Thyroid Cancer

John P. Christodouleas and Updated by Mark Edson

BACKGROUND

Name the anatomic subdivisions/lobes of the thyroid.

Subdivisions/lobes of the thyroid:

1. Right lobe

2. Left lobe

3. Isthmus

4. Pyramidal lobe (in 50% of individuals is remnant of thyroglossal duct)

In the thyroid follicle, what are the normal functions of the epithelial follicular cells and the parafollicular cells?

Epithelial follicular cells: remove iodide from the blood and use it to form T₃ and T₄ thyroid hormones

Parafollicular cells (C cells): lie just outside of the follicle cells and produce calcitonin

What is the most common endocrine malignancy?

Thyroid cancer (TCa) is the most common endocrine malignancy, but is only 1% of all diagnosed malignancies.

What is the incidence of new TCa Dx and deaths in the U.S.?

There are an estimated 60,000 new Dx and 1,850 deaths in 2013.

What are the 3 main TCa histologies in decreasing order of frequency?

Differentiated (follicular-derived) thyroid carcinoma (DTCa) (∼94%) > medullary (2%–4%) > anaplastic (2%)

What are the 3 subtypes of DTCa in decreasing order of frequency?

Papillary (80%–90% of all TCa) > follicular > Hürthle cell carcinoma

What is happening to the incidence of diagnosed papillary TCa?

The incidence of papillary TCa is increasing (by ∼15% over the past 40 yrs, largely driven by better surveillance/detection).

What is the typical age at Dx for follicular vs. papillary TCa?

Follicular incidence peaks at 40–60 yrs of age, whereas papillary peaks at 30–50 yrs of age.

Is there a sex predilection for papillary or follicular TCa?

Yes. Both papillary and follicular TCa more commonly affect females than males (3:1).

What is the strongest risk factor for papillary TCa?

RT exposure to the H&N as a child is the strongest risk factor for papillary TCa. There is no increased risk if exposure is after age 20 yrs. Most papillary cases are sporadic.

Name 4 genetic disorders associated with papillary TCa.

Genetic disorders associated with papillary TCa:

1. Familial polyposis

2. Gardner syndrome

3. Turcot syndrome

4. Familial papillary carcinoma

Name a genetic disorder associated with follicular TCa.

Cowden syndrome (PTEN gene mutation) is associated with follicular TCa.

Medullary TCa arises from what precursor cell?

Medullary TCa arises from the calcitonin-producing parafollicular C cells.

Name 2 genetic syndromes associated with medullary TCa.

MEN 2a and MEN 2b (RET gene mutation) are associated with medullary TCa.

What % of medullary TCa is related to a genetic syndrome?

~25% of medullary TCa is related to a genetic syndrome.

Name the nerve that lies in the tracheoesophageal (TE) groove, post to the right/left thyroid lobes.

The recurrent laryngeal nerve lies in the TE groove.

What are the primary, secondary, and tertiary lymphatic drainage regions of the thyroid?

Primary: central compartment (level VI), TE groove, Delphian (prelaryngeal) LNs

Secondary: cervical, supraclavicular, and upper mediastinal LNs (levels III–IV, VII)

Tertiary: upper cervical (level II)/retropharyngeal LNs

WORKUP/STAGING

What % of palpable thyroid nodules are malignant?

Only 5% of palpable thyroid nodules are malignant.

In a pt with low TSH and a nodule that shows uptake by I-123 or Tc-99 scan, what is the likely Dx?

Adenomas commonly present with low TSH and increased uptake on I-123 or Tc-99 scans.

Which DTCa subtypes are difficult to distinguish from adenomas on FNA?

Follicular and Hürthle subtypes are difficult to distinguish from adenomas. Histologically, they show only follicular structures. Papillary TCa shows both papillary and follicular structures, which helps to distinguish it from adenomas.

What pathologic criteria must be met to make the Dx of Hürthle cell TCa?

The Dx requires hypercellularity with >75% Hürthle cells (also referred to as oncocytic cells), which are characterized by abundant eosinophilic granular content.

