Thyroid Neoplasms

Question 1

What are the risk factors of thyroid cancer? 6

Answer 1

1. FEMALE (3x more likely, 2x more likely anaplastic)
2. Age > 45 (median ~51) - peak women 50-54, men 65-69
3. Exposure to ionizing radiation (higher risk of cancer, increased risk of multifocal, and risk of cervical mets higher) - 30% nodules will be carcinoma
4. Personal history of thyroid cancer
5. Ethnicity: Hawaiian, Filipino
6. Family history of thyroid cancer
   - PTC increased frequency in families with breast, ovarian, renal, or CNS malignancies
   - Gardner syndrome & Cowden disease associated with WDTC
   - Family history of MTC, MEN-2A/B need evaluation for RET point mutation

NO CLEAR ASSOCIATION WITH:
- Dietary iodine
- Goiter (although follicular and anaplastic occur more commonly in areas of endemic goiter)

Question 2

Aside from risk factors, what other questions on history should you ask on a thyroid neoplasm history? What should be done on physical exam?

Answer 2

OPQRST:
- Rapid growth
- Throat/neck pain rarely associated with carcinoma; may occur with hemorrhage into benign nodule
- Compressive symptoms (non-specific): voice change, hoarseness, dysphagia, dyspnea
- Symptoms of hyper/hypothyroid (mostly euthyroid)

EXAM:
- Palpable nodules are at least ~1cm long, malignant more likely to be hard & fixed to trachea/esophagus/straps
- Larger lesions have higher incidence of false negative on FNAb
- Pemberton Maneuver: lifting arms over head to elicit obstruction in setting of substernal goiter – subjective respiratory discomfort, venous engorgement resulting in facial suffusion
- Lymphadenopathy
- FNL for vocal cord examination (see 3 indications later)

Question 3

What are concerns on history or physical or testing for diagnosis of thyroid cancer? 7

Answer 3

1. Enlarging
2. Size > 4cm
3. Dysphagia
4. Hoarseness
5. Cervical adenopathy
6. Fixation to skin
7. Microcalcifications, increased vascularity on US

Question 4

What are the initial tests that should be ordered for the work-up of thyroid nodules? 3

What tests are not as useful to perform initially? 1

Answer 4

1. TSH
   - If low (16% malignancy risk) –> I-123 thyroid scan
   - If high (hot nodule, 4% risk) –> Endocrinology referral
2. Thyroid U/S with survey of cervical lymph nodes
   - Thyroid FNA biopsy = procedure of choice for evaluating nodules that meet criteria for biopsy
   - Do not SCREEN NECK with U/S - has been shown to not reduce morbidity or mortality
3. Serum calcitonin levels (for family history or suspicion of MTC)
   - If RET mutation +, evaluate for pheo with abdominal MRI and 24h urine metanephrines and catecholamines
   - Serum calcium to exclude hyperparathyroidism

Not as useful for initial workup:
- Thyroglobulin Tg (not recommended as also made by normal thyroid tissue - more useful for patients after total thyroidectomy for WDTC

Question 5

What are the indications for CT/MRI with contrast for the pre-operative investigation of thyroid malignancy? 2

What are the indications for a PET scan in thyroid cancer? 4

Answer 5

1. CLINICAL SUSPICION OF ADVANCED DISEASE
   - Invasive primary tumor
   - Clinically apparent or bulky lymph node involvement
2. FDG PET IS NOT ROUTINELY RECOMMENDED, BUT CONSIDER IN: “TIPS”
   - High risk patients with elevated thyroglobulin (>10ng/mL) and negative RAI uptake scan
   - During initial staging for poorly differentiated thyroid cancer and invasive hurthle cell carcinomas
   - Prognostication in patients with metastatic disease
   - Evaluation of response to systemic treatment for metastatic disease

Question 6

Should every thyroidectomy patient have a pre-operative laryngeal exam according to ATA guidelines?

What are 3 indications for a laryngeal exam pre-op?

Answer 6

No, 3 reasons to do so:
1. Pre-operative voice abnormalities
2. History of cervical or upper chest surgery
3. Thyroid cancer with known posterior extension

Question 7

What is the utility of thyroid isotope scanning in the work-up of thyroid nodules?

Answer 7

123-I or TECHNETIUM 99m SESTAMIBI:
- Assess the functional activity of a thyroid nodule and gland
- 123-I: Tests iodine transport and organification of iodine (2 days to complete, more expensive)
- 99m-Tc: Tests only iodine transport

RESULTS:
- Cold/non-functioning/hypo-functional nodules: Nodules with less radioactivity than surrounding tissue (lost functions of fully differentiated thyroid tissue and increased risk of containing carcinoma

CLINICAL UTILITY:
- Not routinely performed given evolution of FNA tests

MAIN INDICATIONS:
- Thyroid nodule + hyperthyroid or low TSH (to differentiate toxic nodule vs. Graves’ disease)

Question 8

List the ultrasound features of a high suspicioun thyroid nodule, according to ATA guidelines? 7

Answer 8

Solid hypoechoic or solid hypoehoic component of a partially cystic nodule with ≥1 of 5:
1. Miicrocalcifications
2. Taller than wide
3. Irregular margins
4. Rim calcifications with small extrusive soft tissue component
5. Extrathyroid extension

Question 9

List the ultrasound features of a intermediate suspicioun thyroid nodule, according to ATA guidelines?

Answer 9

1. Solid hypoechoic nodule without the five features above

Question 10

List the ultrasound features of a low suspicioun thyroid nodule, according to ATA guidelines?

Answer 10

1. Isoechoic; or
2. Hyperechoic nodule; or
3. Partially cystic with eccentric solid areas without high risk features

Question 11

List the ultrasound features of a very low suspicioun thyroid nodule, according to ATA guidelines?

Answer 11

1. Spongiform; or
2. Partially cystic nodules without high suspicion patterns

Question 12

List the ultrasound features of a benign suspicioun thyroid nodule, according to ATA guidelines?

Answer 12

1. Purely cystic nodules (no solid component)

Question 13

What is the estimated risk of malignancy for each ATA guideline ultrasound “level of suspicion” category?

Answer 13

1. High - 70-90%
2. Intermediate - 10-20%
3. Low - 5-10%
4. Very low - < 3%
5. Benign - < 1%

Question 14

For each US category, what is the size cutoffs for ordering FNA biopsy, according to ATA guidelines?

Answer 14

1. High risk > 1cm
2. Intermediate risk > 1cm
3. Low suspicion > 1.5cm
4. Very low suspicion > 2cm
5. Benign - No FNA

Question 15

If patients don’t meet the size criteria for FNA, what is the follow up like, according to ATA guidelines?

Answer 15

Depends on the US risk

1. High risk: Repeat US in 6-12 months
2. Intermediate to low risk: Repeat US in 12-24 months
3. Very low > 1cm nodule: May repeat US in > 24 months
4. Very low, < 1cm nodule: Do not need to follow
5. If > 20% growth in 2 dimensions and increase ≥2mm or 50% volume = perform FNA

Question 16

What is the TIRADS score?

Answer 16

TIRADS = THYROID IMAGING REPORTING DATA SYSTEM
- Guideline put out by the American College of Radiology
- Stratifies risk of thyroid nodules based on US
- Unclear whether ATA guidelines or TIRADS is superior (know both)

Question 17

What are the five parameters the TIRADS system assesses?

Answer 17

1. COMPOSITION:
   - Cystic or almost completely cystic = 0
   - Spongiform = 0
   - Mixed cystic and solid = 1
   - Solid or almost completely solid = 2
2. ECHOGENICITY:
   - Anechoic = 0
   - Hyperechoic or Isoechoic = 1
   - Hypoechoic = 2
   - Very hypoechoic = 3
3. SHAPE:
   - Wider than tall = 0
   - Taller than wide = 3
4. MARGIN:
   - Smooth = 0
   - Ill-defined = 0
   - Lobulated or irregular = 2
   - Extra-thyroidal extension = 3
5. ECHOGENIC FOCI
   - None or large comet-tail artifacts = 0
   - Macrocalcifications = 1
   - Peripheral (rim) calcifications = 2
   - Punctate echogenic foci = 3

All points from all categories are added together for a final score that tells you the risk and what to do

Question 18

What are the 5 TIRADS categories of risk?

Answer 18

TR1: 0 points = benign (0.3%)
TR2: 2 poiints = not suspicious (1.5%)
TR3: 3 points = Midly suspicious (4.8%)
TR4: 4-6 points = Moderately suspicious (9.1%)
TR5: ≥7 points = Highly suspicious (35%)

Question 19

Discuss the management of each TIRADS category

Answer 19

TR1, TR2: No FNA

TR3:
- ≥ 2.5cm = FNA
- ≥ 1.5cm = Follow (1, 3, 5 years)

TR4:
- ≥1.5 cm = FNA
- ≥ 1cm = Follow (1, 2, 3, 5 years)

TR5:
- ≥1 cm = FNA
- ≥0.5 cm = Follow (Annually x 5 years)

Question 20

How often does incidental FDG-PET avid Thyroid nodules occur? How should they be managed?

Answer 20

• 1-2% of all PET scans will have PET-avid thyroid nodule
• 3-4% will have diffuse uptake = benign
• 35-50% will be a malignancy if focal nodules

Management:
- FNA if >1cm
- < 1cm - consider the U/S features and management from there

Question 21

What are the 6 Bethesda categories and the associated risk of malignancy?

Answer 21

1. BT1: Non-diagnostic = 1-4%
2. BT2: Benign = 0-3%
3. BT3: Atypia of Undetermined Significance (AUS) or Follicular lesion of undetermined significance = 5-15%
4. BT4: Suspicious for follicular neoplasm or Follicular neoplasm = 15-30%
5. BT5: Suspicious for malignancy = 60-75%
6. BT6: Malignant = 97-99%

Question 22

What is defined as an adequate FNA biopsy for thyroid, according to ATA guidelines?

Answer 22

The presence of at least 6 groups of well-visualized follicular cells, each group containing at least 10 well-preserved epithelial cells, preferably on a single slide

Question 23

Discuss the management of multiple thyroid nodules > 1cm 2

Answer 23

1. FNA all nodules that meet criteria
2. If TSH is low –> 123-I or Technetium 99m sestamibi scan to ensure whether nodule is hot
3. If Iso or hypo-functioning –> FNA

Question 24

When should you FNA cervical lymph nodes when thyroid nodules are positive for malignancy?

With a thyroglobulin washout test, what is a reasuring level, and what is concerning for malignancy if a patient has an intact thyroid?

