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Table Of Contents
  1. Differentiated Thyroid Cancer
  2. Medullary Thyroid Cancer
  3. Anaplastic Thyroid Cancer

Differentiated Thyroid Cancer

Initial Evaluation of Thyroid Nodules

Tables & Figures

Table 4. Familial & Heritable Forms of Thyroid Cancer
Familial Adenomatosis Polyposis
GeneAPC
Benign Thyroid Disease40%
Cancer0.4–12%
Cancer TypesCMV-PTC: 63%
FV-PTC: 25%
PTC: 12%
PTEN-Hamartoma Tumor (Cowden)
GenePTEN
Benign Thyroid Disease75%
Cancer35%
Cancer TypesPTC: 50%
FV-PTC: 28%
FTC: 14%
Carney Complex Type 1
GenePRKARIA
Benign Thyroid Disease≤ 75%
Cancer< 5%
Cancer TypesPTC
FTC
RET-Associated
GeneRET
Benign Thyroid Disease—
Cancer100%
Cancer TypesMTC
DICER1
GeneDICER1
Benign Thyroid Disease≤ 30%
Cancer—
Cancer TypesFTC
FV-PTC

CMV = Cribiform Morular Variant; FV = Follicular Variant
Percentages refer to disease prevalence.

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Bethesda System
Bethesda Category I
MeaningNon Diagnostic
Estimated Risk of Malignancy5–10%
Bethesda Category II
MeaningBenign
Estimated Risk of Malignancy0–3%
Bethesda Category III
MeaningAtypia of Undetermined Significance (AUS) / Follicular Lesion of Undetermined Significance (FLUS)
Estimated Risk of Malignancy10–30%
Bethesda Category IV
MeaningSuspicious for a Follicular (or Hürthle Cell) Neoplasm
Estimated Risk of Malignancy25–40%
Bethesda Category V
MeaningSuspicious for Malignancy
Estimated Risk of Malignancy50–75%
Bethesda Category VI
MeaningMalignant
Estimated Risk of Malignancy97–99%

As reported in The Bethesda System by Cibas and Ali (DOI 10.1007/978-3-319-60570-8).

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Figure 1. ATA Pattern-Based Ultrasound Findings vs TIRADS Point-based System
ATA Pattern-Based Ultrasound Findings vs TIRADS Point-based System
Figure 1 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the AAES
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Figure 2. ACR TI-RADS Classification of Thyroid Nodules
Figure 2. ACR TI-RADS Classification of Thyroid Nodules
Figure 2 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ACR TI RADS
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Initial Management

Tables & Figures

Figure 4. Levels of the Neck for Lymph Node Classification
Figure 4 Copyright © Jill Gregory TIRO THANC Foundation All rights reserved Available at httpstiroexpert
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Table 3. Anatomic Boundaries of the Neck Levels
Level I
Anterior
Anterior belly of the contralateral digastric muscle.
Posterior
Stylohyoid muscle
Superior
Body of the mandible
Inferior
Hyoid

Triangular boundaries comprising anterior bellies of digastric muscles and hyoid separates IA & IB.

Level II
Anterior
Stylohyoid muscle
Posterior
Posterior SCM
Superior
Skull base
Inferior
Hyoid

CN XI separates IIA & IIB. IIA nodes lie anterior to IJV.

Level III
Anterior
Sternohyoid muscle
Posterior
Stylohyoid muscle
Superior
Hyoid
Inferior
Horizontal plane defined by the cricoid cartilage.
Level IV
Anterior
Sternohyoid muscle
Posterior
Posterior SCM
Superior
Inferior border of the cricoid cartilage.
Inferior
Clavicle
Level V
Anterior
Posterior SCM
Posterior
Anterior border of trapezius.
Superior
Convergence of the SCM and trapezius.
Inferior
Clavicle

Inferior border of cricoid separates VA & VB.

Level VI
Anterior
Anterior layer of the cervical fascia.
Posterior
Deep layer of the cervical fascia.
Superior
Hyoid superiorly
Inferior
Sternal notch
Level VII
Anterior
Sternum
Posterior
Deep layer of the cervical fascia.
Superior
Sternal notch
Inferior
Innominate on right and equivalent plane on the left.