Which TCa subtype is more likely to present with N+ Dz: papillary or follicular?

Papillary TCa (~30% node+) is more likely to spread to LNs than follicular (∼10% node+).

Name the 2 major and 3 minor prognostic factors for DTCa.

Major: age and tumor size (15–44 yo, ≤4 cm, respectively, have better prognosis)

Minor: histology, local tumor extension, LN status

What variables constitute the mnemonic AMES risk group system?

Age, Metastasis, Extent, Size

Which pts are low risk?

1. Young (males <41 yo, females <51 yo), no DMs

2. Older with minor tumor capsule involvement and tumor <5 cm and no DMs

For DTCa, what sizes distinguish AJCC 7th edition T1, T2, and T3 tumors?

T1: <2 cm (T1a if <1 cm; T1b if >1 cm)

T2: 2–4 cm (limited to thyroid)

T3: >4 cm with only min extrathyroidal extension

What is the difference between T4a and T4b TCa lesions?

T4a: local extension but still technically resectable

T4b: unresectable Dz

What is the difference between N1a and N1b in TCa?

N1a: mets to level VI LNs (pre-/paratracheal, prelaryngeal)

N1b: mets to levels I–V, VII (cervical neck, upper mediastinal) or retropharyngeal LNs

List the latest AJCC 7^th-edition (2011) stage groupings for papillary and follicular TCa.

Stage I: M0 and age <45 yrs or T1N0 and age ≥45 yrs

Stage II: M1 and age < 45 yrs or T2N0 and age ≥45 yrs

Stage III: T3N0 or T1–3N1a and age ≥45 yrs

Stage IVA: T4a or N1b and age ≥45 yrs

Stage IVB: T4b and age ≥45 yrs

Stage IVC: M1 and age ≥45 yrs

What is unique about the staging of DTCa?

It is age dependent; it differs for pts > or <45 yo.

Can a pt <45 yo with follicular or papillary TCa have stage III or IV Dz?

No. A pt <45 yo with follicular or papillary TCa cannot have stage III or IV Dz.

What is the stage of a 37-yo pt with DTCa and a solitary bone met?

Stage II. If the pt were 65 yo, he or she would be stage IVc.

What is the stage of a 45-yo pt with an unresectable primary DTCa and no mets?

Stage IVb. If the pt were 44 yo, he or she would be stage I.

What must be done prior to an I-123 or I-131 scan?

TSH stimulation must be done prior to an iodine scan.

What are 2 ways to do TSH stimulation?

TSH stimulation can be accomplished through thyroid hormone withdrawal or by using recombinant TSH.

What are some advantages of recombinant TSH stimulation?

Fewer side effects and a shorter period of elevated TSH (theoretically, a lower risk of tumor progression)

What are the approved indications for recombinant TSH stimulation?

Recombinant TSH is approved for follow-up iodide scans and for the I-131 Tx of low-risk pts.

What sites of the body show a physiologic uptake of iodide?

The salivary glands and the GI tract show physiologic uptake due to the presence of iodide transporters.

Which DTCa subtype has a better long-term prognosis: papillary or follicular?

Papillary has a better 10-yr OS at ∼93% (vs. 85% for follicular).

Is the presentation and Tx of Hürthle cell carcinoma more similar to that of papillary or follicular TCa?

It is more similar to follicular TCa; however, Hürthle cell carcinoma has a slightly higher DM rate and worse prognosis (10-yr OS ∼76%).

Estimate the 10-yr OS for pts with localized vs. N+ medullary TCa.

For localized medullary TCa, the 10-yr OS is ∼90%. If N+, the 10-yr OS is ~70%.

What are the stage groupings for anaplastic TCa?

All anaplastic TCa is stage IV. Stage IVA is resectable, stage IVB is unresectable, and stage IVC is metastatic.

Estimate the MS and the 1-yr OS for pts with anaplastic TCa.

MS is ~6 mos and the 1-yr OS is ~20% for pts with anaplastic TCa.

Does the tall cell variant have a more favorable or unfavorable prognosis when compared to classic papillary TCa?