Answer 24

1. Perform pre-op neck US to evaluate these patients
2. US guided FNA biopsy of LNs > 8-10mm in smallest diameter to confirm malignancy
3. May add thyroglobulin washout test (FNA-Tg washout) in select patients:
   - Test for thyroglobulin with the cervical LN biopsy
   - This test is more useful for evaluation of cervical LAD after total thyroidectomy (as Tg levels will be down, making interpretation more meaningful)
   - Tg < 1ng/mL is reassuring and probability of N1 disease increases with higher levels
   - Good if LNs are cystic, cytology inadeqeuate, or if cytology & US are divergent
   - >32ng/mL has the best sensitivity and specificity in patients with intact thyroid gland

Question 25

Most important genes in thyroid cancer for ptc frc and ATC. 2 each

CHART

Discuss the molecular basis for thyroid neoplasms, with the following genetic alterations, and their % in PTC, FTC, Poorly Diff TC, ATC, and MTC:

1. RET rearrangement
2. NTRK-1 rearrangement
3. RET mutation
4. BRAF mutation
5. RAS mutation
6. P1K3CA mutation
7. PPARG rearrangement
8. TP53

Answer 25

PTC - BRAF, RET
FTC - RAS, PPAR
ATC/PDTC - TP53, RAS

1. RET rearrangement
   - 20% PTC
   - Rare in poorly differentiated thyroid carcinoma
2. NTRK-1 rearrangement
   - 5-13% in PTC
3. RET mutation
   - Sporadic 30-50% in MTC
   - MEN-2 95% in MTC
4. BRAF mutation
   - 45% in PTC
   - 15% in poorly diff TC
   - 44% in ATC
5. RAS mutation
   - 10% in PTC
   - 40-50% in FTC
   - 44% in poorly diff TC (PDTC)
   - 20-60% in ATC
6. P1K3CA mutation
   - Rare in PTC, FTC, PDTC
   - 20% in ATC
7. PPARG rearrangement
   - 35% FTC
   - Rare in PDTC
8. TP53
   - Rare in PTC, FTC, and MTC
   - 15-30% in PDTC
   - 60-80% in ATC

Question 26

Discuss the use of molecular testing for thyroid nodules:
1. What conditions are they NOT useful in?
2. What are the considerations if this test is ordered?
3. What are the two types of molecular testing?
4. How are the result interpreted? If you test positive on BRAF, or if you test positive on RAS?

Answer 26

NOT USEFUL IN:
1. Nodule not meeting FNA criteria
2. Bethesda II or VI (ie. benign or malignant)
3. High incidence of malignancy at a particular institution (e.g. Bethesda V)

CONSIDERATIONS ON ORDERING:
1. Must tell patients it is a new and uncertain field
2. Must use a certified molecular lab

MOLECULAR TESTING OPTIONS (Only 2 validated for AUS/FLUS, FN, and SUS):
1. BRAF: For AUS/FLUS has high specificity for cancer, but low sensitivity
2. 7-gene panel: BRAF, NRAS, HRAS, KRAS, PET/PTC1, RET/PTC3, PAX8/PPARGamma
- A rule “in” test

RESULTS INTERPRETATION:
1. Positive BRAF, RET/PTC or PAX8/PPARgamma - specific for a malignant outcome in 100%
2. RAS mutations - 84% risk of cancer and 16% chance of benign follicular adenoma

Question 27

What is GEC? What is the specficity?

Answer 27

GEC = Gene Expression Classifier (Afirma brand)
- Diagnostic test to evaluate suspicious or indeterminate thyroid nodules for malignancy (a test for a group of molecular markers in thyroid biopsy specimens in order to determine the likelihood that a thyroid nodule is benign or cancerous)

Advantages:
1. Potentially of value in avoiding diagnostic surgery in cytologically indeterminate nodules that are AUS/FLUS or FN and GEC negative
2. Rule out = 90% specific

Question 28

How does molecular testing help in each FNA biopsy category?

Answer 28

• Utility of molecular testing is strongly influenced by the prevalence of cancer in the tested population of nodules (ie. how good your pathologists are)

A. BENIGN/NON-DIAGNOSTIC + HIGH RISK U/S FEATURES OR HIGH CLINICAL SUSPICION:
- Repeat US FNA is also an alternative to molecular testing in this case
- Positive = total thyroidectomy (high malignancy risk)
- Negative = observe

B. AUS/FLUS
- Consider worrisome US features
- Repeat US FNA biopsy or molecular testing to supplement malignancy risk
- Positive = total thyroidectomy
- Negative = Observation or diagnostic hemithyroidectomy (if repeat FNAb or molecular testing not performed/inconclusive, continue surveillance of diagnostic hemi based on cliniical/US pattern/preference)

C. FOLLICULAR NEOPLASM/SUSPICIOUS FOR FN
- Consider 7 gene and GEC testing
- Positive = Oncologic thyroidectomy
- Negative = Diagnostic hemithyroidectomy

D. SUSPICIOUS FOR MALIGNANCY
- Positive = Oncologic thyroidectomy
- Negative = Diagnostic hemithyroidectomy

Total thyroidectomy if positive as above? Or should total really just say Hemi (based on features)

Question 29

How should the results of GEC testing be interpreted?

Answer 29

1. AUS/FLUS or FN nodules reported as “suspicious” using GEC
   - Diagnostic hemithyroidectomy
   - Total thyroidectomy should be considered (considering clinical characteristics)
   - Sensitivity - 94%, NPV of 90-94% (because of the lowest pretest probability of malignancy)
2. Follicular neoplasm
   - GEC - Suspicious (Diagnostic lobectomy - consider total thyroidectomy)
   - GEC - Benign (Active surveillance or diagnostic hemithyroidectomy if clinically indicated or if institutional prevalence of malignancy in the FN is significant)
3. Suspicious for malignancy
   - GEC is not reflexively performed nor routinely recommended for the SMC

Question 30

What is the management for FNA that returns non-diagnostic, according to ATA guidelines?

Answer 30

1. Repeat FNA with on-site pathological evaluation
2. If repeatedly non-diagnostic without high risk US features, either:
   - Active surveillance; or
   - Diagnostic hemithryoidectomy
3. If repeatedly non-diagnostic WITH high risk US features, or US shows growth > 20% in two dimensions during observation or clinical risk factors of malignancy:
   - Diagnostic hemithyroidectomy

Question 31

What are the the situations in which FNA confirmed benign nodule should still be managed surgically, according to ATA guidelines?

Answer 31

1. Large nodule (>4cm)
2. Causing compressive symptoms
3. Concerning ultrasound or clinical features
4. Cosmesis
5. Hyperfunctioning nodule
6. Increasing size

Question 32

What are the options for managing FLUS/AUS on FNA? 4

Answer 32

1. Repeat FNA
2. Molecular testing
3. Active surveillance
4. Diagnostic hemithyroidectomy

Question 33

How is the active surveillance option done for AUS/FLUS?

Answer 33

Depends on the original ultrasound findings:

1. HIGH SUSPICION: Repeat US and US guided FNA within 12 months
2. INTERMEDIATE TO LOW SUSPICION: Repeat US (no FNAb) at 12-24 months
   - If growth >20% in 2 dimensions, or ÷2mm or increased by 50% volume –> repeat FNA
3. VERY LOW SUSPICION: May repeat at > 24 months
4. After second benign FNA = no further FNA unless it meets criteria for enlargement as above

Question 34

What is the management option of FNA that returns suspicious for follicular neoplasm or follicular neoplasm?

What about the management of a hurthle cell neoplasm?

Answer 34

Gold standard = Diagnostic hemithyroidectomy

May supplement risk assessment with molecular testing, but should still proceed to surgery in most cases

• Follicular neoplasm on FNA can undergo Iodine 123 thyroid scan
  – Cold nodule - surgery
  – Hot nodule - can avoid surgery

Hurthle cell neoplasms are also difficult to evaluate:
- Surgery is generally recommended for hurthle cell neoplasms
- Adenoma vs. carcinoma vs. MNG vs Hashimoto thyroiditis

Question 35

What are the management options for an FNA that returns as “suspicious for malignancy”?

Answer 35

Same as “malignant” FNA management options:

1. Hemithyroidectomy; or
2. Total thyroidectomy

The choice of hemi or total depends on other factors - U/S, clinical features, and molecular testing

Question 36

If surgical management of intermediate nodules (FLUS/AUS/Follicular neoplasm) is chosen, when should a total thyroidectomy be considered, according to ATA guidelines?

Answer 36

1. Repeated FNA biopsy = Bethesda 5 (reducing risk of second completion procedure)
2. Positive mutation specific for carcinoma (BRAF)
3. High risk US findings
4. > 4cm
5. Patients with familial carcinoma
6. History of radiation exposure
7. Bilateral nodules, high surgical risk

Question 37

If an FNA of thyroid nodule demonstrates malignancy, in which 4 situations is active surveillance an option, according to ATA guidelines?

Answer 37

1. Papillary microcarcinoma < 1cm without clinically evident metastases, local invasion, or cytological evidence of aggressive disease
2. High surgical risk
3. Limitied life span (ie. will die from something else first)
4. Patients with concurrent medical issues that need to be addressed prior to thyroid surgery

Question 38

What is the work up for pregnant women with thyroid nodules?

Answer 38

1. Same initial work up (TSH, US ± FNA biopsy)
2. However, if TSH low, defer radionucleotide scan until delivery/lactation

Question 39

What is the management of well-differentiated thyroid cancer in early pregnancy, according to the ATA guidelines?

Answer 39

1. Repeat US by 24-26 weeks
   - If growth significantlly, or if cervical LAD –> Thyroidectomy during pregnancy
   - If stable –> delay until after delivery

Question 40

If an FNA of thyroid shows malignancy, in which 4 situations should a total thyroidectomy always be performed, according to the ATA guidelines?

Answer 40

Evidence of advanced local disease:
1. >4cm tumor
2. T4 tumor
3. ≥ N1
4. M1

Question 41

If an FNA of thyroid shows malignancy, in which situations can a hemithyroidectomy be considered, according to the ATA guidelines?

Answer 41

1. Size 1-4cm tumor
2. No extrathyroid extension
3. N0/M0
4. No adverse features on ultrasound

Question 42

If an FNA shows malignancy, in which situations should a total thyroidectomy NOT be done (ie. always do a hemi)? 8

Answer 42

If ALL conditions are met:
1. Papillary microcarcinoma (< 1cm)
2. Unifocial
3. Intrathyroidal
4. No local invasion
5. No evidence of metastasis
6. No cytological evidence of aggressive disease
7. No history of H/N Rads
8. No familial thyroid carcinoma

Question 43

What are 4 main reasons that a total thyroidectomy should be done?

