Thyroid

Question 1

Broad epidemiology of thyroid cancer in general

Answer 1

• 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

Question 2

Broad aetiology of thyroid malignancies:

Relate genetics to specific subtypes

Answer 2

• 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)

Question 3

2 broad categories of thyroid ca?

Answer 3

• Differentiated thyroid carcinoma (DTC) – papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC),
  Medullary thyroid carcinoma (MTC)
• Undifferentiated/ anaplastic thyroid carcinoma (ATC)

Question 4

Basic epidemiology and clinical presentation of papillary thyroid:

Answer 4

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

Question 5

Macro description of PTC (papillary thyroid cancer):

Answer 5

Solid, grey white tumour, firm, invasive with ill-defined margins (<10% surrounded by complete capsule)

Question 6

Micro description of PTC (papillary thyroid cancer):

Answer 6

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

Question 7

How many variants of PTC are there? What are some key prognostic ones?

Answer 7

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

Question 8

General thyroid IHC, relate it to PTC. What about for follicular?

Answer 8

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).

Question 9

Basic epidemiology and clinical presentation of follicular thyroid:

Answer 9

(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

Question 10

Issue with FNA Dx for FTC

Answer 10

As only cytology cannot differentiate architecture - adenoma vs carcinoma.

▪ follicular adenoma thin capsule vs. follicular carcinoma thick capsule

Question 11

Macro description of FTC (follicular thyroid cancer):

Answer 11

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

Question 12

Micro description of FTC (follicular thyroid cancer):

Answer 12

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

Question 13

FTC can be classified into?

Answer 13

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

Question 14

Compare molecular genetics of PTC and FTC:

Answer 14

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%

Question 15

Biological behaviour of FTC

Answer 15

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)

Question 16

Biological behaviour of PTC

Answer 16

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)

Question 17

Prognostic factors PTC

Answer 17

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

Question 18

Prognostic factors FTC

Answer 18

Poor: increase age, tumour size >4cm (T3+), extra-thyroid extension, extensive vascular invasion, distant mets

Question 19

Since 2017 a former subtype of FTC is now considered its own entity. What is’s main dx feature and biological behaviour?

Answer 19

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)

Question 20

How common is medullary thyroid Cancer?

Where does it come from?
What is it associated with?
How does it present?
Key investigation findings?

Answer 20

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

Question 21

For MTC what lad fining is suggestive of mets (and beyond which value?)

Answer 21

Serum calcitonin correlates with tumour burden >500 pg/mL = high risk

Question 22

IHC for MTC

Answer 22

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

Question 23

Prongostic factors for MTC:

Answer 23

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

Question 24

Biological behaviour of MTC

Answer 24

Biological behaviour:
o 75% have nodal mets, and 10% have distant mets
o 5-yr OS 60-90%, 10-yr OS 40-80%

Question 25

Epi and clinical of anaplastic thyroid

Answer 25

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

Question 26

Biological behav of anaplastic thyroid cancer:

Answer 26

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%

Question 27

Broad micro description for anaplastic:

Answer 27

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

Question 28

Work up for thyroid lump:

Answer 28

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)

Question 29

Benign and suspicious findings on Thyroid USS

Answer 29

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

Question 30

Preferred initial tissue Dx technique. What is the diagnostic system. Describe the steps

Answer 30

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