SCM = sternocleidomastoid muscle

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Initial Staging & Response to Therapy

Initial Staging

Tables & Figures

Table 5. AJCC Staging of Differentiated Thyroid Cancer (Disease Specific Mortality)
Age at Diagnosis
Younger than 55 Years
TNMStage Group
Any TAny NM0I
Any TAny NM1II
55 Years or Older
TNMStage Group
T1N0 / NXM0I
T1N1M0II
T2N0 / NXM0I
T2N1M0II
T3a / T3bAny NM0II
T4aAny NM0III
T4bAny NM0IV A
Any TAny NM1IV B
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Figure 10a. Definition of tumor size (T)
Figure 10a Copyright © Jill Gregory TIRO THANC Foundation All rights reserved Available at httpstiroexpert
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Figure 10b. Definition of regional lymph node (N)
Figure 10b Copyright © Jill Gregory TIRO THANC Foundation All rights reserved Available at httpstiroexpert
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Response to Therapy

Management Recommendations Based on Risk Stratification

Tables & Figures

Table 11. Risk Stratification System with Proposed Modifications (ATA 2009)
Risk Level
ATA Low Risk
  • Papillary thyroid cancer (with all of the following):
    • No local or distant metastases,
    • All macroscopic tumor has been resected,
    • No tumor invasion of loco-regional tissues or structures,
    • The tumor does not have aggressive histology (e.g. tall cell, hobnail variant, columnar cell carcinoma),
    • If I131 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 micrometastases (< 0.2 cm in largest dimension).*
  • Intrathyroidal, encapsulated follicular thyroid variant of papillary thyroid cancer.*
  • Intrathyroidal, well-differentiated follicular thyroid cancer with capsular invasion and no or minimal (< 4 foci) vascular invasion.*
  • Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E mutated (if known).*
ATA Intermediate Risk
  • Microscopic invasion of tumor into the perithyroidal soft tissues.
  • RAI-avid metastatic foci in the neck on the first post-treatment whole-body RAI scan.
  • Aggressive histology (e.g. tall cell, hobnail variant, columnar cell carcinoma).
  • Papillary thyroid cancer with vascular invasion.
  • Clinical N1 or > 5 pathologic N1 with all involved lymph nodes < 3 cm in largest dimension.*
  • Multifocal papillary microcarcinoma with ETE and BRAFV600E mutated (if known).*
ATA High Risk
  • Macroscopic invasion of tumor into the perithyroidal soft tissues (gross ETE).
  • Incomplete tumor resection.
  • Distant metastases.
  • Postoperative serum thyroglobulin suggestive of distant metastases.
  • Pathologic N1 with any metastatic lymph node ≥ 3 cm in largest dimension.*
  • Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion).*

* Proposed modifications, not present in the original 2009 initial risk stratification system.

The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.

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Figure 11. ATA Spectrum of Risk of Recurrence
risk of recurrence
The publisher for this copyrighted material is Mary Ann Liebert Inc publishers
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Figure 5. management recommendations in ATA low risk DTC patients who have undergone total thyroidectomy
Figure 5 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ATA
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Figure 6. management recommendations in ATA low risk DTC patients who have undergone less than total thyroidectomy
Figure 6 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ATA
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Figure 7. management recommendations in ATA intermediate risk DTC patients who have undergone total thyroidectomy
Figure 7 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ATA
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Figure 8. management recommendations in ATA high risk DTC patients who have undergone total thyroidectomy and have no gross residual disease
Figure 8 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ATA
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Figure 9. management recommendations in patients with Follicular Neoplasms
Figure 9 Copyright © TIRO THANC Foundation All rights reserved Available at httpstiroexpert
Adapted from the ATA
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Response to Therapy Based on Initial Management

Tables & Figures

Table 2a. Response to Therapy: Total Thyroidectomy & RRA (ATA compared to ESMO)

ATA // ESMO

Response to Therapy
Excellent
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
< 0.2 ng/mL
TSH-Stim TG
< 1 ng/mL
TgAB
• Not specified (ATA)
• Undetectable (ESMO)
Biochem Incomplete
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
1 ng/mL
TSH-Stim TG
10 ng/mL
TgAB
Rising TgAB levels
Structural Incomplete
Imaging
Evidence of structural or functional disease. *
TSH-Suppressed Tg
*
TSH-Stim TG
*
TgAB
*
Indeterminate
Imaging
Nonspecific findings on US/CT.
— OR —
Faint uptake in thyroid bed on RAI scanning.
TSH-Suppressed Tg
• Tg detectable, but < 1 ng/mL (ATA)
• 0.2–1 ng/mL (ESMO)
TSH-Stim TG
• Stimulated Tg detectable, but < 10 ng/mL (ATA)
• 1–10 ng/mL (ESMO)
TgAB
TgAB levels stable or declining in the absence of structural or functional disease.