Answer 43

1. Potential for multicentricity
2. Faciliate I-131 ablation and Tg follow-up

Note:
- Morbidity of second side only 3% increased
- Reduce recurrence rate (15-25%)

Question 44

What is the accuracy of FNA biopsy at identifying each thyroid tumor histology?

Answer 44

1. Anaplastic and Medullary - 90%
2. Papillary = 80%
3. Follicular = 40%
4. Lymphoma and poorly differentiated are difficult

FNA biopsy cannot diagnosed follicular carcinoma because vascular and/or extracapsular invasion are required on pathology to make this diagnosis

Question 45

DIAGRAM/CHART

Outline the WHO Histologic Classification of Thyroid Tumors

Answer 45

BROAD CATEGORIES:
1. Epithelial tumors
2. Non-epithelial tumors
3. Malignant tumors
4. Miscellaneous tumors
5. Secondary tumors
6. Unclassified tumors
7. Tumor-like lesions

EPITHELIAL TUMORS:
A. BENIGN TUMORS
1. Follicular Adenoma
i. Architectural patterns
- Normofollicular (simple)
- Macrofollicular (colloid)
- Microfollicular (fetal)
- Trabecular and Solid (embyronal)
- Atypical
- Non-invasive follicular thyroid neoplasm with papillary-like nuclear features
ii. Cytologic patterns
- Oxyphilliic cell type
- Clear cell type
- Mucin-producing cell type
- Signet-ring cell type
- Atypical

2. Others
   i. Salivary gland-type tumors
   ii. Adenolipomas
   iii. Hyalinizing trabecular tumors

B. MALIGNANT TUMORS
1. Follicular carcinoma
- Degree of invasiveness: Minimally invasive (encapsulated), widely invasive
- Variants: Oxyphilic (Hurthle) cell type, clear cell type
2. Papillary carcinoma; variants:
- Papillary microcarcinoma
- Encapsulated variant
- Follicular variant
- Diffuse sclerosing variant
- Oxyphilic (Hurthle) cell type
3. Medullary thyroid cancer
- Variant: Mixied medullary-follicular carcinoma
4. Undifferentiated (anaplastic) carcinoma
5. Other carcinomas
- Mucinous carcinoma
- SCC
- MEC

MISCELLANEOUS TUMORS
1. Parathyroid tumors
2. PGLs
3. Spindle cell tumors with mucous cysts
4. Teratomas

TUMOR-LIKE LESIONS:
1. Hyperplastic goiters
2. Thyroid cysts
3. Solid cell nests
4. Ectopic thyroid tissue
5. Chronic thyroiditis
6. Riedel thyroiditis
7. Amyloid goiter

NOTABILITY NOTES

Question 46

Regarding thyroid adenomas, discuss:
1. What are they?
2. Clinical presentation?
3. Pathology, including microscopic findings and stains?
4. Management and prognosis?

Answer 46

THYROID ADENOMA:
- Benign neoplasm derived from follicular cells, in setting of any type of thyroid (normal, nodular goiter, toxic goiter, or thyroiditis)

CLINICAL PRESENTATION:
- Women > 30 yo common
- Usually solitary, mobile thyroid nodule
- Not frequently associated with any S/S, but sudden hemorrhage may cause sudden increase in size and pain

PATHOLOGY:
1. Gross pathology: Fleshy and pale in color, ± areas of necrosis/hemorrhage/cystic change
2. Microscopic findings:
- Large and/or small follicles with abundant colloid
- Flat, cuboidal, or columnar cells
- Small and round nuclei with an even chromatic pattern
- Mixed populations of macrophages, lymphocytes, fibrosis, hemosiderin, and calcification
3. Oxyphilic (Hurthle) cell adenoma contains mitochondria-rich eosinophilic cells
4. IHC Stains: Distinguish clear cell adenoma vs. parathyroid adenoma vs. metastasis (from renal carcinoma)
5. Autonomously hyperfunctioning thyroid adenomas: “hot” nodules - which may or may not cause thyrotoxicosis

MANAGEMENT AND PROGNOSIS:
1. Growth not indication for malignancy, but indication for repeat biopsy
- Serial US examinations for benign nodules at 6-18 months intervals, and repeat biopsy with growth
2. Surgical excision via lobectomy or total thyroidectomy, depending on risk factors
3. Autonomously hyperfunctioning adenoma
- No treatment if stable
- Surgery or RAI can be used (Surgery preferred if < 40 years old (unilateral lobectomy); Ethanol injection more common in Europe)

Question 47

Regarding thyroid cysts, discuss:
1. Clinical presentation
2. Pathology findings
3. Management and prognosis. What does the color of fluid tell you about prognosis?
4. What are the options for management of thyroid cysts, according to ATA guidelines?

Answer 47

CLINICAL PRESENTATION:
- 15-25% of thyroid nodules are cystic or have a cystic component
- Cyst does NOT indicate benign: Papillary carcinoma may be present in 14-32% of cystic nodules

PATHOLOGY:
- Most cysts result from intranodular ischemia that cause tissue necrosis and liquefaction
- True epithelial-lined cysts are rare (May be parathyroid (high PTH level) or TGDC (columnar epithelium))

MANAGEMENT AND PROGNOSIS:
1. Aspiration (Tend to recur) - if persists after 3 drainage attempts, or re-accumulates quickly, suspicion for carcinoma increases
2. Surgery: for most cysts that recur or cause symptoms (hemithyroidectomy)
3. Sclerotherapy with ethanol (Europe) - not as preferred due to potential for carcinoma

Fluid color:
1. Brown = likely old hemorrhage from adenoma
2. Red = Suspicious for carcinoma
3. Clear, colorless = Parathyroid cyst, can be assessed for PTH

Question 48

What are the WHO Histologic subtypes of thyroid follicular adenoma? 5

Answer 48

1. Clear cell
2. Hyalinizing trabecular
3. Atypical
4. Oxyphiliic / Oncocytic (Hurthle) cell
5. Signet-ring

“CHAOS”

Question 49

If the FNA biopsy demonstrates “Hurthle cells”, what are the possibilities of diagnosis?

Answer 49

1. Follicular adenoma
2. Follicular carcinoma or Hurthle cell carcinoma
3. Hashimoto’s thyroiditis
4. Papillary carcinoma
5. Medullary carcinoma
6. Other lesions include: Grave’s, post-XRT, aging

“FF, PH, MO”
like FOMO

Question 50

If the FNA biopsy demonstrates “clear cells”, what are the possibilities?

How do you differentiate them?

Answer 50

1. Follicular adenoma
2. Follicular carcinoma
3. Metastatic Renal cell carcinoma
   - RCC can be distinguished by lack of colloid on PAS, Tg and TTF-I (thyroid transcription factor) stains negative, CD10 and RCC marker stains positive

Question 51

What are the risk factors for worse prognosis for well differentiated thyroid cancer? 6

Answer 51

1. Older age (Men > 40, women > 50) has worse prognosis
2. Size of primary: >5cm worse, < 1.5cm improved prognosis; thus size >1.5cm considered worse
3. Extrathyroidal extension
4. Distant mets
5. Unifocal disease likely to be malignant compared to multifocal disease; Multifocality increases with age
6. Cervical metastasis - does not impact overall survival but does increase chances of local recurrence

Question 52

What are the 6 most common thyroid malignancies?

Answer 52

1. Papillary 80%
2. Follicular 10-15%
3. Medullary 5%
4. Anaplastic < 5%
5. Lymphoma
6. Metastasis

Question 53

What is the most aggressive well-differentiated thyroid carcinoma?

Answer 53

Hurthle cell (50-60% five year survival)

Question 54

What are 5 factors that are better for prognosis, low risk for tumor recurrence and disease-specific mortality?

What is the most significant overall indicator of poor prognosis?

Answer 54

1. Younger at diagnosis
2. Smaller primary tumors
3. Lack of extrathyroidal extension
4. Lack of regional/distant mets (MOST SIGNIFICANT OVERALL INDICATOR OF POOR PROGNOSIS = DISTANT METS, especially bone)
5. Complete gross resection of disease at initial surgery

Question 55

Besides TNM staging, what are three other types of thyroid staging scales for well-differentiated thyroid cancer?

Answer 55

AMES System: Stratification of patient in low vs. high risk groups
- Recurrence in low risk patients ~5%, high risk ~55%
- DAMES system = Nuclear DNA content added

1. AMES stands for:
   - Age
   - Metastases presence
   - Extent of tumor invasion
   - Size of tumor
2. Low risk:
   - Young (men < 41, women < 51)
   - No distant mets
   - No ETE
   - Primary tumor < 5cm in diameter

AGES System: Infrequent practice of tumor grading, now modified to the MACIS system instead
1. AGES:
- Age at diagnosis
- Histologic tumor grade
- Extent of disease presentation
- Size of tumor

MACIS SYSTEM:
1. MACIS stands for:
- Metastasis
- Age at diagnosis
- Completeness of surgical resection
- Extrathyroidal Invasion
- Size of tumor

2. Calculation:
   - 31 (if page age < 40) OR 0.08xAge (if patient age ≥40); PLUS
   - 0.3 x tumor size (in cm;
   - + 1 (if ETE)
   - +1 (if incomplete resection)
   - + 3 (if distant mets)

Results:
- Stratified by their prognostic scores into 4 groups with statistically different 20 year disease-specific mortality

Question 56

What are the favourable and unfavourable variants of well differentiated thyroid cancer, according to the ATA guidelines?

Answer 56

UNFAVOURABLE:
1. Tall cell
2. Columnar cell
3. Hobnail variant
4. Widely invasive follicular thyroid carcinoma
5. Poorly differentiated carcinoma
6. HUrthle cell carcinoma

FAVOURABLE:
1. Encapsulated follicular variant of PTC without invasion (NIFTp)
2. Minimally invasive follicular thyroid carcinoma

Question 57

Regarding Papillary thyroid cancer, discuss:
1. What is the epidemiology?
2. What are the aggressive subtypes? What are other subtypes?
3. What are the typical spread patterns?
4. What is the clinical presentation? Including common age and gender at presentation, risk of cervical and distant mets on presentation?
5. Risk factors?
6. Diagnostic investigations?
7. Prognostic factors?
8. What is the 5, 10, and 20 year survivals?

