Differentiated Thyroid cancer American cancer guidelines. Risk grouping and radioactive Iodine Ablation Low dose vs High dose RAI Ablation. Initial assessment of a thyroid nodule

1. Thyroid Cancer: Update and Review of
ATA Guidelines
Dr Abubaker Shahid; Dr Misbah Masood; Dr Ahmad Farooq
INMOL Hospital Lahore

2. Thyroid Cancer Incidence and Prevalence
• Approximately 65,000 new cases of thyroid cancer are
diagnosed annually and the incidence is increasing by
5–6% per year in the United States.
• Thyroid cancer prevalence approximately
450,000 in the United States.
• The majority of patients with thyroid cancer have an
excellent prognosis,
• WHEREAS patients who have distant metastasis have
only 50% 5-year survival rate.

3. Trends in incidence and mortality
2001-2010
SEER Cancer Statistics Review (CSR), 1975-2010

4. OBJECTIVES
1.To understand how to diagnose thyroid
cancer.
2.To learn how to apply ATA Guidelines to
patients with thyroid cancer.
3. To understand the relevant molecular
clinical aspects of thyroid cancer.

5. Thyroid Nodules and Cancer
• Epidemiology
• Clinical Findings
• Management
• Research

6. Prevalence of Thyroid Nodules
• In an autopsy study, 12% of thyroid glands
contained one nodule, 37% multiple nodules;
2.1% of all glands contained thyroid cancer
(Mortensen JD, et al, JCEM 15: 1270, 1955).
• Using thyroid sonograms in a clinical study,
22% of thyroid glands contained solitary and
45% contained multiple thyroid nodules
(Ezzat et al, Arch Int Med 154:1828, 1994).

7. Thyroid Nodules and Cancer
• Epidemiology
• Clinical Findings
• Management
• Research

8. Clinical Findings Associated with an Increased Risk That a Thyroid NoduleIs
Malignant
Burman KD, Wartofsky L. N Engl J Med
2015;373:2347

9. Causes of Thyroid Nodules
BENIGN
• Adenoma
• Cysts
• Thyroiditis
• Infections
• Infiltrative Diseases
 Thyroglossal duct cyst
• Teratoma
NON THYROIDALCAUSES
• Parathyroid cyst or adenoma
• Thymoma
• Lipoma
• Cystichygroma
• Brachial cleftcyst
• Paraganglioma
MALIGNANT
 Papillary cancer
 Follicular cancer
 Medullary cancer
 Anaplastic cancer
 Lymphoma
 Metastatic cancer
Renal
Breast
Melanoma
Colon

10. Thyroid Nodules and Cancer
• Epidemiology
• Clinical Findings
• Management
• Research

11. ROLE OF MEASUREMENT OF TUMOR MARKERS IN
DIAGNOSIS
RECOMMENDATION 3&4
 Routine measurement of serum thyroglobulin (Tg) for
initial evaluation of thyroid nodules is not recommended.
 The panel cannot recommend either for or against routine
measurement of serum calcitonin in patients with thyroid
nodules

12. Thyroid Sonography
RECOMMENDATION 6
 Thyroid sonography with survey of the cervical lymph
nodes should be performed in all patients with known
or suspected thyroid nodules.
(Strong recommendation, High-quality evidence)

15. FNAC CYTOLOGY REPORTING
RECOMMENDATION 9
 Thyroid nodule FNA cytology should be reported using
diagnostic groups outlined in the Bethesda System for
Reporting Thyroid Cytopathology.
(Strong recommendation, Moderate-quality evidence)

16. Diagnostic Categories of Thyroid Nodules
and Risk of Cancer
Burman KD, Wartofsky L. N Engl J Med 2015;373:2347

17. [18F]Fluorodeoxyglucose positron emission
tomography
RECOMMENDATION 5
 Focal 18FDG-PET uptake within a sonographically
confirmed thyroid nodule conveys an increased risk of
thyroid cancer, and FNA is recommended for those
nodules ≥1 cm.
(Strong recommendation, Moderate-quality evidence)
 Diffuse 18FDG-PET uptake in conjunction with
sonographic and clinical evidence of chronic
lymphocytic thyroiditis, does not require further
imaging or FNA.
(Strong recommendation, Moderate-quality evidence)

