and clinical presentation of papillary thyroid:
80% of thyroid maligs
Epi: M:F ratio 1:3; >90% of thyroid malignancies in children
Clinical:
o Painless thyroid nodule/ mass in neck/ cervical nodes
o At presentation, 2/3 thyroid only disease, 1/3 nodal disease
o Cold on RAI scan
Macro description of PTC (papillary thyroid cancer):
Solid, grey white tumour, firm, invasive with ill-defined margins (<10% surrounded by complete capsule)
Micro description of PTC (papillary thyroid cancer):
Dx based heavily on distinct nuclear features:
▪ Changes in nuclear size and shape: large ovoid nuclei, nuclear elongation
▪ Irregularities of nuclear membranes: abundant
nuclear grooves (from infolding of nuclear membrane), highly irregular nuclear contour
▪ *Chromatin pattern: empty appearance of nucleoplasm, ground-glass nuclei (Orphan-Annie nuclei. i.e. empty looking)
o Papillary Architecture
o Presence of psammoma bodies (rounded, concentrically laminated calcification, from necrosis) in 50% of cases
How many variants of PTC are there? What are some key prognostic ones?
13 variants:
Classic (most common, and default variant)
Diffuse sclerosing variant (locoregionally aggressive, high rate of nodal mets, and locoregional recurrence, usually in younger patients, require aggressive surgical management including more
extensive node dissection)
Hobnail, Tall cell and columnar also worse prognosis
General thyroid IHC, relate it to PTC. What about for follicular?
IHC (seldom of value): to show presence of thyroid tissues
TTF1+, thyroglobulin+, PAX8+, cytokeratin AE1/ AE3 + for thyoid tissue
o Cytokeratin: CK7+ and CK20-
o Calcitonin negative (Medullary thyroid cancer is positive - i.e c-cells making calcitonin)
Follicular IHC: TTF1+, thyroglobulin+, PAX8+ (i.e. just like PTC, IHC shows PTC comes from the thyroid).
Basic epidemiology and clinical presentation of follicular thyroid:
(15%) (arise from follicular cells)
Epi: 75% women, older age than PTC (peak 40-60y/o), rare in children
Clinical:
o Associated with iodine deficiency (response to RAI, except Hurtle cell variants)
o Usually solitary ‘cold’ nodule on radionuclide scan
Issue with FNA Dx for FTC
As only cytology cannot differentiate architecture - adenoma vs carcinoma.
▪ follicular adenoma thin capsule vs. follicular carcinoma thick capsule
Macro description of FTC (follicular thyroid cancer):
Brown-tan solid cut surface, can have cystic changes and haemorrhage
o Minimally invasive – usually single encapsulated nodule, with thickened/ irregular capsule
▪ follicular adenoma thin capsule vs. follicular carcinoma thick capsule
o Widely invasive – extensive permeation of capsule/ no capsule
Micro description of FTC (follicular thyroid cancer):
Dx is a bit of a contasting with PTC findings:
o Trabecular or solid pattern of follicles (small, normal, or large size)
o No nuclear features of PTC
o Capsular invasion: capsule is typically thickened and irregular, needs penetration through the capsule
(full thickness), may have reactive pseudo-capsule around invasion edge
o Vascular invasion: vessel within or beyond capsule, tumour covered with endothelium, attached to
wall/ with thrombus
o May have nuclear atypia, focal spindled area, low mitotic figures (<1 per 10HPF)
o No necrosis, usually no squamous metaplasia, no psammoma bodies, no/ rare lymphatic invasion
FTC can be classified into?
