2. Thyroid carcinoma Thyroid carcinoma is uncommon Life time risk of being diagnosed with thyroid carcinoma is less than 1% (less than 1.5% of all adult cancers) The peak incidence is around age 49 years Three times more common in females than males Differentiated Thyroid Cancer which includes papillary and follicular carcinoma comprises the vast majority (>90%) of all thyroid cancer

3. Risk factors: 1-radiation exposure :Accidental or therapeutic (7% of individuals exposed to the atomic bombs in Japan developed thyroid carcinoma) 2-family history 3-possible (not proven) risk factors : hepatitis C and late age at first pregnancy

4. preoperative staging Preoperative neck US for cervical lymph nodes is recommended in all patients US-guided FNA of sonographically suspicious lymph nodes >= 8–10mm should be performed with or without FNA-Tg washout

5. Suspicious sonographic features : short axis >5mm presence of cystic areas microcalcifications peripheral vascularity absence of a hilum

6. Preoperative use of cross-sectional imaging studies (CT, MRI) is recommended as an adjunct to US for patients with clinical suspicion for advanced disease (invasive primary tumor, multiple or bulky lymph node involvement) Routine preoperative 18FDG-PET scanning is not recommended. Routine preoperative measurement of serum Tg or anti-Tg antibodies is not recommended.

7. Operative approach The initial surgical procedure should be a near-total or total thyroidectomy in thyroid cancer with any of the following: 1- tumor size >=4 cm 2- extra-thyroidal extension 3-lymph nodal metastases 4-distant sites metastases

8. the initial surgical procedure can be either a bilateral or unilateral procedure in thyroid cancer >1 cm and <4 cm with all of the following: 1-Unifocal 2-no extra-thyroidal extension 3-no lymph node metastases 4-absence of prior head and neck radiation and familial thyroid carcinoma

9. Surgical procedure should be a Thyroid lobectomy for thyroid cancer <1 cm with all of the following: 1-unifocal 2-intrathyroidal 3-no lymph nodal metastases. 4-absence of prior head and neck radiation and familial thyroid carcinoma

10. Lymph node dissection: Prophylactic dissection Prophylactic central-compartment neck dissection should be considered in patients PTC with: primary tumors (T3 or T4) or involved lateral neck nodes (cN1b) Therapeutic dissection lateral : biopsy proven Central : clinically involved

11. Pathologic report Resection margins Extrathyroidal extension Tumor size Vascular invasion Lymph node Histologic variant

12. Initial approach Initial risk stratification Post-operative staging Post-operative disease status

13. American Joint Committee on Cancer(AJCC) staging system definition T1a<1 cm T1b1-2 cm T22-4 cm T3Tumor >4 cm with minimal extra-thyroidal extension T4aany size extending beyond the thyroid capsule to invade subcutaneous soft tissues T4bTumor of any size invading prevertebral fascia or encasing carotid artery or mediastinal vessels N0No metastatic nodes N1aMetastases to central cervical level N1bMetastases to unilateral or bilateral cervical levels Or retropharyngeal or superior mediastinal lymph nodes M0No distant metastases M1Distant metastases

14. American Joint Committee on Cancer(AJCC) staging system Patients age =< 45 years old at diagnosis IAny TAny NM0 IIAny TAny NM1 Patients age> 45 years old at diagnosis IT1a-1bN0M0 IIT2N0M0 IIIT1a-1bN1aM0 T1-3N1aM0 T3N0M0 IVaT1-3N1aM0 T4aAny NM0 IVbT4bAny NM0 IVcAny TAny NM1

15. risk stratification The 2009 ATA Initial Risk Stratification System is recommended for DTC patients treated with thyroidectomy based on its utility in predicting risk of disease recurrence and/or persistence. 1- ATA low risk 2-ATA intermediate risk 3-ATA high risk

16. ATA low risk Papillary carcinoma with all of the following: All macroscopic tumor has been resected No invasion of loco-regional tissues No aggressive histology or vascular invasion no RAI-avid metastatic foci outside the thyroid bed Clinical N0 or <= 5 pathologic N1 micrometastases (<0.2 cm ) No local or distant metastases Follicular carcinoma Intrathyroidal, well differentiated follicular thyroid cancer with capsular invasion and no or minimal (<4 foci) vascular invasion

