Initial Staging & Response to Therapy

Initial Staging & Response to Therapy

Clinical Outline

Educational Clips from TIROxMDS

1. Initial Staging & Assessing RTT

2. Follow-up Recommendations

A. Excellent Response to Therapy

ii. TSH Goals

D. Structural Incomplete Response to Therapy

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  • Differentiated Thyroid Cancer
    • Initial Evaluation of Thyroid Nodules
    • Initial Management
    • Initial Staging & Response to Therapy
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    • Use of Radioactive Iodine
    • Recurrent & Persistent Disease
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1. Initial Staging & Assessing Response to Therapy

A. The Process of Staging a Patient

ATA // AAES // ESMO // JAES // NCCN

1. Thyroid cancer management recommendations should be based on patient specific risk assessments.^​1–5​
2. AJCC/UICC TNM staging system is recommended for prediction of disease specific mortality.^​1–5​

Tables & Figures

Table 5. AJCC Staging of Differentiated Thyroid Cancer (Disease Specific Mortality)

Age at Diagnosis

Younger than 55 Years

T	N	M	Stage Group
Any T	Any N	M0	I
Any T	Any N	M1	II

55 Years or Older

T	N	M	Stage Group
T1	N0 / NX	M0	I
T1	N1	M0	II
T2	N0 / NX	M0	I
T2	N1	M0	II
T3a / T3b	Any N	M0	II
T4a	Any N	M0	III
T4b	Any N	M0	IV A
Any T	Any N	M1	IV B

Figure 10a. Definition of tumor size (T)

Figure 10b. Definition of regional lymph node (N)

3. A three-tiered risk stratification system (low, intermediate or high)^{​1–3,5​} or a four-tiered risk stratification system (very low, low, intermediate or high)^​4​ is recommended for predicting the risk of having persistent or recurrent disease.

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 BRAF^V600E 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 BRAF^V600E 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.

Figure 11. ATA Spectrum of Risk of Recurrence

4. Recognizing that the risk of structural disease recurrences is best thought of as a continuum rather than as discrete risk categories, the use of additional prognostic variables is recommended to further refine individual risk estimates.^​1–5​
   
   Factors Associated with Increasing Risk of Disease Recurrence^​1–5​
   • Age at diagnosis. Recurrence rates higher at extremes of age.
   • Increasing size of the primary tumor.
   • Increasing size of cervical lymph node metastases.
   • Increasing number of cervical lymph node metastases.
   • Extranodal extension in lymph node metastases.
   • Increasing extent of vascular invasion. Greater than 4 foci.
   • Potentially more aggressive histology. For example, tall cell variant papillary thyroid cancer, diffuse sclerosing variant papillary thyroid cancer, Hürthle cell carcinoma and poorly differentiated thyroid cancer.
   • Potentially aggressive mutational profile. For example, BRAF^V600E + TERT promoter mutation, or RAS + TERT promoter mutation.
   • Abnormal postoperative thyroglobulin at least 4–6 weeks after thyroid surgery.
   • Abnormal findings on post-operative diagnostic or post-radioactive iodine (I¹³¹) therapy whole body scans (if done).

5. The lowest risk of recurrence is associated with classic papillary thyroid cancer:
   • ≤ 1 cm.
   • Confined to the thyroid.
   • Without clinically apparent lymph node metastasis.
6. Initial risk estimates should be continually modified during follow-up as additional data is accumulated.^​1,3,5​
7. One method to facilitate ongoing risk assessment is to classify patients at each follow up based on their response to therapy as having either an:^​1,5​
   • Excellent Response. No clinical, biochemical, or structural evidence of disease.
   • Biochemical Incomplete Response. Abnormal Tg or rising anti-Tg antibodies in the absence of localizable disease.
   • Structural Incomplete Response. Persistent or newly identified loco-regional or distant metastases.
   • Indeterminate Response. Non specific biochemical or structural findings that cannot be confidently classified as either benign or malignant including patients with stable or declining anti-Tg antibodies without definitive structural evidence of disease.

2. Follow-up Recommendations After Response to Therapy is Established

A. Excellent Response to Therapy

ATA // ESMO // NCCN

In low and intermediate risk patients, an excellent response to therapy should lead to an early decrease in the intensity and frequency of follow-up and the degree of TSH suppression.^​1,3,5​

i. Follow-up Intervals

• In ATA low and intermediate risk patients, the time interval between Tg measurements can be lengthened to at least 12–24 months.^​1,3,5​
• Regardless of response to initial therapy, ATA high risk patients should have Tg determinations done at 6–12 month intervals for several years.^​1,5​

TSH stimulated Tg testing is not recommended for low and intermediate risk patients with an excellent response to therapy.^​1,3,5​

Non-stimulated Tg measurements should be considered in patients treated with either lobectomy or total thyroidectomy without radioactive iodine therapy.^​1,5​

Serum TSH should be measured at least every 12 months in all patients on thyroid hormone therapy.^​1,3​

ii. TSH Goals

•  In low and intermediate risk patients demonstrating an excellent response to therapy TSH goal can be in the low reference range (0.5–2 mU/L).^​1,3,5​
• In high risk patients with an excellent response to therapy, the ATA guidelines recommend keeping the TSH between 0.1–0.5 mU/L for up to 5 years, while the ESMO guidelines recommends a TSH goal of 0.5–2 mU/L.^​1,5​

Neck ultrasound can be done periodically depending on the patient’s risk for recurrence and Tg status.^​1,3,5​