18. AUS/FLUS
RECOMMENDATION 15
 For nodules with AUS/FLUS cytology, after
consideration of worrisome clinical and sonographic
features, investigations such as repeat FNA or
molecular testing may be used to supplement
malignancy risk assessment in lieu of proceeding
directly with a strategy of either surveillance or
diagnostic surgery.
(Weak recommendation, Moderate-quality evidence)

19. Oncogenic Alterations
Papillary thyroid cancer (About 70% have alteration):
 RET/PTC rearrangement: Ret is a trans membrane
receptor tyrosine kinase.
 BRAF mutations: a cytoplasmic serine/threonine tyrosine
kinase type 1.
 Ras mutations: Ras super family of small GTPases.
 RAS/RAF/MAPK signaling pathway
 PI3K/PDK1/Akt signaling pathway
 Ouyang et al, Clin Cancer Research 12:1785,06.

20. Proposed clinical algorithm for management of patients with
cytologically indeterminate thyroid FNA applying the results of
mutational analysis
Nikiforov Y E et al. JCEM
2011;96:3390.
©2011 by Endocrine

21. Afirma® Overall Performance: FLUS, FN, and
SMC

22. FN/SFN
RECOMMENDATION 16
 Diagnostic surgical excision is the long- established
standard of care for the management of FN/SFN
cytology nodules. However, after consideration of
clinical and sonographic features, molecular testing
may be used to supplement malignancy risk
assessment data in lieu of proceeding directly with
surgery.
(Weak recommendation, Moderate-quality evidence)

23. ROLE OF PET SCAN IN INDETERMINATE NODULES
RECOMMENDATION 18
 18FDG-PET imaging is not routinely recommended for the
evaluation of thyroid nodules with indeterminate cytology.
(Weak recommendation, Moderate-quality evidence)

24. False Negative Thyroid FNA
RECOMMENDATION 23
• Given the low false-negative rate of US-guided FNA
cytology and the higher yield of missed malignancies
based upon nodule sonographic pattern rather than
growth, the follow-up of thyroid nodules with benign
cytology diagnoses should be determined by risk
stratification based upon US pattern.
• Nodules with high suspicion US pattern: repeat US and
US-guided FNA within 12 months.
(Strong recommendation, Moderate-quality evidence)

25. Indeterminate FNA
RECOMMENDATION 23
 Nodules with low to intermediate suspicion US
pattern: repeat US at 12–24 months.
 If sonographic evidence of growth (20% increase in at
least two nodule dimensions with a minimal increase
of 2 mm or more than a 50% change in volume) or
development of new suspicious sonographic features,
the FNA could be repeated or observation continued
with repeat US, with repeat FNA in case of continued
growth.
(Weak recommendation, Low-quality evidence)

26. Indeterminate Nodules
RECOMMENDATION 23
 Nodules with very low suspicion US pattern (including
spongiform nodules): the utility of surveillance US and
assessment of nodule growth as an indicator for
repeat FNA to detect a missed malignancy is limited.
If US is repeated, it should be done at about 24
months.
(Weak recommendation, Low-quality evidence)

27. 60 yo female hoarse voice and palpable adenopathy US –
3.1 cm suspicious pattern nodule, adenopathy
Laryngoscopic exam – left VC paralysis
CT neck with contrast CT neck without contrast
 PET/CT
Thyroidectomy, central/L neck dissection
RECOMMENDATION 33
A) Preoperative use of cross-sectional imaging studies (CT, MRI) with
intravenous contrast is recommended as an adjunct to ultrasound for
patients with clinical suspicion for advanced disease including invasive
primary tumor, or clinically apparent multiple or bulky lymph node
involvement.
(Strong recommendation, low-quality evidence)
B) Routine preoperative FDG-PET scanning is not recommended.
(Strong recommendation, low-quality evidence)
 Choi JS, Am J Roent 2009
 Lesnik D, Head Neck 2014