Answer 57

EPIDEMIOLOGY:
- Most common type of thyroid cancer (80%)

AGGRESSIVE SUBTYPES: “DITCHH’S”
1. Diffuse sclerosing
2. Insular
3. Tall cell (WORST PROGNOSIS)
4. Columnar
5. Hurthle cell
6. Hobnail
7. Spindle cell

Other subtypes:
- Clear cell
- Oxyphilic
- Follicular variant
- Cribriform morular

SPREAD PATTERNS:
- Often multifocal (36%)
- Often bilateral (80%) - includes microscopic disease (clinically apparent recurrent 10%)
- Usually poorly encapsulated
- Lymphatic spread –> LNs common (50% - though significance of micromets to LNs debatable (no change in survival))
- Lymphatic invasion therefore also common

CLINICAL PRESENTATION:
- 30-40 years old
- F:M (2:1)
- Microcarcinoma - < 1cm
- Slow growth, painless, euthyroid
- Predominant type in children (more advanced disease with mets at diagnosis, but overall still better prognosis)
- 30-65% cervical mets at diagnosis
- Lower rate of distant mets (2-17%)

RISK FACTORS:
1. Radiation exposure history (low dose)
2. 6% Familial
- Cowden Syndrome
- Gardner Syndrome

DIAGNOSIS:
1. FNA
2. Thyroid function studies
3. CT/MRI: substernal disease, LN involvement

PROGNOSTIC FACTORS: (Think AGES/AMES/MACIS)
- Age
- Size (increased risk mortality > 5cm)
- Sex
- Presence of distant mets
- Histology of cancer
- Extracapsular extension

Survival:
1. 5-year = 90%
2. 10 year = 80-90%
3. 20 year = 70-80%

Question 58

What subtypes of papillary thyroid cancer are associated with familial syndromes?

Answer 58

1. Cribriform-morular variant of papillary (FAP)
2. Follicular or papillary carcinoma (PTEN-Hamartoma tumor syndrome - Cowden’s)

Question 59

Regarding Cowden Disease, discuss:
1. Genetics and inheritance
2. What are the classic features?

Answer 59

COWDEN DISEASE

Genetics and Inheritance:
1. PTEN tumor suppressor mutation, chromosome 10
2. Autosomal Dominant

FEATURES:
1. Trichelimmomas (benign tumor outer rooth sheath of hair follicles)
2. Intestinal hamartomas
3. Cancers: Breast, Endometrial, Thyroid, Renal

Question 60

Regarding Gardner Syndrome, discuss:
1. Genetics and inheritance
2. What are the classic features?

Answer 60

GARDNER SYNDROME

Genetics and Inheritance:
- Familial adenomatous polyposis
- Mutation in APC gene, chromosome 5
- Autosomal dominant

FEATURES:
1. Colonic polyps
2. Osteomas
3. Papillary thyroid carcinoma

Question 61

Describe the histopathology of papillary thyroid carcinoma.
What are the common stains used?
How does the follicular tall cell subtype or the columnar subtype differ?

Answer 61

GROSS:
- Firm, white, not encapsulated

HISTOLOGY:
- Can display mucinous, ciliary, or squamous metaplasia
- Multicentricity
- Arise from thyroid follicular cells, contain papillary structures consisting of neoplastic epithelium overlying a true fibrovascular core stalk
- Elongated follicles
- Cuboidal cells, pale, abundant cytoplasm
- Crowded nuclei with grooved nuclear margins
- Intranuclear cytoplasmic inclusions
- Inspissated colloid
- Prominent nucleoli (Organ Annie appearance)
- Laminated calcium densities = Psammoma bodies (round collection of calcium)
- Nuclei featuers:
1. Enlarged,
2. Irregularly shaped
3. Overlapping/crowding
4. Stippling of chromatin (“chromatin clearing”)
5. Optically cleared/Orphan Annie eyes
6. Nuclear Grooves
7. Intranuclear inclusions/Vacuoles (“pseudoinclusions”)

IHC:
1. BRAF
2. HMBE-1
3. TTF-1
4. Gelactin-3
5. Thyroglobulin
6. Cytokeratin

FOLLICULAR COMPONENT:
- May have predominant follicular components, but papillary features and still behave like PTC
- = Follicular variant of PTC, or mixed papillary follicular carcinaom

TALL CELL:
- Well formed papillae covered by cells twice as tall as wide

COLUMNAR:
- Prominent nuclear stratification

Vancouver 147 image

Psammoma bodies:
https://prod-images-static.radiopaedia.org/images/1048/fd8b8137aaadae2c3c486ba9e029dc_gallery.jpeg

Question 62

What are 3 common mutations found in sporadic papillary thyroid cancer?

Answer 62

1. BRAF 40-50% of all PTC
2. RAS 10-20% of all PTC (40-50% of follicular)
3. RET 10-20% of all PTC
   - Higher in Rads exposure (50-80%)
   - Higher in pediatrics (40-70%)

Question 63

What are Orphan Annie eyes?

Answer 63

Vesicular, “ground glass” nuclei (looks like coffee beans)

Vancouver Pg 147

Question 64

What is the prognosis of papillary thyroid cancer?

Discuss in terms of cervical recurrence

Answer 64

• Prognosis overall based on LN mets / LN density

1. Micromets < 1cm - no survival impact, but increased recurrence risk
2. Overall LN density ≤ 0.19 - 98% 10 year OS
3. Overall LN density more than 0.19 - 90% 10 year OS
4. Low risk patients - 20% cervical recurrence
5. High risk - 59% cervical recurrence
6. Age - over 55 is worse; men is worse. Under 40 or female have about similar prognoses

Question 65

When should a neck dissection be performed in well differentiated thyroid cancer?

Answer 65

LEVELS FOR NODE POSITIVE DISEASE:
1. Level II-VI
2. Level I only if clinically positive

LEVELS FOR NODE NEGATIVE (N0) DISEASE:
1. Central compartment (upper mediastinum to hyoid, laterally to carotids)
2. Lateral ND not indicated in WDTC

INDICATIONS FOR LEVEL VI:
1. Advanced T3/T4 (Obvious ETE on imaging)
2. Evidence of lateral neck lymphadenopathy

INDICATIONS FOR LATERAL NECK II-Vb:
1. Biopsy proven lateral lymph node involvement (need to ensure pre-op US of central and lateral neck, FNA any LN >8mm in smallest dimension, can add Tg washout if node is cystic or FNA/US are divergent/contradictory)

Question 66

What are all the types of immunohistochemical markers for well-differentiated thyroid cancer?

Answer 66

PTC/FTC:
1. TG (thyroglobulin)
2. TPO (thyroperoxidase)
3. TTF-1 (Thyroid tissue factor 1)
4. TTF-2
5. CK-19
6. HMBE-1
7. PAX8
8. BRAF

MTC:
1. Calcitonin
2. CEA
3. Vimentin
4. Chromagranin
5. Synaptophysin

Question 67

Regarding NIFTP, discuss:
1. What is it?
2. What are the two pain subtypes?
2. What is the clinical presentation? How can it be diagnosed?
3. Genetics
4. Management?

Answer 67

NIFTP: NON-INVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES:
- Follicular variant of papillary thyroid carcinoma (FVPTC)
- Tumor consisting of neoplastic follicles rather than papillae, with follicular cells showing nuclear features of PTC
- Two main subtypes:
1. Non-encapsulated (infiltrative): Behaves like carcinoma, invading into surrounding thyroid parenchyma
2. Encapsulated: Behaves like indolent tumor with non-existent metastatic potential and recurrence rates (Increased in incidence, now 10-20% of all thyroid cancer diagnoses; Renamed as NIFTP in 2016 to reflect its lack of invasion and indolent nature)

CLINICAL PRESENTATION:
- Similar to thyroid neoplasms, similar diagnostic symptoms and exam
- Detection with FNA difficult to assess as cannot assess capsular invasion (NIFTP shares nuclear features of PTC, Shares follicular architecture like follicular neoplasms)
- 29% false positive rate for FNA, 9-58% PPV for detecting NIFTP

GENETICS:
- 40% rate of RAS mutations
- 0% BRAF mutations (compared to 26-50% for infiltrative FVPTC)

MANAGEMENT AND PROGNOSIS:
- Several studies have found no recurrence or metastases after >10 years of follow up
- Not officially considered a malignancy
- Adequately treated with thyroid lobectomy, without need for completion thyroidectomy/CND/post-op RAI

Question 68

Describe the histopathology of NIFTP. What is the 6 diagnostic criteria for NIFTP?

Answer 68

Gross Pathology:
- Solid
- Well-circumscribed
- Thin capsule, clear demarcation between tumor vs. thyroid
- Paler, rarely demonstrates necrosis and hemorrhage

NIKIFOROV DIAGNOSTIC CRITERIA FOR NIFTP:
1. Encapsulation or clear demarcation from adjacent thyroid tissues (no invasion - vascular or capsular)
2. A follicular growth pattern with < 1% papillae
3. No psammoma bodies
4. < 30% solid/trabecular/insular growth pattern
5. Nuclear features of PTC (enlargement, elongation, irregular contous, grooves, pseudoinclusions, chromatin clearing)
6. Absence of vascular or capsular invasion, tumor necrosis, and high mitotic activity (< 3 per 10 hpf)

Question 69

Regarding follicular thyroid cancer, discuss:
1. What are the specific risk factors? 2
2. What are the subtypes? 3
2. What are the growth patterns? 5
3. Clinical presentation? What age, gender, and geographic location is common
4. What are the patterns of spread/route of metastasis? Where is the most common distant mets?
5. Overall prognosis. What 7 factors worsen prognosis?

Answer 69

FOLLICULAR THYROID CANCER:
- 10% of thyroid malignancies

RISK FACTORS:
- Correlated with pregnancy
- Correlated with certain HLA subtypes (DR1, DRW, DR7

SUBTYPES:
1. Classic Follicular
2. Clear cell
3. Hurthle cell (aka Oxophillic) –> BAD!

GROWTH PATTERNS:
1. Microfollicular
2. Macrofollicular
3. Normofollicular
4. Trabecular
5. Solid

CLINICAL PRESENTATION:
- Age ~50 years old mean (vs. 35 for PTC)
- F:M 3:1
- More common in iodine-deficient areas
- Some history include a slow-growing/chronic goister that suddenly increases in size
- Painless, although hemorrhage into nodule may cause pain
- 1% hyperfunction (presents with thyrotoxicosis)
- LN rare. atpresentation
- More commonly have distant mets

PATTERNS OF SPREAD/ROUTE OF METS:
1. Usually unifocal
2. Malignancy defined by capsular invasion
3. Angioinvasion = BAD (worse prognosis with increased invasiveness)
4. Direct or Hematogenous spread more common than lymphatic channel spread (< 10% lymphatic)–> LN mets rare (20%), distant mets more common (65%)
5. Distant mets: Bone MOST COMMON, Liver, lung, brain

PROGNOSIS:
- Recurrence ~30%
- Overall worse prognosis compared to PTC
- 5-year survival 70%

Factors that worsen prognosis:
1. Age > 50
2. > 4cm tumor
3. High grade
4. Marked vascular/angio invasion
5. ETE
6. Distant mets at diagnosis
7. > 4 foci

Question 70

Regarding Follicular thyroid cancer, discuss:
1. How is it typically diagnosed?
2. Describe the histopathology
3. What clinical markers can be used?
4. What are the categories of follicular carcinoma?