* Regardless of Tg or TgAB levels.

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Table 2b. Response to Therapy: Total Thyroidectomy Alone

ESMO

Response to Therapy
Excellent
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
< 0.2 ng/mL
TSH-Stim TG
Not Specified
TgAB
Undetectable
Biochem Incomplete
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
Tg > 5 ng/mL
– OR –
Rising Tg values with similar TSH levels.
TSH-Stim TG
—
TgAB
Rising TgAB levels
Structural Incomplete
Imaging
Evidence of structural or functional disease. *
TSH-Suppressed Tg
*
TSH-Stim TG
*
TgAB
*
Indeterminate
Imaging
Nonspecific findings on US/CT.
— OR —
Faint uptake in thyroid bed on RAI scanning.
TSH-Suppressed Tg
< 0.2–5 ng/mL
TSH-Stim TG
Not Specified
TgAB
TgAB levels stable or declining in the absence of structural or functional disease.

* Regardless of Tg or TgAB levels.

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Table 2c. Response to Therapy: Lobectomy Alone

ESMO

Response to Therapy
Excellent
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
Stable
TSH-Stim TG
Stable
TgAB
Undetectable
Biochem Incomplete
Imaging
No relevant findings on imaging.
TSH-Suppressed Tg
Rising Tg values with similar TSH levels
TSH-Stim TG
TgAB
Rising
Structural Incomplete
Imaging
Evidence of structural or functional disease. *
TSH-Suppressed Tg
*
TSH-Stim TG
*
TgAB
*
Indeterminate
Imaging
Nonspecific findings on US/CT.
TSH-Suppressed Tg
*
TSH-Stim TG
*
TgAB
*

* Regardless of Tg or TgAB levels.

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Genetic Alterations & Histologic Features

Tables & Figures

Table 7. Gene Alterations & Histology
Phenotype
Toxic Adenoma

Known Somatic Genetic Mutation / Alterations

  • TSH-R
  • GNAS
Benign Thyroid Nodules

Known Somatic Genetic Mutation / Alterations

  • N-, H- and K-RAS
  • EIF1AX
Noninvasive Follicular Tumor with Papillary-like Features (NIFTP)

Known Somatic Genetic Mutation / Alterations

  • N-, H- and K-RAS
  • BRAF K601E
Infiltrative Follicular Variant Papillary Thyroid Carcinoma (FVPTC)

Known Somatic Genetic Mutation / Alterations

  • N-, H- and K-RAS
  • BRAF V600E
Papillary Thyroid Carcinoma (PTC)

Known Somatic Genetic Mutation / Alterations

  • RET/PTC
  • BRAF V600E
  • N-, H-, K-RAS
  • TERT
Columnar Cell, Tall Cell, Hobnail Variant PTC

Known Somatic Genetic Mutation / Alterations

  • BRAF V600E
Diffuse-sclerosing Variant PTC

Known Somatic Genetic Mutation / Alterations

  • RET/PTC
Follicular Thyroid Carcinoma (FTC)

Known Somatic Genetic Mutation / Alterations

  • N-, H- and K-RAS
  • PAX8/PPAR
  • PTEN
Hürthle Cell Carcinoma

Known Somatic Genetic Mutation / Alterations

  • NRAS
  • Genes in the PI3K-Akt Pathway
Poorly Differentiated Thyroid Carcinoma (PDTC)

Known Somatic Genetic Mutation / Alterations

  • N-RAS (Insular)
  • BRAF V600E
  • PIK3CA
  • RET/PTC
  • TERT
Anaplastic Thyroid Carcinoma (ATC)

Known Somatic Genetic Mutation / Alterations

  • N-RAS, BRAF V600E
  • PIK3CA
  • TP53
  • β-catenin
  • EIF1AX
Medullary Thyroid Carcinoma (MTC)

Known Somatic Genetic Mutation / Alterations

  • RET (Germ Line Mutation in Inherited MTC, Somatic Mutation)
  • N-, H- and K-RAS (Somatic Mutations)

Adapted with permission from Wolters Kluwer Health, Inc.: the author(s), titles of article, title of journal, volume number, issue number, inclusive pages and website URL to the journal page.