Subclassified into 3 groups (WHO)
o Minimally invasive – capsular invasion only
o Encapsulated angio-invasive – limited vascular invasion (<4 vessels)
o Widely invasion – extensive invasion of thyroid, and extra-thyroid invasion
Compare molecular genetics of PTC and FTC:
PTC
o BRAF mutation (30-90%) (=poor prognosis) – most frequent mutation esp. tall cell and classic variants
o TERT promoter mutation (5-25%) (=poor prognosis)
FTC
tumours with rearrangement tends to be overtly invasive, but can be seen in adenoma
o NRAS and HRAS mutation in 50%
o PAX8-PPAR gamma rearrangement in 33%
o PI3CA and PTEN mutation in 10%
Biological behaviour of FTC
Biological behaviour FTC
o Capsular invasion = good; vascular invasion = bad
o More aggressive than PTC
o more haematogenous spread compared to lymphatic/ nodal spread for PTC (<5% ipsilateral nodal
mets, >50% distant mets esp. lung and bone)
Biological behaviour of PTC
Biological behaviour PTC:
o Generally indolent, good prognosis (except diffuse sclerosing, tall cell, and columnar cells)
o 5-20% local recurrence
o 30% nodal involvement (cervical nodes involvement does not affect prognosis)
o 5% distant mets (lung and bone)
Prognostic factors PTC
age >55, ETE, aggressive variant (Hobnail, Tall cell and columnar) vascular invasion, higher T or N stage, distant mets, Molecular genetics:
o BRAF mutation (30-90%) (=poor prognosis) – most frequent mutation esp. tall cell and classic variants
o TERT promoter mutation (5-25%) (=poor prognosis
Prognostic factors FTC
Poor: increase age, tumour size >4cm (T3+), extra-thyroid extension, extensive vascular invasion, distant mets
Since 2017 a former subtype of FTC is now considered its own entity. What is’s main dx feature and biological behaviour?
Hurtle cell carcinoma (was a variant of FTC)
* if >75% of carcinoma is composed of large oncocytic cells (due to accumulation of dysfunctional mitochondria)
* Micro: Large nucleus, distinct C border, more likely to be bilateral and multifocal
* Biological behaviour: Poorer prognosis than standard FTC due to low uptake of RAI (higher frequency of
ETE, local recurrence, and nodal mets)
How common is medullary thyroid Cancer?
Where does it come from?
What is it associated with?
How does it present?
Key investigation findings?
MEDULLARY THYROID CARCINOMA (MTC) (5%) (arise from para-follicular C-cell)
* Neuroendocrine tumour of C-cells, 30% a/w MEN2 (RET mutation)
Clinical:
o Often present with painless thyroid mass
▪ usually found in upper and middle region of thyroid gland (C-cells predominantly located in upper portion of thyroid glands), does not arise from isthmus
Workup
o excrete calcitonin (inc calcium);
serum calcitonin correlates with tumour burden (>500 pg/mL = high risk
of local and distant mets)
o Cold of RAI scan
o Not iodine avid → no role for RAI treatment
For MTC what lad fining is suggestive of mets (and beyond which value?)
Serum calcitonin correlates with tumour burden >500 pg/mL = high risk
IHC for MTC
o Calcitonin+, CEA+, TTF1 (weak-moderate), PAX8 (variables to weak),
o Thyroglobulin -!!!