Answer 70

DIAGNOSIS:
- Impossible on FNA (requires capsular/vascular invasion on diagnosis, therefore need to see capsule)
- Differentiation between follicular adenoma & carcinoma depends on histologic capsular or vascular invasion, which requires evaluation of the entire thyroid nodule
- 20% of follicular neoplasm have carcinoma

CYTOLOGY: (Alone is not enough for diagnosis)
1. Small follicular arrays/solid sheets of cells
2. Follicular lumens have NO/minimal colloid
3. Architecture depends on degree of tumor differentation

HISTOLOGY: (Frozen section not enough)
1. Capsular invasion present
2. Potential microvascular invasion of vessels along tumor capsule
3. High mitotic rate
4. Necrosis
5. Widespread nuclear atypia
6. Usually unifocial, multicentricity uncommon

CLINICAL MARKERS: None useful

CATEGORIES OF FOLLICULAR CARCINOMA: (need to evaluate entire capsule)
1. Minimally invasive tumors
- Evidence of invasion INTO but not through tumor capsule at 1 or more sites
- No small-vessel invasion
2. Frankly invasive tumors
- Invasion through tumor capsule AND has small vessel invasion

Question 71

Discuss the overall treatment for follicular neoplasm.
What are the indications for total thyroidectomy? 6

Answer 71

1. Follicular neoplasm:
   - Subtotal lobectomy (including isthmus)
   - Ultrasound follow up to monitor (20% malignant)
2. Total thyroidectomy indications:
   - Older age
   - > 4cm (risk 50% cancer)
   - Family history of thyroid cancer
   - Radiation exposure
   - Patient preference
   - Completion after diagnosis of follicular adenoma (Angioinvasion)

Question 72

Regarding Hurthle cell tumors, discuss:
1. What are they? What patient population are they most common in?
2. What cells are they derived from?
2. Clinical presentation
3. Histopathological findings
4. Management. What type of imaging would you do? What is the treatment?
5. What is the post-op management for these patients?
5. Prognosis

Answer 72

HURTHLE CELL TUMORS:
- Subtype of Follicular cell neoplasm (“follicular carcinoma, oxyphillic type; different than PTC, oxyphillic type)
- Found in patients with Hashimoto’s thyroiditis or Graves’ or within a nodular goiter
- Derived from Oxyphilic cells of the thyroid gland (akin to C-cells but arise within the follicular cells)
- Hurthle cells express TSH receptors and produce thyroglobulin
- ~3-10% incidence of all WDTCs

CLINICAL PRESENTATION:
- Hurthle cell neoplasm typically diagnosed by FNAc (~20% lesions are malignant)
- 3% of all thyroid malignancies are Hurthle cell carcinoma
- Mean age older than follicular carcinoma
- Behave more aggressively than PTC or FTC
- Multifocal and bilateral at presentation
- More likely to metastasize to cervical nodes and distant sites

CYTOLOGY:
- Hypercellularity
- Presence of rich granular eosinophilic cells - sheets of eosinophilic cells packed with mitochondria

HISTOLOGY:
- Capsular or vascular invasion confirms HCC

MANAGEMENT:
1. Workup may include PET-CT scan
2. Similar to follicular neoplasms
3. Lobectomy sufficient for adenoma
4. Invasive findings/carcinoma warrant total or completion thyroidectomy (ie. Hurthle cell carcinoma)
- Hurthle cell carcinoma is more aggressive and less amenable to RAI (decreased tendency to uptake RAI)
- Examine for local disease extension given risk of mets

5. Post-op management:
   - TSH suppression
   - Thyroglobulin monitoring
   - Periodic US evaluation for central and lateral cervical compartments
   - 99m Tc scan for persistent local or metastatic disease
   - 123I scan and ablation may be considered to remove residual normal thyroid tissue (Oxyphillic cells / C cells don’t take up iodine well - ~10% take up RAI)

PROGNOSIS:
- Worse than follicular carcinoma
- Highest incidence of distant metastases among the WDTC
- 5 year - 70% without metastasis, 20% with
- 10 year - 40%

Vancouver 147 images

Question 73

Indications for Total / Completion thyroidectomy

Answer 73

1. > 4cm tumor
2. T4 tumor
3. ≥ N1
4. M1

https://www.liebertpub.com/doi/full/10.1089/thy.2015.0020 Table 14

Question 74

When do you decide whether the patient needs radioactive iodine ablation following thyroidectomy?

Answer 74

Based on ATA2015 risk stratification - see next card

Intermediate risk - Consider ablation
High risk - Ablation

Question 75

Outline the ATA risk stratification tool for low risk (4) + 7

Answer 75

ATA LOW RISK:

1. Papillary thyroid carcinoma with ALL of the following:
   - No local or distant mets
   - All macroscopic tumor has been resected
   - No tumor invasion of locoregional tissues or structures
   - The tumor does not have aggressive histology (e.g. tall cell, hobnail, columnar)
   - If 131-I is given, there are no RAI-avid metastatic foci outside the thyroid bed on the first post-treatment whole-body RAI scan
   - No vascular invasion
   - Clinical N0 or ≤5 pathologic N1 micrometastasis (< 0.2cm in largest dimention
2. Intrathyroidal, encapsulated folliicular variant of papillary thyroid cancer
3. Intrathyroidal, well differentiated follicular thyroid cancer with capsular invasion, and no or minimal (< 4 foci) vascular invasion
4. Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E mutated (if known)

https://www.liebertpub.com/doi/full/10.1089/thy.2015.0020

Table 11

Question 76

What is the ATA intermediate stratification? 6

Answer 76

ATA INTERMEDIATE RISK:
1. Microscopic invasion of tumor into the perithyroidal soft tissues
2. RAI-avid metastatic foci in the neck on the first post-treatment whole-body RAI scan
3. Aggressive histology (e.g. tall cell, hobnail variant, columnar cell carcinoma)
4. Papillary thyroid carcinoma with vascular invasion
5. Clinical N1 or >5 pathologic N1 with all involved lymph nodes < 3cm in largest dimension
6. Multifocal papillary microcarcinoma with ETE and BRAFV600E mutated

Question 77

What is the ATA high risk stratification? 6

Answer 77

ATA HIGH RISK:
1. Macroscopic invasion of tumor into the perithyroidal soft tissues (gross ETE)
2. Incomplete tumor resection
3. Distant metastases
4. Postoperative serum thyroglobulin suggestive of distant metastases
5. Pathologic N1 with any metastatic lymph node ≥3cm in largest dimension
6. Follicular thyroid cancer with extensive vascular invasion (>4 foci of vascular invasion)

Question 78

Describe the ATA risk staging and discuss through each category whether post-surgical RAI is indicated or not

Answer 78

LOW RISK:

1. T1a N0/Nx, M0/Mx (Tumor size ≤1cm, uni or multifocal)
   - No indication for RAI
2. T1b, T2, N0/Nx, M0/Mx (Tumor size 1-4cm)
   - Conflicting data on whether RAI improves disease free survival
   - No evidence of disease-specific survival
   - Not routinely indicated, but may be considered for patients with intermediate risk features (aggressive histology or vascular invasion)

LOW TO INTERMEDIATE RISK:

1. T3, N0/Nx, M0/Mx (with Tumor > 4cm)
   - Conflicting data on whether RAI improves disease-free or disease-specific survival
   - Consider RAI especially if presence of adverse features.
   - Advancing age may favour RAI use in some cases, but specific age and tumor size cutoffs subject to some uncertainty
2. T3, N0/Nx, M0/Mx (with Microscopic ETE, of any tumor size)
   - No evidence RAI improves disease-specific survival, but conflicting on whether it improves DFS
   - RAI generally favoured based on risk of recurrent disease. Smaller tumors with microscopic ETE may not require RAI
3. T1-3, N1a, M0/Mx (With central compartment neck LN metastases)
   - Possibly group ≥45 yo benefit from RAI DSS, but conflicting for DFS
   - RAI generally favoured, due to somewhat higher risk of persistent or recurrent disease; especially in: (1) Increasing number of large >2-3cm or (2) clinical evidence LN or (3) ENE or (4) Advancing age
   - Insufficient data to mandate RAI in patients with few < 5 microscopic nodal metastases in central compartment in absence of other adverse features
4. T1-3, N1b, M0/Mx (with Lateral neck or mediastinal LN metastases)
   - Similar evidence levels to #3 above for DSS/DFS
   - RAI generally favoured due to higher risk of persistent or recurrent disease, especially with increasing number of macroscopic or clinically evident LN or presence of ENE, or advanced age

HIGH RISK
- Indications for RAI for pretty much anything with high risk features
- RAI for T4, Any N, Any M
- RAI for M1, Any T, Any M

Table 14 https://www.liebertpub.com/doi/full/10.1089/thy.2015.0020

Question 79

What are the complications of radioactive iodine treatment? 8
What are some considerations, especially to fertile females/males, that should be taken with RAI?

Answer 79

1. Salivary gland damage (sialadenitis) - 150-200mCi
2. Tumor swelling (due to increased TSH and iodine) - thyroiditis or hemorrhage
3. Dental damage
4. Nasolacrimal duct obstruction
5. Long term dysphagia
6. Secondary malignancy (absolute excess risk of 4.6 per 10000 - very low) - commonly salivary gland, leukemia, breast, and bladder
7. Transient infertility (recommendation is to avoid trying to get pregnant for at least 6 months)
8. Others: case reports of pulmonary fibrosis following treatment of lung metastasis

Considerations:
- Women of child-bearing age should have negative bHCG prior to RAI and avoid pregnancy for 6-12 months after RAI
- Do not give RAI to nursing women (if possible, delay until women have stopped breastfeeding or pumping for at least 3 months)
- Men receiving >400mCi should be counseled on potential risks of infertility

Question 80

Regarding Thyrogen and Thyroid Hormone Withdrawal, discuss:
1. What is it thyroid hormone withdrawal?
2. What is thyrogen?
3. What are the indications for use?