17. ATA intermediate risk minimal extra-thyroid extension ETE Papillary carcinoma with aggressive histology (e.g., tall cell, hobnail variant, columnar cell carcinoma) papillary carcinoma with vascular invasion Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm RAI-avid metastatic foci in the neck (outside thyroid bed) on whole-body RAI scan

18. ATA high risk Incomplete tumor resection Macroscopic invasion of tumor into the peri-thyroidal soft tissues (gross ETE) Pathologic N1 with any metastatic lymph node >3cm Postoperative serum thyroglobulin suggestive of distant metastases Distant metastases Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion)

19. Post-operative disease status Imaging: Neck US ±RAI WBS Laboratory: Thyroglobulin (Tg) +anti-Tg

20. Post-operative serum Tg: Postoperative serum Tg can help in assessing the persistence of disease or thyroid remnant and predicting potential future disease recurrence The Tg should reach its nadir by 3–4 weeks postoperatively in most patients

21. The optimal cutoff value for postoperative serum Tg or state in which it is measured is not known. However, values greater than 5–10 ng/ml increase the likelihood of persistent, recurrent and metastatic disease.

22. Postoperative Imaging studies: Neck US in all patients Postoperative diagnostic RAI WBS may be useful when the extent of the thyroid remnant or residual disease cannot be accurately ascertained from the surgical report and neck ultrasonography. pretherapy diagnostic scans should utilize I 123 (1.5–3 mCi) or a low activity of I 131 (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity.

23. the role of RAI therapy (including ablation, adjuvant therapy, or therapy for persistent disease) after thyroidectomy in primary management of DTC

24. ATA High risk DTC patients RAI therapy is routinely recommended Either adjuvant (up to 150 mCi) Or therapy for persistent disease (100-200 mCi )

25. ATA low risk DTC patients RAI therapy not routinely recommended in the absence of other high risk features If done ablation with 30mCi is favored

26. ATA intermediate risk DTC patients RAI therapy should be considered ablation or adjuvant depending on other high risk features

27. What is the appropriate degree of initial TSH suppression ?

28. ATA high-risk DTC patients initial TSH suppression below 0.1

29. ATA intermediate risk DTC patients initial TSH suppression: 0.1– 0.5

30. ATA low risk DTC patients undetectable Tg TSH 0.5–2 low level Tg TSH 0.1-0.5 had lobectomy TSH 0.5–2

31. External Beam Radiation Therapy(EBRT): no role for routine adjuvant EBRT to the neck in patients with DTC. selective use can be considered in: 1- patients over age 60 with locally advanced disease. 2-Unresectable gross residual/recuurent disease 3-patients undergoing multiple and frequent serial neck re-operations for palliation of loco-regionally recurrent disease

32. Response evaluation: Evaluating the response to initial therapy can occur as early as several weeks to several months 1-Serum Tg and anti-Tg antibodies measurement 2-imaging (neck US ± RAI WBS) 3-other imaging studies (if needed)

33. Serum Tg and anti-Tg antibodies measurement: Measurement of serum Tg anti-Tg antibodies levels is an important modality to monitor patients for residual or recurrent disease. a Tg assay with a functional sensitivity of 0.1–0.2 ng/mL may reduce the need to perform TSH-stimulated Tg measurements of some patients.

34. Low serum Tg levels during TSH suppression (Tg<0.2 ng/mL) or after stimulation (Tg <1 ng/mL) in the absence of interfering antibodies has a high likelihood of identifying patients completely free of tumor on follow-up

35. diagnostic RAI WBS in follow-up Low or intermediate-risk High or intermediate risk Not routinely required if: 1- Undetectable Tg 2-negative US 3-no uptake outside the thyroid bed on the initial WBS can be useful 6–12 months after adjuvant RAI therapy

36. Response to therapy reclassification in DTC patients: 1-excellent response 2-biochemical incomplete response 3-structural incomplete response 4-indeterminate response