• Following total thyroidectomy and radioactive iodine remnant ablation, low risk patients that achieve an excellent response can be followed primarily with clinical examination.^​1​
• In high risk patients that achieve an excellent response to therapy, periodic surveillance using neck ultrasound, CT scans, and/or MRI scans can be considered.^​1,5​

iii. Diagnostic Whole Body Scan

• In low risk or intermediate risk patients achieving an excellent response to therapy, routine diagnostic whole body radioactive iodine scans are not recommended.^​1,3,5​
• In ATA high risk or in intermediate risk with higher risk features, a diagnostic whole body radioactive iodine scan may be useful.^​1,3​

B. Indeterminate Response to Therapy

ATA // ESMO // NCCN

Serum Tg on thyroxine therapy should be measured every 6–12 months. More frequent Tg measurements may be appropriate for ATA high-risk patients.^​1,3,5​

i. TSH Goals

• It is generally recommended to maintain thyroid hormone therapy at a level to achieve serum TSH levels in a range of 0.1–0.5 mU/L for up to 5 years.^​1,5​
• In patients initially classified as low risk for recurrence, the serum TSH may be targeted within the low reference range (0.5–2 mU/L).^​1​
• After five years, the degree of TSH suppression can be reconsidered and potentially reduced with close surveillance.^​1​

Cervical US should be performed every 6–12 months.^​1,5​

In patients with abnormal or indeterminate US findings, TSH-stimulated radioiodine whole body scans together with Tg and Tg antibodies measurement can be considered.^​3​

In patients with elevated serum Tg or rising Tg antibodies with or without negative RAI imaging, CT scan of the chest and/or 18 FDG-PET should be considered.^​1,3,5​

Recurrence risk estimates should be reassessed and modified during follow-up.^​1,5​

Nonspecific findings that become suspicious over time or rising Tg or anti-Tg antibody levels can be further evaluated with additional imaging or biopsy when feasible.^​1​

If a positive result would change management, ultrasonographically suspicious lymph nodes ≥ 8–10 mm in the smallest diameter should be biopsied for cytology with Tg measurement in the needle washout fluid.^​1​

Suspicious lymph nodes < 8–10 mm in the smallest diameter may be followed without biopsy with consideration for FNA or intervention if there is growth or if the node threatens vital structures.^​1​

C. Biochemical Incomplete Response to Therapy

ATA // ESMO // NCCN

Follow-up should be performed at least every 6–12 months for several years, and then periodically depending on the patient’s risk and Tg status.^​1,3,5​

Serum TSH should be maintained between 0.1 and 0.5 mU/L, taking into account the initial ATA risk classification, Tg level, Tg trend over time, and risks associated with TSH suppression.^​1,5​

Neck ultrasonography is the main surveillance tool to identify either tumor bed recurrence or lymph node disease.^​1,3,5​

Stimulated Tg testing (following either recombinant human TSH or thyroid hormone withdrawal) may be considered in patients with a biochemical incomplete response following either additional therapies or a spontaneous decline in Tg over time in order to reassess response to therapy.^​1​

Functional assessment with TSH stimulated RAI imaging with either I¹²³ (preferable as it avoids stunning) or low activity (2–5 mCi or 74–185 MBq) I¹³¹ with SPECT/CT may be performed to determine suitability for RAI therapy.^​1,3,5​

F-18 FDG PET/CT ( with or without TSH stimulation) may be performed particularly for patients with negative RAI imaging but also in patients suspected of de-differentiated disease who may have neoplastic foci with no RAI uptake.  FDG PET positive lesions are associated with a worse prognosis and RAI refractory disease.^​1,3,5​

If further structural assessment is to be undertaken, then CT with iodine contrast or MRI is available.  Chest CT is undertaken for the diagnosis of pulmonary and/or mediastinal metastases. MRI brain, MRI skeletal survey and CT or MRI abdomen may be required if patients have symptoms referable to these organs or prior to RAI therapy and are at risk of complications of tumor swelling.  If iodinated contrast is administered, then there is a need to defer RAI assessment for 6–8 weeks.^​1,5​

Rising Tg or TgAb indicates need for imaging and consideration of additional therapy. ^1,2,3

D. Structural Incomplete Response to Therapy

ATA // ESMO // JAES // NCCN

Serial monitoring is generally recommended every 6 months or less.^{​1,3–5​}

Patients with structurally recurrent or persistent disease should receive suppressive TSH therapy with a goal < 0.1 mIU/L.^​1,3​

Identification of structural recurrent or persistent disease (incomplete response) is confirmed most commonly through abnormal imaging findings with subsequent USg-FNA.  There may be times when USg-FNA is not possible or not needed.^​1–4​

If a positive result would change management, ultrasonographically suspicious lymph nodes ≥ 8–10 mm in the smallest diameter should be biopsied for cytology with Tg measurement in the needle washout fluid.^​1​

Suspicious lymph nodes < 8–10 mm in the smallest diameter may be followed without biopsy with consideration for FNA or intervention if there is growth or if the node threatens vital structures.^​1​

Structural persistent or recurrent disease that is followed conservatively should be monitored through regular periodic assessment using:

1. clinical evaluation,
2. imaging (primarily ultrasound), and
3. thyroglobulin and thyroglobulin antibodies measurement.^{​1,3–5​}

Tables & Figures

Figure 5. management recommendations in ATA low risk DTC patients who have undergone total thyroidectomy

Figure 6. management recommendations in ATA low risk DTC patients who have undergone less than total thyroidectomy

Figure 7. management recommendations in ATA intermediate risk DTC patients who have undergone total thyroidectomy

Figure 8. management recommendations in ATA high risk DTC patients who have undergone total thyroidectomy and have no gross residual disease

Figure 9. management recommendations in patients with Follicular Neoplasms

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