o CEA+, chromogranin A+, synaptophysin+
o Para-ganglioma-like variant: melanin+, calcitonin+, S100+
o Small cell variant: calcitonin+
o Tubular variant: calcitonin+
- Molecular genetic:
o RET proto-oncogene gain in function mutation (exon 6 M918T mutation is most common), in majority of familial MTC, and 50% of sporadic MTC (germline mutation testing on peripheral blood)
o HRAS/ KRAS mutation in RET negative MTC
Prongostic factors for MTC:
Prognostic factors:
Poor: high stage, old age, cervical nodal mets, male, sporadic form, high mitotic activity, vascular
invasion
▪ MEN-2B more aggressive than MEN-2A
▪ RET (M918T mutation) = worse outcomes
▪ RAS mutation less aggressive disease
Favourable: young age, female, familial form, microcarcinoma
Biological behaviour of MTC
Biological behaviour:
o 75% have nodal mets, and 10% have distant mets
o 5-yr OS 60-90%, 10-yr OS 40-80%
Epi and clinical of anaplastic thyroid
UNDIFFERENTIATED/ ANAPLASTIC CARCINOMA (<5%)
* Epi: mean age 70, M:F 1:2
- Clinical:
50% have prior multinodular goitre , 20% have prior differentiated carcinoma, 20% have concurrent differentiated carcinoma
Rapidly enlarging firm, ill-defined mass causing hoarseness, dyspnoea, dysphagia, cough (including
haemoptysis)
majority have extra-thyroid extension
90% have regional/ distant spread at time of diagnosis
Biological behav of anaplastic thyroid cancer:
Biological behaviour:
o Aggressive, all considered Stage IV
o 90% have nodal/ distant spread at diagnosis
o common sites of distant mets – lung (90%), bone (10%)
o Median OS ~ 3 months, 1-yr OS 10-20%
Broad micro description for anaplastic:
Large pleomorphic cells, undifferentiated, high mitosis, necrosis, vascular invasion (with obliteration of lumen)
o Three patterns:
▪ Sarcomatoid: malignant spindle cells resembling HG pleomorphic sarcoma
▪ Giant cells: highly pleomorphic tumour cells with tumour giant cells
▪ Epithelial: squamoid/ squamous tumour nest with occasional focal keratinisation
Work up for thyroid lump:
Blood * Thyroid function (TSH, T3/T4), thyroglobulin
* PTH and calcium (to rule out hyperparathyroidism)
* In MTC: Calcitonin (calcitonin level correlates with tumour burden), CEA, RET proto-oncogene
germline mutation
* Urine and serum catecholamine (to rule out pheochromocytoma)
To exclude other DDx
- LDH/ ESR (elevated in lymphoma)
- beta-HCG and AFP (elevated in germ cell tumour)
Imaging:
Thyroid ultrasound
o Benign: purely cystic
o Suspicious for malignancy: solid hypoechoic nodule, irregular margin (infiltrative, micro-lobulated), microcalcification, taller (than wide) shaper, rim calcification with extrusive soft tissue component, evidence of ETE
- Radioactive iodine I123 (RAI) scan
o If hot – unlikely malignancy, evaluate and treat for thyrotoxicosis as indicated, no
FNA
o If cold – likely malignant → FNA
CT neck (non-contrast – iodine contrast will preclude RAI treatment for next 1-2 months)
* Systemic staging if high risk of distant mets
o CT chest/ liver
o Bone scan
o FDG PET – useful only in poorly differentiated/ undifferentiated cancer (will have high Glut1/ glucose receptor = will be FDG avid)
Benign and suspicious findings on Thyroid USS
Thyroid ultrasound
o Benign: purely cystic
o Suspicious for malignancy: solid hypoechoic nodule, irregular margin (infiltrative, micro-lobulated), microcalcification, taller (than wide) shaper, rim calcification with extrusive soft tissue component, evidence of ETE
Preferred initial tissue Dx technique. What is the diagnostic system. Describe the steps
FNA = Bethesda system, 1= insufficient sample (0-5% risk malignancy) 6 = malignant do a totalthroidectomy.
- U/S guidance recommended for – non-palpable nodules (e.g. in posterior lobe), significant cystic component (>25%), previously non-diagnostic/ unsatisfactory sample
- Fine needle (25-27 gauge) ideal (because thyroid gland vascular = risk of bleeding)
- 1-2 FNA passes sufficient, if pathologist on site to evaluate for adequacy; otherwise 2-5 FNA
passes recommended - > 2 FNA passes (in different location) for large nodule to ensure adequate sampling of potentially heterogenous nodule
- Thyroid cyst should be drained, and any residual solid component visible on ultrasound should be subjected to biopsy; suspicious calcification should be targeted/ sampled