28. Surgery
RECOMMENDATION 19
 When surgery is considered for patients with a solitary,
cytologically indeterminate nodule, thyroid lobectomy
is the recommended initial surgical approach.
 This approach may be modified based on clinical or
sonographic characteristics, patient preference, and/or
molecular testing when performed.
(Strong recommendation, Moderate-quality evidence)

29. Total thyroidectomy (2009)
‘For thyroid cancer >1 cm, initial surgery should be
total thyroidectomy unless there are
contraindications. Lobectomy may be sufficient for <1
cm, low‐risk, unifocal, intrathyroidal PTCs w/o prior
head/neck irradiation or nodal metastases.’
(Recommendation rating: A)
- ATA Guidelines 2009

30. Total thyroidectomy or lobectomy (2015)
‘For patients with thyroid cancer >1 cm and <4 cm w/o
extrathyroidal extension, and cN0, the initial surgery
can be either total thyroidectomy (high‐risk tumors
with nodal mets, requiring RAI), or thyroid lobectomy
(low and medium‐risk tumors).’
(Strong recommendation, Moderate-quality evidence)
‐ATA Guidelines 2014

31. Surgery
RECOMMENDATION 20
Because of increased risk for malignancy, total thyroidectomy
may be preferred in patients with
 Indeterminate nodules that are cytologically suspicious for
malignancy,
 Positive for known mutations specific for carcinoma,
sonographically suspicious,
 Large (>4 cm), or in patients with familial thyroid carcinoma or
history of radiation exposure.
(Strong recommendation, Moderate-quality evidence)

32. 28 yr female 3.5 cm high suspicion sonographic
pattern .No abnormal neck LN FNA - PTC
Thyroidectomy with central neck dissection
Thyroidectomy or lobectomy
Observation

33. 28 yr female 3.5 cm high suspicion sonographic
pattern .No abnormal neck LN FNA - PTC
3.5cm 2009 Recommendation: Thyroidectomy
Bilimoria KY, Ann Surg 2007
PTC >1 cm and <4 cm
No extrathyroidal extension, cN0 (preoperative assessment)
NTT/TT or lobectomy
(Strong Recommendation, Moderate-quality evidence)
No need for prophylactic central neck dissection for:
T1/T2 PTC and cN0 and for most FTC.
(Strong Recommendation, Moderate-quality evidence)
Randolph GW, Thyroid 2012

34. Pathology reports should include
Recommendation 46 (NEW)
 AJCC/TNM criteria
 Vascular invasion and number of vessels
 Number of LN examined and involved
 Size of the largest metastatic LN focus
 Extranodal extension
(Strong recommendation, Moderate-quality evidence)
 Variants with favorable and unfavorable outcomes
(Strong recommendation, Low-quality evidence)
 Variants associated with familial syndromes
(Weak recommendation, Low-quality evidence)

35. ATA RISK STRATIFICATION
LOW RISK
– No local or distant metastases
– All microscopic tumor resected
– No locoregional tumor invasion
– No aggressive histology or vascular
invasion
– If 131-I given, no uptake outside of thyroid bed
on post-Rx scan

36. ATA RISK STRATIFICATION
INTERMEDIATE RISK
– (+) microscopic perithyroidal invasiveness
– (+) lymph nodes or uptake outside thyroid bed
– (+) aggressive histology or vascular invasion
HIGH RISK
– Macroscopic invasion of tumor
– Incomplete tumor resection
– Distant mets or Tg suggestive of distant mets

37. WHOM TO ABLATE?
RECOMMENNDATION 51
Decision based on ATArisk of recurrence stratification system
post thyroidectomy.
Do not give RAI for “low risk” DTC*
(Recommendation; Low Quality evidence)
Do not give RAI for unifocal Micro PTC*
(Strong Recommendation; Moderate Quality evidence)
Do not give RAI for multifocal Micro PTC *
(Recommendation; Low Quality evidence)
*absent any other higher risk features

