Thyroid Neoplasms Flashcards

Question

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 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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%)

Answer 20

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

Answer 21

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 ## Footnote NOTABILITY NOTES

Answer 22

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)

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

Hurthle cell (50-60% five year survival)

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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%

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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 ## Footnote Vancouver 147 image Psammoma bodies: https://prod-images-static.radiopaedia.org/images/1048/fd8b8137aaadae2c3c486ba9e029dc_gallery.jpeg

Answer 38

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%)

Answer 39

Vesicular, "ground glass" nuclei (looks like coffee beans) ## Footnote Vancouver Pg 147

Answer 40

- 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

Answer 41

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)

Answer 42

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

Answer 43

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

Answer 44

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)

Answer 45

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

Answer 46

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

Answer 47

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)

Answer 48

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% ## Footnote Vancouver 147 images

Answer 49

1. >4cm tumor 2. T4 tumor 3. ≥ N1 4. M1 ## Footnote https://www.liebertpub.com/doi/full/10.1089/thy.2015.0020 Table 14

Answer 50

Based on ATA2015 risk stratification - see next card Intermediate risk - Consider ablation High risk - Ablation

Answer 51

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) ## Footnote https://www.liebertpub.com/doi/full/10.1089/thy.2015.0020 Table 11

Answer 52

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

Answer 53

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)

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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

Answer 58

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

Answer 59

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

Answer 60

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)

Answer 61

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

Answer 62

- 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)

Answer 63

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)

Answer 64

- 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

Answer 65

- Cabozantinib and Vandetanib (medullary thyroid cancer) - Lenvatinib and Sorafenib (differentiated thyroid cancer) - Combination dabrafenib/trametinib (anaplastic thyroid cancer) CV LS DT

Answer 66

1. Thyroglobulin 2. Anti-thyroglobulin antibody

Answer 67

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

Answer 68

- 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

Answer 69

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

Answer 70

- 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)

Answer 71

- 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

Answer 72

- Mediastinum - Liver - Lung - Bone

Answer 73

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)

Answer 74

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 ## Footnote Vancouver 152

Answer 75

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

Answer 76

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!)

Answer 77

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

Answer 78

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

Answer 79

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

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

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)

Answer 84

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

Answer 85

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

Answer 86

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

Answer 87

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

Answer 88

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)

Answer 89

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

Answer 90

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

Answer 91

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 ## Footnote Vancouver 154

Answer 92

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

Answer 93

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

Answer 94

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

Answer 95

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

Answer 96

- 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)

Answer 97

- 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

Answer 98

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

Answer 99

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

Answer 100

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

Answer 101

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

Answer 102

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

Answer 103

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)

Answer 104

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

Answer 105

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%

Answer 106

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

Answer 107

Identifies location of RLN in the neck during thyroidectomy - Medial: Tracheal sidewall - Lateral: Carotid sheath - Superior: Surface of retracted thyroid pole inferiorly

Answer 108

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

Answer 109

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

Answer 110

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

Answer 111

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)

Answer 112

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)