Answer 80

THYROID HORMONE WITHDRAWAL:
- A method to produce high levels of TSH in patients by stopping thyroid hormone medication and causing short-term hypothyroidism; OR by using Thyrogen
- This is mainly used in thyroid cancer patients before treating with radioactive iodine or performing a whole body scan - so that the thyroid will want to “uptake” more (because it is craving thyroid hormone)

THYROGEN:
- rhTSH = Recombinant human thyrotropin
- Acceptable alternative to thyroid homrone withdrawal for achieving remnant ablation

INDICATIONS:
- ATA intermediate risk - ok to use for DTC
- ATA high risk - more data needed before recommending this medication

Note: In patients with DTC of any risk level with significant comorbidity (psych, medical, inability to tolerate endogenous TSH with withdrawal, pituitary problem) that may preclude thyroid hormone withdrawal prior to iodine RAI administration, then consider thyrogen

Question 81

Regarding RAI dosing and protocol, discuss:
1. What is the necessary doses required for each stage of disease?
2. What is a typical protocol for treatment?
3. Other considerations to be done during treatment?

Answer 81

DOSAGE:
- Remnant ablation for ATA low risk: 30mCi (If less than total or near total thyroidectomy is performed may need more mCi)
- RAI for adjuvant treatment of microscopic residual disease: up to 150mCi (uncertain if >150mCi will reduce disease recurrence for T3 or N1)

PROTOCOL:
1. Low iodine diet for 2 weeks for patients undergoing RAI
2. Ideal TSH > 25 pre-treatment
3. Day 1+2 = Thyrogen injection
4. Day 3 = RAI
5. Post-ablation scan 3-5 days
6. Whole Body Scan - 6-12 months for intermediate/high risk (recommended to inform disease staging and document RAI avidity of any structural disease)
7. Avoid > 150mCi in patients > 70
8. Maximum accumulated dose:
- Pediatric - 500mCi
- Adults - 700-1000mCi

Half life = 8 days

No recommendation can be made about types of RAI that should be administered for locoregional recurrence

Question 82

What are 3 thyroid cancers that cannot be treated with radioactive iodine?

Answer 82

1. Medullary (no TSH receptors)
2. Hurthle cell (Use EBRT)
3. Anaplastic (Systemic therapy or EBRT)

“MAH”

Question 83

What is considered RAI-refractory DTC? 4

Answer 83

1. Malignant/metastatic tissue doesn’t ever concentrate RAI on first therapeutic Whole Body Scan
2. Tumor loses ability to concentrate RAI after previously concentrating it
3. RAI is concentrated in some lesions but not in others
4. Metastatic progression despite concentration of RAI

Question 84

What are the 5 treatment options for thyroid metastases that do not pick up RAI?

Answer 84

1. Surgical excision
2. Ethanol injections
3. Radiofrequency or laser ablation under local anesthesia (not first line)
4. Stereotactic radiotherapy
5. EBRT - not RAI sensitive or non-surgical candidate
6. Systemic therapy tyrosine kinase inhibitors (levatinib) - multi-kinase inhibitor (VEGFR), fibroblast growth factor receptor inhibitor (FGFR)

Question 85

What are 4 indications for post-op EBRT for thyroid cancer?

Answer 85

1. Advanced locoregional WDTC whether superficial excision is complete or incomplete
2. Tumor no longer concentrates radioiodine
3. Palliation of unresectable bone metastasis
4. Hurthle cell carcinoma

Question 86

What is the role of directed therapy in advanced thyroid cancer?

Answer 86

• Can consider stereotactic radiation and thermal ablation for individual distant metastasis as an alternative to surgery
• Stereotactic radiation/ thermal ablation > chemotherapy
• Surgical resection and stereotactic radiation are the mainstays of therapy for CNS metastasis (consider RAI if the mets concentrate RAI. If going to use RAI, consider stereotactic rads and steroids prior to decrease the risk of cerebral edema)

Question 87

What are the different types of systemic therapies for thyroid cancer that can be considered?
What are the indications for kinase inhibitors? 4
What are the indications for bisphosphonates? 1

Answer 87

Systemic therapies:
1. Kinase inhibitors - many share common target of VEGF receptor VEGFR (e.g. Sorafenib, Lenvatinib, Pazopanib, Sunitinib, Axitinib, Cabozatinib, and Vandetanib)
2. Other selective therapies
3. Convenitional chemotherapy
4. Bisphosphonates
5. Denosumab

1. KINASE INHIBITORS:

Kinase inhibitors are considered in RAI refractory patients with:
1. Metastases
2. Rapidly progressive
3. Symptomatic
4. Imminently threatening disease not amenable to control using other approaches

• If patient fails first line kinase inhibitor, without any adverse effects, can consider second line kinase inhibitor

2. CYTOTOXIC CHEMOTHERAPY:
   - Same indications as kinase inhibitors
   - In generally, work well
3. BISPHOSPHONATES or DENOSUMAB
   - Patients with diffuse or symptomatic bony metastasis from RAI refractory disease
   - Denosumab (receptor activator of nuclear factor kappa-B ligand inhibitor - RANKL)

Question 88

What are the side effects of kinase inhibitors? 6

Answer 88

• Diarrhea
• Fatigue
• Induced hypertension (requiring initiation of antihypertensive therapy in about half of all previously normotensive individuals)
• Hepatotoxicity
• Skin changes
• Nausea
• Increased LT4 dosage requirement
• Changes in taste
• Weight loss

Question 89

What are the current FDA approved targeted agents for advanced thyroid cancer treatment?

Answer 89

• Cabozantinib and Vandetanib (medullary thyroid cancer)
• Lenvatinib and Sorafenib (differentiated thyroid cancer)
• Combination dabrafenib/trametinib (anaplastic thyroid cancer)

CV
LS
DT

Question 90

What are two lab markers of recurrent well differentiated thyroid cancer?

Answer 90

1. Thyroglobulin
2. Anti-thyroglobulin antibody

Question 91

How are the initial disease responses classified for thyroid cancer?

Answer 91

Allows for recurrence risk estimates

1. Excellent response: No clinical, biochemical, or structural evidence of disease (TSH-stimulated Tg of < 1ng/mL)
2. Biochemical incomplete response: Abnormal Thyroglobulin or rising anti-Tg antibody levels in absence of localizable disease
3. Structural incomplete response: Persistent or newly identified locoregional or distant metastasis
4. Indeterminate response: Non-specific biochemical or structural findings that cannot be confidently classified as either benign or malignant
5. Stable or declining anti-Tg antibody levels without structural evidence of disease
6. Disease free: No clinical imaging (RAI uptake) evidence of disease + Tg in the target range

Question 92

What is the long term follow-up of thyroid cancer patients?

Answer 92

• Generally follow up q3mo x 2 years, q6mo x 3 years, then annually for life

Bloodwork:
- Follow up should measure Tg, anti-Tg, T4, TSH, and neck ultrasound

Long-term treatment:
1. TSH should be suppressed (start at 1.6-2.2mcg/kg and titrate) - normal TSH 0.5-5.
- Need to be aware of subclinical hyperthyroidism - tachyarrhythmias, atrial fibrillation, osteoporosis, early menopause

Question 93

What is the level of immediate TSH suppression therapy vs long term TSH suppression therapy?

Answer 93

Post-op TSH suppression based on ATA risk category:
1. High risk: TSH –> < 0.1 mU/L
2. Intermediate risk: TSH –> 0.1-0.5
3. Low risk (and undetectable serum Tg levels) –> lower end of reference range (0.5-2)
4. Low risk + low detectable Tg levels –> 0.1-0.5
5. Low risk and lobectomy –> 0.5-2 while surveillance is continued, may not need T4

Long term suppression therapy:
1. Structural incomplete < 0.1mU/L indefinitely
2. Biochemically incomplete 0.1-0.5
3. High risk but excellent /indeterminate = 0.1-0.5 x 5 years then reduce and reassess
4. Low risk and excellent/indeterminate = 0.5-2
5. No post op RAI, but excellent/indeterminate response, normal neck US and undetectable/low Tg = 0.5-2mU/L

Question 94

At a post-thyroidectomy follow up, Tg = 0, but detected anti-Tg. What is the significance?

Answer 94

• Presence of anti-Tg antibodies signifies that absence of Tg is likely misleading
• Signifies biochemically incomplete response to treatment
• Should prompt additional investigations (imaging) and treatment (radioactive iodine)

Question 95

Discuss post-treatment ultrasound surveillance for thyroid cancer

Answer 95

• Cervical ultrasound should be performed 6-12 months post-op, and then periodically depending on patient’s ATA risk category and Tg
• Ultrasound suspicious LNs > 8-10mm = FNAb + Tg measurement in washout fluid
• LN < 8-10mm in smallest diameter may be followed without biopsy (biopsy if growth or node threatens vital structures)

Note: Low risk patients who have had remnant ablation, negative cervical US and low serum Tg on thyroid suppressive therapy can be followed primarily with clinical exam and thyroglobulin measurement without U/S
- If Tg increases –> Stop suppressive therapy –> iodine uptake scan

Question 96

Where are the common locations for distant thyroid metastases?

Answer 96

• Mediastinum
• Liver
• Lung
• Bone

Question 97

Regarding medullary thyroid cancer, discuss:
1. What is the pathophysiology and origin?
2. What does it secrete?
2. What is the epidemiology, age of onset?
3. What is the clinical presentation? What % of mets are present at presentation?
4. What are the genetics?
5. What is the prognosis? 5 and 10 year survival? Which subtypes are the worst to best prognosis among the hereditary MTC?

Answer 97

PATHOPHYSIOLOGY:
- Originates from parafollicular C-cells or neuroectodermal origin - originates in lateral portion of superior pole (therefore do not uptake iodine!)
- Secretes Calcitonin, CEA, serotonin, prostaglandins, and histaminidases

EPIDEMIOLOGY:
- 1-2% of all thyroid cancers in the US
- 75% sporadic (more solid)
- 25% familial (multicentric)
- Age of onset younger (20-30) in familial; mean age 50 in sporadic

CLINICAL PRESENTATION:
- Male = Female
- Neck mass with palpable LN common (50% have LN or distant mets on initial presentation)
- Invasive behaviour is common
- Multifocal disease common if hereditary form

GENETICS:
- 70% Sporadic (multiple genetic hits to manifest = worse prognosis)
- 30% RET oncogene (familial/MEN2a/b - Autosomal dominant, 100% penetrance)

PROGNOSIS:
- 88% 5 year survival
- 65% 10 year survival (45% if cervical nodes)
- Worst = MEN2B –> Sporadic –> MEN 2A –> Familial (best outcome)

Question 98

Describe the histopathology of medullary thyroid cancer.
What are the pathognomonic findings?
What are the IHC stains?