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Table 8. Histologic Subtypes of PTC
Subtype
Follicular-variant
Nuclear Features of PTC Present?
Yes
Characteristics
• RAS mutation more common.
• Follicular growth pattern.
Prognosis
10-year DSS 93%
Follicular-variant Encapsulated, Invasive
Nuclear Features of PTC Present?
—
Characteristics
• RAS mutation or PPARG rearrangement more common.
• Low rate of LNM.
Prognosis
10-year DSS ~100%
Follicular-variant Nonencapsulated / Infiltrative
Nuclear Features of PTC Present?
—
Characteristics
BRAF V600E more common.
Prognosis
Equivalent to classic / conventional PTC
Columnar Cell
Nuclear Features of PTC Present?
No
Characteristics
• Papillae lined by columnar cells with nuclear stratification.
• Large tumors with capsular invasion are associated with LNM and DM.
Prognosis
Variable
Cribiform Morular
Nuclear Features of PTC Present?
Occasionally
Characteristics
• Presence of morules—squamoid areas with intranuclear inclusions and nuclear clearing.
• Associated with Familial Adenomatosis Polyposis Syndrome.
Prognosis
Equivalent to classic / conventional PTC
Classic / Conventional
Nuclear Features of PTC Present?
Yes
Characteristics
LNM Common
Prognosis
• 5-year DSS 97.4%
• 10-year DSS 93%
Diffuse Sclerosing
Nuclear Features of PTC Present?
Yes
Characteristics
• Diffuse fibrosis.
• Dense lymphoid infiltration.
• Squamous metaplasia.
Prognosis
• 5-year DSS 96%
• Equivalent to high-risk PTC
Tall Cell
Nuclear Features of PTC Present?
Yes
Characteristics
• Extrathyroidal extension and LNM possible.
• > 30% cells are 2x tall as wide and eosinophilic cytoplasm.
Prognosis
5-year DSS 95.6%
Hobnail
Nuclear Features of PTC Present?
Yes
Characteristics
• Increased risk of DM.
• > 30% have hobnail features (eccentric nuclei and tapering cytoplasm).
• Syncytial or micropapillary clusters with apically placed nuclei.
• BRAF V600E or p53 positive
Prognosis
5-year DSS 83%

Adapted with permission from Wolters Kluwer Health, Inc.: the author(s), titles of article, title of journal, volume number, issue number, inclusive pages and website URL to the journal page.

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Use of Radioactive Iodine

Tables & Figures

Table 9. Remnant Ablation Decision Making
Tumor Description
Tumor ≤ 1 cm
ATA RiskLow
Disease specific survival
improved by RAI		No
Disease free survival
improved by RAI		No*
RAI indicatedNo
Tumor > 1–4 cm
ATA RiskLow
Disease specific survival
improved by RAI		No
Disease free survival
improved by RAI		Unclear data*
RAI indicatedNot routinely
Tumor > 4 cm
ATA RiskLow
Disease specific survival
improved by RAI		Unclear data*
Disease free survival
improved by RAI		Unclear data*
RAI indicatedConsider
Micro ETE (Any tumor size)
ATA RiskLow / Intermediate
Disease specific survival
improved by RAI		No
Disease free survival
improved by RAI		Unclear data*
RAI indicatedConsider
Central LN Mets
ATA RiskLow / Intermediate
Disease specific survival
improved by RAI		No
Disease free survival
improved by RAI		Unclear data*
RAI indicatedConsider
Lateral or Mediastinal LN Mets
ATA RiskLow / Intermediate
Disease specific survival
improved by RAI		No
Disease free survival
improved by RAI		Unclear data*
RAI indicatedConsider
Any Size Gross ETE
ATA RiskHigh
Disease specific survival
improved by RAI		Yes
Disease free survival
improved by RAI		Yes*
RAI indicatedYes
Distant Metastasis
ATA RiskHigh
Disease specific survival
improved by RAI		Yes
Disease free survival
improved by RAI		Yes*
RAI indicatedYes

* Conflicting observational data.

The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers. This table is reprinted and adapted from THYROID.