The tall cell variant has an unfavorable prognosis (10-yr OS ∼75%) when compared to classic papillary carcinomas.

What is the most frequent site of DM in papillary and follicular TCa?

Lung (∼50%), followed by bone, CNS.

TREATMENT/PROGNOSIS

Generally, what is the Tx paradigm for DTCa?

DTCa Tx paradigm: primary surgery (even in M1 Dz) → observation vs. adj Tx

What are the 3 surgical options in TCa?

Surgical options in TCa are:

1. Lobectomy + isthmusectomy

2. Near-total thyroidectomy

3. Total thyroidectomy

What is the difference between near-total and total thyroidectomy?

Near-total is less aggressive around the recurrent laryngeal nerve.

For which pts with papillary TCa is a lobectomy + isthmusectomy adequate?

This is controversial. It is a good option for pts with none of the following risk factors: age >45 yrs, tumor >4 cm, aggressive histology variant, prior Hx of RT, DM, N+, local extension, and +margins.

In addition to improved LC, what is another reason to advocate for a total thyroidectomy even in low-risk pts?

It allows for easier follow-up with whole-body iodide scans and serum thyroglobulin.

Per NCCN guidelines (Version 2.2013), what are 4 indications for recommending adj Tx after GTR in DTCa?

Indications for adj Tx after GTR in DTCa are (if any present):

1. >4-cm tumor

2. DM

3. Extensive vascular invasion

4. pT4 (gross extrathyroidal extension)

What are the 5 aggressive histologic subtypes of DTCa that merit consideration of adj Tx?

Aggressive histologic subtypes that merit consideration of adj Tx are:

1. Tall cell

2. Columnar cell

3. Insular cell

4. Oxyphilic

5. Poorly differentiated

Generally, what is the adj Tx paradigm for DTCa?

DTCa adj Tx paradigm: long-term TSH suppression alone or with I-131 +/- EBRT

What are the indications for adj I-131 in addition to TSH suppression for DTCa?

Suspected or proven residual normal thyroid tissue or residual tumor are indications for adj I-131.

What is the mCi dose range to ablate residual normal thyroid tissue?

30 mCi is as effective as 100 mCi to ablate residual normal thyroid tissue in low-risk DTCa (Mallick U et al., NEJM 2012).

What is the mCi dose range to ablate a residual DTCa lesion?

The dose to ablate a residual DTCa lesion is 100–200 mCi.

What are the 4 indications for adj EBRT in addition to TSH suppression and I-131 in TCa?

Indications for adj EBRT in addition to TSH suppression and I-131 are:

1. pT4 papillary and ≥ 45 yo

2. Gross residual Dz in the neck after I-131

3. Bulky mets after I-131

4. Lesions with inadequate iodide uptake

What 3 regions should be irradiated with EBRT in a pt ≥45 yo with pT4 papillary TCa?

Thyroid bed, bilat neck, and the upper mediastinal nodes

What is the prognosis for pts with locoregional vs. distant recurrence of DTCa?

The prognosis is excellent if recurrence is locoregional (long-term OS is 80%–90%). It is much worse with distant recurrences.

What are the typical EBRT doses for DTCa?

Gross Dz: 66–70 Gy, positive margins: 63–66 Gy

Microscopic Dz: 60 Gy

–Nodal basins: 50–54 Gy

Generally, what is the Tx paradigm for medullary TCa?

Medullary TCa Tx paradigm: definitive surgery and EBRT for palliation

Generally, what is the Tx paradigm for anaplastic TCa?

Anaplastic TCa Tx paradigm: max safe resection → adj CRT; taxane, and/or doxorubicin, and/or platin chemo with conventional or hyperfractionated EBRT (Smallridge RC et al., Thyroid 2012)

For which group of anaplastic TCa pts does PORT improve survival?

Per a recent SEER analysis (Chen J et al., Am J Clin Oncol 2008), PORT improved survival in pts with T4b/extrathyroid extension of Dz but not for those with T4b/thyroid-confined or stage IVC/metastatic Dz.