Radiation Oncology: A Question-Based Review

Thyroid Cancer

John P. Christodouleas and Vincent J. Lee

image Background

Name the 4 anatomic subdivisions/lobes of the thyroid.

Subdivisions/lobes of the thyroid:

1.     Right lobe

2.     Left lobe

3.     Isthmus

4.     Pyramidal lobe

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

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

2.     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.

TCa represents what % of all diagnosed human cancers?

TCa is rare and only represents 1% of all diagnosed malignancies.

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

Main TCa histologies (in decreasing order of frequency): follicular-epithelial derived (FED) (~94%) > medullary (2%–4%) > anaplastic (2%)

What are the 3 subtypes of FED TCa in decreasing order of frequency?

Subtypes of FED TCa (in decreasing order of frequency): papillary > follicular > Hurthle cell carcinoma

What is the incidence of papillary TCa in autopsy series?

30%–40% of cases have “microcarcinomas.”

What is happening to the incidence of diagnosed papillary TCa?

The incidence of papillary TCa is increasing (approximately by 15% over the past 40 yrs).

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 gender 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 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 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?

1.     Primary: central compartment (level VI), TE groove, delphian nodes

2.     Secondary: cervical/supraclavicular nodes

3.     Tertiary: sup mediastinal/retropharyngeal nodes

image 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 FED subtypes are difficult to distinguish from adenomas on FNA?

Follicular and Hurthle subtypes are difficult to distinguish from adenomas. Histologically, they show only follicular structures. Papillary TCa shows both papillary and follicular structures that help to distinguish it from adenomas.

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

The Dx requires hypercellularity with >75% Hurthle 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 FED TCa.

1.     Major: age, tumor size

2.     Minor: histology, local tumor extension, LN status

For FED TCa, what sizes distinguish T1, T2, and T3 tumors?

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

2.     T2: 2–4 cm (limited to thyroid)

3.     T3: >4 cm with only min extrathyroidal extension

What is difference between T4a and T4b TCa lesions?

1.     T4a: local extension but still technically resectable

2.     T4b: unresectable Dz

What is the difference between N1a and N1b in TCa?

1.     N1a: mets to pre/paratracheal nodes, prelaryngeal nodes (level VI)

2.     N1b: mets to cervical neck (levels I–V), upper mediastinal nodes

List the latest AJCC 7th edition stage groupings for papillary and follicular TCa.

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

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

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

4.     Stage IVA: T4a or N1b and age ≥45 yrs

5.     Stage IVB: T4b and age ≥45 yrs

6.     Stage IVC: M1 and age ≥45 yrs

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 delphian node?

The delphian node is a prelaryngeal node that is often involved in TCa.

What is unique about the staging of FED TCa?

The staging of FED is age dependent; it differs for pts greater or less than 45 yo.

What is the stage of a 37-yo pt with FED TCa 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 FED TCa 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 % of pts with FED TCa will have residual uptake on an iodide scan after thyroidectomy?

~80% of pts will have residual uptake after thyroidectomy.

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 FED 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 Hurthle cell carcinoma more similar to that of papillary or follicular TCa?

It is more similar to follicular TCa; however, Hurthle 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 considered 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 when compared to classic papillary carcinomas.

image Treatment/Prognosis

Generally, what is Tx paradigm for FED TCa?

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

What are the 3 surgical options in TCa?

Surgical options in TCa:

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, what are 4 possible indications for adj Tx after GTR in FED TCa?

Indications for adj Tx after GTR in FED TCa:

1.     >1-cm tumor

2.     N+ or DM

3.     Aggressive histologic subtypes

4.     pT4 + papillary histology and age ≥45 yrs

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

Aggressive histologic subtypes that merit consideration of adj Tx:

1.     Tall cell

2.     Columnar cell

3.     Insular cell

4.     Oxyphilic

5.     Poorly differentiated

Generally, what is the adj Tx paradigm for FED TCa?

FED 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 FED TCa?

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?

30–100 mCi is the dose range to ablate residual normal thyroid tissue.

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

The dose to ablate a FED TCa 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 supression and I-131:

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 necks, and the upper mediastinal nodes

What are the typical EBRT doses (in 2 Gy/fx) for FED TCa?

1.     Gross Dz: 68–70 Gy

2.     Microscopic Dz: 60 Gy

3.     −Nodal basins: 45–50 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; promising results with postop cisplatin/doxorubicin before and after 40 Gy in bid fractionation (De Crevoisier R et al., IJROBP 2004)

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 those with T4b/thyroid-confined or stage IVC/metastatic Dz.

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

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

image Toxicity

What are the acute side effects of >100 mCi of I-131?

GI irritation, sialadenitis, and cystitis

What are the 3 most important long-term side effects of >100 mCi of I-131?

Pulmonary fibrosis, oligospermia, and leukemia

What does the follow-up of TCa pts entail?

TCa follow-up: H&P + TSH/thyroglobulin levels at 6 and 12 mos, then annually if no Dz; neck US; TSH-stimulated iodine scans if clinically indicated

What kind of additional imaging can be considered if the I-131 scan is neg-ative but the stimulated thyroglobulin level is elevated?

If the I-131 scan is negative but the stimulated thyroglobulin level is elevated, PET/CT can be considered.

What is the max recommended lifetime dose for I-131?

The max recommended lifetime dose is 800–1,000 mCi.