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Medullary Thyroid Cancer

Initial Evaluation of Thyroid Nodules Suspicious of MTC

Tables & Figures

Table 12. Most Common RET Mutations with Associated Risks
RET Mutation
Highest Risk Level (HST)
M918T
RET Exon16
Risk of Aggressive MTCHighest
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
Table 12. Most Common RET Mutations with Associated Risks

High Risk Level (H)
C634F/G/R/S/W/Y
RET Exon11
Risk of Aggressive MTCHigh
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism20–30%
A883F
RET Exon15
Risk of Aggressive MTCHigh
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
Moderate Risk Level (MOD)
G533C
RET Exon8
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
C609F/G/R/S/Y
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C611F/G/S/Y/W
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C618F/R/S
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C620F/R/S
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C630R/Y
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
D631Y
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
K666E
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
E768D
RET Exon13
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma–
Incidence of Hyperparathyroidism–
L790F
RET Exon13
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
V804L/M
RET Exon14
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism10%
S891A
RET Exon15
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism10%
R912P
RET Exon16
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma–
Incidence of Hyperparathyroidism–

Table adapted from Table 4, Wells et al, Revised ATA guidelines for the management of medullary thyroid carcinoma, Thyroid 2015. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.

Management of Inherited Forms

Tables & Figures

Figure 12. ATA Management of Patients with RET Germline Mutation Detected on Genetic Screening.
Figure 11. ATA Management of Patients with RET Germline Mutation Detected on Genetic Screening.
ATA American Thyroid Association risk categories for appressive medullary thyroid carcinoma MTC HST highest H high risk MOD moderate risk Ctn Calcitonin CEA carcinoembryonic antigen HPTH hyperparathyroidism PHEO pheochromocytoma RET REarranged during Transfection TTX total thyroidectomy US ultrasound
Table 12. Most Common RET Mutations with Associated Risks
RET Mutation
Highest Risk Level (HST)
M918T
RET Exon16
Risk of Aggressive MTCHighest
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
Table 12. Most Common RET Mutations with Associated Risks

High Risk Level (H)
C634F/G/R/S/W/Y
RET Exon11
Risk of Aggressive MTCHigh
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism20–30%
A883F
RET Exon15
Risk of Aggressive MTCHigh
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
Moderate Risk Level (MOD)
G533C
RET Exon8
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
C609F/G/R/S/Y
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C611F/G/S/Y/W
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C618F/R/S
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C620F/R/S
RET Exon10
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
C630R/Y
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10–30%
Incidence of Hyperparathyroidism10%
D631Y
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma50%
Incidence of Hyperparathyroidism–
K666E
RET Exon11
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
E768D
RET Exon13
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma–
Incidence of Hyperparathyroidism–
L790F
RET Exon13
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism–
V804L/M
RET Exon14
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism10%
S891A
RET Exon15
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma10%
Incidence of Hyperparathyroidism10%
R912P
RET Exon16
Risk of Aggressive MTCModerate
Incidence of Pheochromocytoma–
Incidence of Hyperparathyroidism–

Table adapted from Table 4, Wells et al, Revised ATA guidelines for the management of medullary thyroid carcinoma, Thyroid 2015. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.

Anaplastic Thyroid Cancer

Tables & Figures
Table 16. Panel of Routine Immunohistochemical Markers
IHC Marker
Pan-cytokeratins
DTC+++
PDTC+++
ATC+++/–
MTC+++
SCC+++
Lymphoma–
Thyroglobulin
DTC+++
PDTC+/–
ATC–
MTC–
SCC–
Lymphoma–
Thyroid-transcription factor 1
DTC+++
PDTC+/–
ATC–/+
MTC+/–
SCC–
Lymphoma–
BRAFV600E
DTC+/–
PDTC–/+
ATC–/+
MTC–
SCC–
Lymphoma–
PAX8
DTC+++
PDTC+++
ATC+/–
MTC+/–
SCC–
Lymphoma+/–a
Ki-67b
DTC< 5%
PDTC5–30%
ATC> 30%
MTC< 20%
SCC> 30%
Lymphomavariable
Chromogranin
DTC–
PDTC–
ATC–
MTC+++
SCC–
Lymphoma–
Calcitonin
DTC–
PDTC–
ATC–
MTC+++/–
SCC–
Lymphoma–
Carcinembryonic antigen
DTC–
PDTC–
ATC–
MTC+++
SCC–
Lymphoma–
p53
DTC– (rare +)
PDTC–/+
ATC+/–
MTC–
SCC+/–
Lymphoma+/–
CD45, other lymphoid markers
DTC–
PDTC–
ATC–
MTC–
SCC–
Lymphoma+++

“+” = relative positive staining; “–” = negative staining; “+/–” = variable positivity.
a PAX8 antibodies can cross-react with PAX5, which is expressed in lymphoid cells.
b Percentage of nuclei positive for Ki-67.
DTC = differentiated thyroid cancer; IHC = immunohistochemistry; MTC = medullary thyroid cancer; PDTC = poorly-differentiated thyroid cancer.