38. WHOM TO ABLATE?
Decision based on ATA risk of recurrence stratification system
post thyroidectomy.
Yes, RAI ablation for Intermediate risk
 Selected patients with 1– 4 cm tumors confined to
thyroid and LN metastases
 Other high risk features (when combination of age,
tumor size, LN status, and histology predicts an
intermediate/ high risk of recurrence or death)
(Weak Recommendation; Low Quality evidence)

39. WHOM TO ABLATE
Decision based on ATA risk of recurrence stratification system
post thyroidectomy.
Yes, RAI ablation for High risk.
 known distant metastases
 Extra thyroidal extension regardless of tumor size
 Tumor size >4 cm even absent other high risk features.
(Strong Recommendation; Moderate Quality evidence)

41. What activity of 131I should be used for remnant
ablation or adjuvant therapy?
RECOMMENDATION 55
 If RAI remnant ablation is performed after total
thyroidectomy for ATA low-risk thyroid cancer or
intermediate-risk disease with lower risk features (i.e.,
low-volume central neck nodal metastases with no
other known gross residual disease or any other
adverse features), a low administered activity of
approximately of 30 mCi is generally favored over
higher administered activities.
(Strong recommendation, High-quality evidence)

42. What activity of 131I should be used for
remnant ablation or adjuvant therapy?
RECOMMENDATION 56
 When RAI is intended for initial adjuvant therapy to
treat suspected microscopic residual disease,
administered activities above those used for remnant
ablation up to 150 mCi are generally recommended (in
absence of known distant metastases).
 It is uncertain whether routine use of higher
administered activities (>150 mCi) in this setting will
reduce structural disease recurrence for T3 and N1
disease.
(Weak recommendation, Low-quality evidence)

44. Molecular Testing
RECOMMENDATION 52
 The role of molecular testing in guiding postoperative
RAI use has yet to be established; therefore, no
molecular testing to guide postoperative RAI use can be
recommended at this time.
(No recommendation, Insufficient evidence)

45. Post 131-I Therapy Scans
RECOMMENDATION 58
 A post therapy WBS (with or without SPECT/CT) is
recommended after RAI remnant ablation or
treatment, to inform disease staging and document
the RAI avidity of any structural disease
(Strong recommendation, Low-quality evidence)

46. ROLE OF PET SCAN IN HIGH RISK DTC
RECOMMENDATION 68
 18FDG-PET scanning should be considered in high-risk
DTC patients with elevated serum Tg (generally >10
ng/mL) with negative RAI imaging
(Strong recommendation, Moderate-quality evidence)

47. CT and MRI IN HIGH RISK DTC
RECOMMENDATION 69
 Imaging of other organs including MRI brain, MR
skeletal survey, and/or CT or MRI of the abdomen
should be considered in high-risk DTC patients with
elevated serum Tg (generally >10 ng/mL) and negative
neck and chest imaging who have symptoms referable
to those organs or who are being prepared for TSH-
stimulated RAI therapy (withdrawal or rhTSH) and may
be at risk for complications of tumor swelling.
(Strong recommendation, Low-quality evidence)

48. Follow up
RECOMMENDATION 62
 ATA high-risk patients (regardless of response to
therapy) and all patients with biochemical incomplete,
structural incomplete, or indeterminate response
should continue to have Tg measured at least every 6–
12 months for several years.
(Weak recommendation, Low-quality evidence)

49. Follow Up
RECOMMENDATION 63
 In ATA low-risk and intermediate-risk patients who have
had remnant ablation or adjuvant therapy and negative
cervical US, serum Tg should be measured at 6–18
months on thyroxine therapy with a sensitive Tg assay
(<0.2 ng/mL) or after TSH stimulation to verify absence
of disease (excellent response).
(Strong recommendation, Moderate-quality evidence)

50. ASSESSING RESPONSE TO THERAPY

51. Management Approaches Based on
Response to Therapy

52. TSH in Thyroid Cancer Long-Term
1. PERSISTENT DISEASE <0.1
2. DISEASE FREE, HIGHER RISK .1-.5
3. DISEASE FREE,LOW RISK .5-2