37. Negative imaging Suppressed Tg<0.2 or stimulated Tg <1 Excellent response

38. Negative imaging Suppressed Tg >=1 or stimulated Tg >=10 Or Rising anti-Tg Biochemical incomplete response

39. Structural or functional evidence of disease Structural incomplete response any Tg and anti-Tg level

40. Non specific image (Faint uptake in thyroid bed on RAI scanning) Non-stimulated Tg detectable but <1 Stimulated Tg Detectable but <10 or Anti-Tg antibodies stable or Declining Indeterminate response

41. TSH suppression during thyroid hormone therapy in long-term follow-up of DTC

42. Structural incomplete response Maintain TSH below 0.1

43. Biochemical incomplete response Maintain TSH between (0.1-0.5) Taking into account initial ATA risk,Tg level, Tg trend and risk of TSH suppression

44. Excellent or indeterminate response ATA high risk Maintain TSH 0.1-0.5 ATA low risk Maintain TSH 0.5-2

45. Structural neck recurrence Therapeutic neck dissection should be performed for patients with biopsy-proven persistent or recurrent disease for central neck nodes >=8mm and lateral neck nodes >=10mm in the smallest Dimension. Other therapeutic options: 1-Ethanol injection 2-Radiofrequency or laser ablation 3-EBRT using modern techniques such as intensity modulated radiotherapy and sterotactic radiation

46. aerodigestive invasion: When technically feasible, surgery for aerodigestive invasive disease is recommended in combination with RAI and/or EBRT.

47. pulmonary metastases 1-Pulmonary micro-metastases should be treated with RAI therapy and RAI therapy should be repeated every 6–12 months as long as disease continues to concentrate RAI and respond clinically because the highest rates of complete remission are reported in these subgroups.

48. 2-Radioiodine-avid macro-nodular metastases may be treated with RAI and treatment may be repeated when objective benefit is demonstrated (decrease in the size of the lesions, decreasing Tg), but complete remission is not common and survival remains poor

49. 3-Patients with solitary pulmonary DTC metastases may be considered for surgical resection, although the potential benefit weighed against the risk of surgery is unclear.

50. CNS metastases surgical resection and stereotactic EBRT are the mainstays of therapy for CNS metastases RAI can be considered if CNS metastases concentrate RAI. If RAI is being considered, stereotactic EBRT and concomitant glucocorticoid therapy are recommended prior to RAI therapy to minimize the effects of a potential TSH-induced increase in tumor size and RAI-induced inflammatory response.

51. bone metastases Directed therapy of bone metastases include surgery, external beam radiation therapy RAI therapy of bone metastases iodine-avid has been associated with improved survival and should be employed although RAI is rarely curative bone-directed agents (Bisphosphonate or denosumab) therapy should be considered in patients with diffuse and/or symptomatic bone metastases from RAI-refractory DTC, either alone or concomitantly with other systemic therapies.

52. Kinase inhibitors: Kinase inhibitor therapy should be considered in RAI refractory DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not otherwise amenable to local control using other approaches.

53. sorafenib and lenvatinib are approved for use in the United States and the European Union for patients with advanced RAI-refractory Additional VEGFR-directed kinase inhibitors including vandetanib,axitinib, pazopanib, cabozantinib, and sunitinib also have activity in metastatic DTC based upon phase 2 therapeutic Trials. Ideally, such therapy should be undertaken within the context of therapeutic clinical trials

54. Other novel agents: Activation of the MAP-kinase pathway was associated with downregulation of the genes involved in iodine metabolism Recently, two proof-of-principle pilot clinical trials have confirmed that targeted blockade of the MAP kinase pathway can result in clinically relevant restoration of RAI avidity in a substantial percentage of RAI-refractory thyroid cancer patients.

55. In the first trial, 1 month of the MEK inhibitor selumetinib increased RAI uptake in 12 of 20 iodine- refractory thyroid cancer patients, with structural tumor shrinkage seen in five of the eight patients. In the second trial, 1month of the BRAF inhibitor dabrabenib restored RAI avidity on diagnostic WBS in 6 of 10 RAI-refractory patients, resulting in structural responses in two patients and a decrease in serum Tg in four patients.

56. immunotherapy including checkpoint inhibitors (e.g., PD-1/PD-L1) has shown promise in other cancers and is being investigated in advanced RAI refractory thyroid cancer.