Answer 98

GROSS PATHOLOGY:
1. Solid, firm, gray cut surface
2. Unencapsulated but well circumscribed

HISTOLOGY:
1. Sheets of infiltrating neopalstic cells, heterogeneous size/shape
2. Cells separated by collagen, amyloid, dense irregular calcification
3. AMYLOID Deposits (polymerized calcitonin) PATHOGNOMONIC –> demonstrates apple green birefringence with congo red stain
4. More aggressive features: Increased mitotic figures, nuclear polymorphism, areas of necrosis

IHC STAINS:
1. Calcitonin (most sensitive and specific)
2. NSE - Neuron Specific Enolase
3. Chromogranin A
4. Synaptophysin
5. CEA (sensitive, not specific)
6. Congo red stain

Vancouver 152

Question 99

FNA returns positive for medullary thyroid cancer, what are the three initial tests that should be ordered?

Answer 99

1. Neck Ultrasound (should’ve been done already)
2. RET gene mutation DNA analysis (often analysis is done in chunks, with the first analysis done on only the “hotspot” exons. If RET comes back negative, or phenotype is inconsistence with RET negative, ask them to sequence the remaining exons) - do not screen for pheo or hyperpara prior to RET testing!
3. Calcitonin and CEA levels
   - Can be false elevated in < 3 years old, M > F
   - If CEA significantly > calcitonin, suggestive of poorly differentiated CEA

Question 100

If RET mutation is positive, what further management tests are required prior to surgery?

Answer 100

RET Mutation Positive = Familial or MEN2A/B
- Therefore, must screen for MEN syndrome

Management:
1. Offer genetic counselling to patient and first degree relatives
2. Evaluate for hyperparathyroidism (PTH, iCa)
3. Evaluate for pheochromocytoma (24h urine metanephrines and catecholamines or plasma fractionated metanephrine; AND MRI Abdomen)

If you miss a pheo, patient will die during surgery! (not good!)

Question 101

What are the 3 indications to investigate for distant metastasis on the initial work up of MTC? What imaging tests should be done to do so?

Answer 101

INDICATIONS:
1. Calcitonin > 500 pg/mL
2. Extensive neck disease
3. SIgns or symptoms of distant metastasis

TESTS:
1. CT Neck and chest with contrast
2. Three phase CT contrast enhanced multi-detector of the liver, or MRI of liver
3. Axial MRI
4. Bone scintigraphy
5. Note: PET scan is NOT recommended

Question 102

Describe the surgical management of thyroid and neck in medullary thyroid carcinoma?

Answer 102

THYROID:
- Total Thyroidectomy

NECK: Controversial; some recommend only operating on US positive nodes in central and lateral neck, but others recommend elective neck dissection based on Calcitonin level
1. Calcitonin < 20 –> no neck dissection
2. Calcitonin 20-200 –> Ipsilateral central and lateral neck dissection
3. Calcitonin > 200 –> Bilateral central and lateral neck dissection

Question 103

Describe how the parathyroids should be managed in medullary thyroid carcinoma?
What happens if all 4 parathyroids are enlarged?

Answer 103

1. Sporadic or MEN2B
   - Auto-transplant into muscle
2. MEN 2A with NO hyperparathyroidism
   - Reimplant into remote site in case hyperparathyroidism ever evolves
3. MEN 2A with hyperparathyroidism
   - Remove visibly enlarged
   - If all four enlarged, see below

In patients with hyperparathyroidism, only patients with visibly enlarged parathyroids should be resected at the time of surgery.

If all four are enlarged, then:
1. Subtotal parathyroidectomy with part of 1 gland left in situ on a vascular pedicle
2. Total parathyroidectomy with heterotopic autograft (grafting into a different site that is not the neck - so don’t have to go back to the same spot later to get it if needed)
- Per Cummings, can also mark the parathyroid so easy to identify when coming back to it

Question 104

What are the adjuvant radiation therapies for medullary thyroid carcinoma? Indications for radiation EBRT 4

Answer 104

1. No role for RAI (MTC is not RAI avid)
2. Post-op adjuvant EBRT to neck and mediastinum should be considered in high risk for local recurrence, including:
   - Microscopic or macroscopic residual MTC
   - Extrathyroidal extension
   - Extensive LN metastasis
   - Those at risk of airway obstruction

Question 105

Regarding systemic therapy for medullary thyroid cancer, discuss:
1. What are the indications 2
2. What are the contraindications 2
3. What are the options 2

Answer 105

INDICATIONS:
1. Metastatic disease
2. DIsease that is not surgically amenable

CONTRAINDICATIONS (or relative):
1. Not recommended as primary monotherapy (poor response rate)
2. Should not be given to patients with increasing calcitonin and CEA levels without documented metastatic disease, or patients with stable low volume disease (no change on imaging, calcitonin and CEA double times > 2 years)

OPTIONS:
1. TKI targeting RET, VEFFR, EGFR (Vandetanib/Cabrzantinib)
- Shown benefit in advanced, progressive, and refractory disease

Question 106

If after hemithyroidectomy, you discover MTC, what is the treatment protocol?

Answer 106

1. Completion thyroidectomy if: RET mutation, elevated calcitonin (above normal), or imaging suggestive of residual disease
2. In patients having an inadequate LN dissection at initial thyroidectomy, Completion compartment-oriented ND if pre-op Calcitonin < 1000 and < 5 LN removed

Question 107

Describe the post-operative follow up for patients with medullary thyroid carcinoma

Answer 107

1. At 3 months –> calcitonin and CEA measured
2. Every 6 months x 1 year
3. Then yearly afterwards

TSH suppression not necessary (parafollicular cells)

Question 108

On post-thyroidectomy follow up, calcitonin is found to be above the normal range but < 150pg/mL. What are the management recommendations?

Answer 108

1. Look for local recurrence: Physical exam and neck ultrasound
2. If negative, repeat calcitonin and US in 6 months to obtain the doubling time

Question 109

On post-thyroidectomy follow up, calcitonin is found to be above 150pg/mL. What are your management considerations?

Answer 109

1. Look for metastasis:
   - Neck ultrasound
   - Chest CT
   - Liver: contrast enhanced MRI or 3-phase contrast enhanced CT of the liver
   - Bone: Bone scintigraphy and MRI of the pelvis and axial skeleton
2. If neck positive above, neck dissection is recommended (not “berry picking”)
3. Distant metastases can be treated with surgical resection

Question 110

How is CEA doubling time used in predicting survival in MTC?

Answer 110

1. < 6 months = 5-year 25%, 10-year 8%
2. > 6 months = 5-year 92%, 10-year 37%

Question 111

Discuss the RET gene - what is it, how is it affected in MTC?
What is your chance of MTC with a RET positive mutation?

Answer 111

RET = Proto-oncogene on chromosome 10
- Rearranged during transfection
- Encodes tyrosine kinase receptor
- Mutation = “gain of function mutation”
- RET positive = 90% MTC within 20 years

Question 112

Regarding MEN 1, discuss:
1. What is the genetics and inheritance?
2. What are the clinical features and what percentage of people have these?
3. What is the treatment?

Answer 112

MEN 1 = “WERMER SYNDROME”

GENETICS/INHERITANCE:
- Autosomal dominant
- Chromosome 11, Menin gene (tumor suppressor gene)

FEATURES: “PPP”
1. Pituitary lesions / adenoma (e.g. prolactinoma) - 30-65%
2. Parathyroid adenoma - 90%
3. Pancreatic tumors / adenomas (e.g. gastrinoma, insulinoma) - 60-75%

TREATMENT:
- Often includes subtotal parathyroidectomy with thymectomy (to remove any parathyroid glands and prevent thymic carcinoid tumors)

Question 113

Regarding MEN2, discuss:
1. What is the genetics and Inheritance?
2. What are the similarites and differences between MEN2a and MEN2b?

Answer 113

GENETICS/INHERITANCE:
- Autosomal dominant
- RET proto-oncogene mutation on chromosome 10

MEN 2A/2B:
1. Medullary thyroid carcinoma - 100%
2. Pheochromocytoma (50%)

MEN2A: 95% (Sipple Syndrome)
- Parathyroid adenoma/hyperplasia –> Hyperparathyroidism (30%)

MEN2B: (Wagenmann-Froboese)
- Marfanoid habitus (100%)
- Multiple mucosal neuromas (100%), hyperplastic corneal nevus

Question 114

Regarding MEN2A, discuss the classic clinical features and 3 other types of phenotypes

Answer 114

MEN2A: 95% (SIPPLE SYNDROME) - “PPM”

Classic:
1. Medullary thyroid carcinoma - 100%
2. Pheochromocytoma - 50%
3. Parathyroid adenoma

Other types:
1. MEN2A with CLA (cutaneous lichenoid amyloidosis)
2. MEN2A with Hirchsprung’s disease
3. Familiial Medullary thyroid carcinoma - RET germline mutation with MTC but no pheo or hyperparathyroidism

Question 115

Regarding MEN2B, discuss the clinical features and overall presentation

Answer 115

1. Medullary thyroid carcinoma - 100%
2. Pheochromocytoma/PGL - 50%
3. Marfanoid habitus - 100%
4. Mucosal neuromas (e.g. tongue neuromas) - 100%

Overall presentation:
- Rarest and most aggressive inherited MTC syndrome
- Presents 10 year earlier than MEN2A
- > 95% codon 918
- NO hyperparathyroidism

Vancouver 154

Question 116

What are 3 endocrinome anomalies in MEN syndromes?

Answer 116

1. Hyperparathyroidism
2. Increased catecholamines (pheo)
3. Increased serotonin in Carcinoid, more common in MEN1, but can happen in MEN2 - screen for 24 hour 5-HIAA urine

Question 117

What are 10 clinical signs of Marfan’s syndrome?
What is the inheritance pattern?

Answer 117

AUTOSOMAL DOMINANT

“MARFANS”
M: Mitral valve collapse
A: Aortic root dilation
R: Retinal detachment
F: Flat feet
A: Arachnodactyly (long, spiderly fingers)
N: Nearsighted
S: Subluxed lens, scoliosis, SNHL (or other hearing loss CHL/mixed)

Other features:
1. Tall and thin body structure
2. Hammer toe
3. PIgeon breast
4. Long head (Dolichocephaly)
5. Low hairline

Question 118

What is the pheochromocytoma rule of 10s?