Table 13. T Staging for ATC
T Stage
T1

Description

< 2 cm

T2

Description

> 2 cm and < 4 cm

T3a

Description

> 4 cm

T3b

Description

Invasion of the strap muscles.

T4a

Description

Any size cancer with invasion of the larynx, trachea, esophagus, or the recurrent laryngeal nerve.

T4b

Description

Any size cancer with extension to the vertebrae or involvement of the carotid artery.

Adapted from the 8th edition AJCC.

Table 14. Prognostic Staging for ATC
Stage Group
IVA
T StageT1–T3b
N StageN0, NX
M StageM0
Survival Rate
IVB
T StageT1–T3a
N StageN1
M StageM0
Survival Rate
T StageT3b
N StageAny N
M StageM0
Survival Rate
T StageT4
N StageAny N
M StageM0
Survival Rate
IVC
T StageAny T
N StageAny N
M StageM1
Survival Rate

Adapted from the 8th edition AJCC.

Figure 13. Treatment Algorithm of ATC
1 Rapid initiation of radiation therapy for airway management can start with conventional non intensity modulated radiation therapy technique APPA using the QUAD shot 37Gy BID x 2 days regimen for 1 cycle and then pending on response either continue QUAD shot up to 46 cycles allow 14 weeks in between cycle pending on clinical scenario intensity modulated radiation therapy preferred or change to fractionated RT intensity modulated radiation therapy preferred Starting cytotoxic chemotherapy for disease control while urgently arranging for radiation therapy should be considered
2 Next generation sequencing to identify targetable mutations is recommended Specific inhibitors of oncogenic ALK NTRK or RET fusion mutations can be considered preferably within the context of a clinical trial
3 Chemo radiation Typically intensity modulated radiation therapy is given to 70 Gy to gross tumor 6066 Gy to the post op bed and 5054 Gy to potential microscopic residual disease regions with standard daily fractionation The dose of radiation can change if clinically indicated QUAD shot RT regimen can also be considered typically for M1 disease 37Gy BID x 2 days can give up to 46 cycles allow 14 weeks in between cycle pending on clinical scenario At MSKCC doxorubicin 20 mgm2 weekly or paclitaxel 50 mgm2 weekly is used throughout the radiation course but there are other reasonable regimens described in the literature
4 If resectable surgery followed by chemo radiation can be considered as an alternative to neoadjuvant BRAFiMEKi
5 Discontinue BRAF inhibitorMEK inhibitor therapy 2 days before surgery and resume 23 days after surgery
6 Discontinue BRAF inhibitorMEK inhibitor therapy 2 days before initiation of chemo radiation
7 Consider radiation therapy if it can be done without causing a significant delay in BRAF inhibitorMEK inhibitor therapy
Table 17. Mutations & Clinical Implications.
Mutations
BRAFV600E

Clinical Implications
Commonly seen in DTC which may be precursor to ATC.

Incidence in ATC
40–70% of ATCs and often seen in ATC arising from PTC.

RAS

Clinical Implications
Commonly seen in DTC which may be precursor to ATC.

Incidence in ATC
—

TP53

Clinical implications
Considered late stage in the carcinogenesis process. More commonly found in ATC.

Incidence in ATC
Found in 50–70% of ATC.

TERT

Clinical Implications
Considered late stage in the carcinogenesis process. More commonly found in ATC.

Incidence in ATC
Seen in 65–75% of ATC.

P13K/AKT

Clinical Implications
Considered late stage in the carcinogenesis process.

Incidence in ATC
30–40% of ATC.

EIF1AX

Clinical Implications
Often present with RAS mutations.

Incidence in ATC
—

None of the above mutations, although found in ATCs, is diagnostic for ATC.

Table 18. Specific Targetable Molecular Events
Molecular Target
BRAF
Agent
Dabrafenib (BRAF inhibitor )
Trametinib (MEK inhibitor)
ALK Fusions 
Agent
Crizotinib (ALK inhibitor)
TSC2
Agent
Everolimus (mTOR inhibitor)
PD-L1
Agent
Immunotherapy
NTRK Fusions
Agent
—