53. Radioiodine Remnant Ablation
LT4 withdrawal vs rhTSH
RECOMMENDATION 54
 ATA intermediate risk (higher risk features)
May consider rhTSH (Thyrogen)
(Weak recommendation, Low-quality evidence)
 ATA high risk
No recommendation,
(Insufficient evidence)

54. Radioidine-refractory DTC How is radioiodine
refractory DTC defined? (new question)
RECOMMENDATION 91 (NEW)
Radioiodine-refractory structurally-evident DTC is defined in
patients with appropriate TSH stimulation and iodine
preparation in four basic ways:
1) The malignant/metastatic tissue does not ever concentrate
radioiodine
2) The tumor tissue loses the ability to concentrate radioiodine
3) Radioiodine is concentrated in some lesions but not in others
4)Metastatic disease progresses despite significant
concentration of radioiodine.
When a patient with DTC is classified as refractory to
radioiodine, there is no indication for further radioiodine
treatment.
(Strong recommendation, Moderate-quality evidence)

55. What to do with patients who have RAI-
refractory DTC?
 Monitor (New recommendation 92)
 Directed Therapy (New recommendation 93)
– Surgery, EBRT, thermal ablation
 Clinical trials (New recommendation 95)
– Clinicaltrials.gov
 Systemic therapy (New recommendations 96-99)
– Kinase inhibitors, Bone-directed therapy

56. Thyroid Nodules and Cancer
• Epidemiology
• Clinical Findings
• Management
• Research

57. Kaplan–Meier Estimate of Progression-free
Survival: Lenvatinib vs. Placebo
Schlumberger M et al. N Engl J Med 2015;372:621-630.

58. SUMMARY
2015 ATA Guidelines on Thyroid Nodules and DTC – substantial change
 Don’t need to biopsy every nodule > 1 cm
 Lobectomy may be reasonable approach
 More detailed pathology reports
 Use of selective radioiodine
 Cross-sectional imaging for higher risk disease
 Stage (AJCC/TNM), ATA recurrence risk, response to therapy
 Radioiodine refractory DTC
– Definition, monitoring, directed-therapy, clinical trials and systemic
therapy

59. Effect of Current Therapy:
Thyroid Cancer Survival
Percent
Survival
10
90
80
70
60
50
40
30
20
10
0
2 4 6 8 10
Years Since Diagnosis
Stage 4 (38%)
Stage 1 (100%)
Stage 2 (98%)
Stage 3(82%)

60. Year Wise Frequency of Patients registered for
CA Thyroid at INMOL
104 100
117 114 104
539
2012 2013 2014 2015 2016 Total
Frequency

61. Gender wise Distribution of Patients
Female
73%
Male
27%

62. Number of patients in respective age Groups
(Years)
2
31
119
134
113
80
43
13
4
0
20
40
60
80
100
120
140
0-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90

63. 396
70
26
42
3 1 1
Papillary CA
Thyroid
Follicular CA
Thyroid
Medullary CA
Thyroid
Anaplastic CA
Thyroid
Hurthle Cell CA Insular CA Clear Cell CA
Thyroid
Histopathology
Series1

64. Nodularity
Multinodular
40%
NA
34%
Single
26%

65. Size of Nodule in Study Population
28
225
114
172
539
<1cm 1-4cm >4cm NA Total
Size of Nodule in Study Population
Frequency

66. Ablation Dose
4 5 2 6
98
1
47
5
152
2
27
190
539
29mci 30mci 50mci 80mci 100mci 110mci 120mci 130mci 150mci 180mci 200mci No Total
Series1

67. Type of Surgery
105
356
78
539
Subtotal Thyroidectomy Total Thyroidectomy NA Total

68. Surgery Types in Percentages
19.50%
66.00%
14.50%
Subtotal Thyroidectomy Total Thyroidectomy NA
Series1

69. Days of Admission
Ablation Dose (mci) Average Days of Admission
Upto 29 No Admission
50 to 100 2 Days
100 to 150 2 to 3 Days
150 to 200 3 Days