Answer 118

1. 10% bialteral
2. 10% malignant
3. 10% extra-adrenal

Question 119

What are the 3 categories of risk for medullary thyroid carcinoma based on the RET gene mutations?

Answer 119

1. ATA-HST (Highest) - M918T
2. ATA-H (High) - C634F, A883F
3. ATA-Mod (Moderate) - All others

Question 120

Discuss the management of a child with M918T RET mutation (ATA-HST risk) 3

Answer 120

• Generally only seen in MEN2B:

1. Total thyroidectomy in first year of life (prophylactic)
2. Prophylactic Level VI Neck dissection (only if parathyroids can be identified and managed)
3. Screen for pheochromocytoma starting at age 11 (and check pre-op)
4. No need to screen for hyperparathyroidism (MEN2B don’t get this)

Question 121

Discuss the management of a child with C634F and A883F mutations (ATA-H risk)

Answer 121

• Generally seen only in MEN2A

At 3 years of age, start annual:
1. Physical exam
2. Ultrasound
3. Calcitonin levels

Treatment:
1. Total thyroidectomy by age 5, earlier if increased calcitonin detected
2. Prophylactic central neck dissection if Calcitonin > 40 pg/ml or nodal positive on exam/Ultrasound

Other:
1. Screen for pheochromocytoma starting age 11 (and pre-op)
2. Screen for hyperparathyroidism at age 11
3. Always treat the pheochromocytoma first

Question 122

Discuss the management of a child with ATA-MOD risk (ie. all other RET mutations)

Answer 122

At 5yo, there are two options:
1. q6 months vs. annual physical exam, ultrasound, and calcitonin level (may extend for years or decades)
2. Total thyroidectomy

Other:
1. Screen for pheochromocytoma starting age 16 (or pre-op)
2. Screen for hyperparathyroidism starting age 16

Question 123

Discuss the management considerations if a pheochromocytoma is identified pre-operatively

Answer 123

Avoid hypertension crisis:
1. Pre-op removal; OR
2. Pre-op alpha adrenergic blockade (phenoxybenzamine) or alpha-methyltyrosine

Question 124

Regarding Anaplastic thyroid cancer, discuss:
1. What is the epidemiology? What is the common age, gender, and risk factor of patients patients who get this?
2. What are the genetics involved?
3. What is the clinical presentation? What % present with local and distant mets?
4. What is the differential?
4. What are the classic growth patterns?
5. What investigations could be done?

Answer 124

EPIDEMIOLOGY:
- Rare
- Age > 60 year
- F > M (3:2)
- May arise from existing / WD thyroid cancer (80%) - risk factors including previous papillary CA (transformation of this subtype), follicular cancer, follicular adenoma

GENETICS:
- 40% BRAF (target treatment BRAF V600E)
- 30% RAS
- 50% tp53

CLINICAL PRESENTATION:
- Rapidly growing neck mass, pain, large, fixed to trachea/larynx
- Symptoms of invasion/compressive symptoms
- Vocal fold paralysis
- 80% nodal mets at presentation
- 50% distant mets at presentation
- Differential: Poorly differentiated thyroid cancer, laryngeal cancer, B-cell lymphoma

GROWTH PATTERNS: “BPS”
1. Biphasic spindle cell
2. Pleomorphic giant cell
3. Squamoid
Tumors may show features of all 3

INVESTIGATIONS:
1. FNA biopsy
2. Formal open neck biopsy r/o lymphoma
3. Molecular studies for targeted treatment

Question 125

What is the histopathology of anaplastic thyroid cancer?

Answer 125

GROSS PATHOLOGY:
1. Necrosis
2. Macroscopic invasion
3. Lymph node involvement

HISTOPATHOLOGY:
- Sheets of heterogeneous cells
- Spindle, polygonal, giant multi-nucleated cells with occasional foci of WDTC
- High mitotic rate, infiltration
- No thyroglobulin, no iodine transport, no thyroid hormone receptors

Question 126

Discuss the workup of anaplastic thyroid carcinoma

Answer 126

1. Whole body FDG-PET scan preferred ± MRI Brain
2. Endoscopic exam of larynx ± esophagoscopy
3. MDT referral + palliative care
4. Establish a diagnosis via biopsy before proceeding with surgical management, as surgery may be inappropriate (rule out lymphoma)
5. Expedite BRAF V600E mutation molecular testing

Question 127

Discuss the treatment of anaplastic thyroid carcinoma.
What are the systemic therapies offered depending on the type of mutation?

Answer 127

1. Avoid trach if at all possible

If T4a/b and R0/R1 anticipated:
- Surgery is preferred (total thyroidectomy)
- IMRT within 6 weeks / systemic therapy within 1 week

If R2/non-surgical: IMRT ± Tyrosine Kinase inhibitors recommended
- Dabrafinib/Trametanib (TKI/MEK)
- If no BRAF mutation identified: PD-1 inhibitor (Pembrolizumab)
- If NTRK mutation positive: Larotrectanib/Entrectanib
- If RET mutation positive: Salpercaptinib/Pralsetinib
- If no mutation: Cisplatin/Carboplatin ± Taxanes

Radiotherapy: 60Gy in 40 fractions over 4 weeks
- No role for RAI (Do not take up iodine)

Question 128

What is the general prognosis of anaplastic thyroid cancer?

Answer 128

Death in 2-6 months
- Asphyxiation
- Vena cava syndrome
- Exsanguination

Question 129

Regarding thyroid lymphoma, discuss:
1. What is the epidemiology?
2. What are the risk factors? 3
3. What is the types of lymphoma commonly seen, and clinical presentation?
4. How is it typically diagnosed? Stains?
5. What is the treatment?
6. What is the prognosis? Survival at 5 years?

Answer 129

EPIDEMIOLOGY:
- < 1% of all thyroid malignancies (Vancouvers ~5%)
- More common than anaplastic carcinoma

RISK FACTORS:
1. Hashimoto’s disease (70x risk!!) - Chronic lymphocyte stimulation leads to resultant lymphocyte transofmration/deregulation
2. Age over 50-60
3. F:M 3:1

SUBTYPES (from most to least common): “NHP”
1. Non-hodgkin B-cell type (immunoblastic)
2. Hodgkin
3. Plasmacytoma

CLINIICAL PRESENTATION:
- Can mimic anaplastic: rapidly enlarging neck mass, compressive/invasive symptoms
- But typically PAINLESS (unlike anaplastic that is more painful)
- Dysphagia
- VF paralysis
- Hypothyroid/Hashimoto’s
- Look for associated adenopathy

DIAGNOSIS:
1. Look for other involved nodal groups
2. Core/open biopsy
3. Stains: POSITIVE for LEUKOCYTE ANTIGEN

TREATMENT:
1. CHOP (Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone)
2. Thyroidectomy/ND can be considered depending on symptoms of airway compromise if not quickly responding to treatment
3. ± XRT

PROGNOSIS:
- 85% survival if intrathyroidal
- 45% survival if extrathyroidal
- Overall survival at 5 year ~ 50%

Question 130

Regarding carcinoma in the thyroglossal duct cyst, discuss:
1. What is the epidemiology?
2. How is it typically worked up? List 2 investigations and why
3. What are other possible diagnoses?
4. What are the treatment options?

Answer 130

EPIDEMIOLOGY:
- Rare
- < 1% TGDC
- 73% are diagnosed incidentally after Sistrunk procedure

WORKUP:
- FNA
- Ultrasound or CT - critical to ensure presence of intact thyroid in the neck

POSSIBLE DIAGNOSES:
1. Papillary and follicular (over 90%)
2. SCC - thought to arise from cyst lining

TREATMENT (Controversial):
1. If discovered incidentally on pathology from a Sistrunk procedure, perform total thyroidectomy only if suspicious of multifocal disease or if RAI is anticipated
2. If malignancy discovered prior to surgery, some advocate for total thyroidectomy

Question 131

What are the boundaries of Lore’s triangle, and what does it identify?

Answer 131

Identifies location of RLN in the neck during thyroidectomy

• Medial: Tracheal sidewall
• Lateral: Carotid sheath
• Superior: Surface of retracted thyroid pole inferiorly

Question 132

What are the four branches of the thyrocervical trunk?

Answer 132

1. Ascending cervical: supplies prevertebral muscle region
2. Transverse cervical: Supplies the trapezius muscle (mid and lower island flap)
3. Inferior thyroid: to inferior pole of thyroid gland
4. Suprascapsular

Thyrocervical trunk = originates off the 1st portion of the subclavian artery

Question 133

What are 3 instances when median sternotomy will be likely necessary for a retrosternal goiter?

Answer 133

• Cannot feel the mass in the neck
• Goiter very low or posterior in the mediastinum
• Cannot finger dissect the retrosternal mass

Question 134

Regarding insular thyroid carcinoma, discuss:
1. What is it?
2. What is the histology?
3. What is the prognosis and treatment?

Answer 134

INSULAR THYROID CARCINOMA:
- Insular: Named for the cluster of cells containing small follicles, resembling pancreatic islet cells
- Very rare, independent lesion or concomitantly with PTC or FTC

HISTOLOGY:
- Stain for Thyroglobulin antibodies
- DO NOT stain for calcitonin
- Capsular and vascular invasion typically present at diagnosis
- Angioinvasion hallmark of insular thyroid carcinoma

PROGNOSIS:
- More aggressive, with increased recurrence and decreased survival
- Focal insular carcinoma within FTC/PTC not adversely affecting recurrence/survival

TREATMENT:
- Many insular thyroid carcinomas can concentrate radioiodine

Question 135

What are the most common cancers that metastasize to the thyroid? 5
How is this typically treated?

Answer 135

1. Hypernephroma (renal cell adenocarcinoma or clear cell carcinoma of kidney) - most common
2. Kidney
3. Breast
4. Lung
5. Skin (melanoma)
6. Bronchogenic

Treatment:
- Thyroidectomy can be considered for palliation, especially if primary lesion is very slow growing (E.g. renal cell carcinoma)

Question 136

Regarding SCC of the thyroid, discuss:
1. What is the epidemiology?
2. What are the risk factors?
3. Workup?
4. Treatment?

Answer 136

EPIDEMIOLOGY:
- Very rare
- Fraction of 1% of all thyroid cancer
- Can progress rapidly with local invasion and metastases

RISK FACTORS:
- Older age

WORKUP:
- Rule out metastasis from another

TREATMENT:
1. Surgical
2. Adjuvant radiation generally indicated (similar to other SCC of H/N)