1. The patient has a history of thyroid cancer with metastases to the lungs and skull, and underwent total thyroidectomy and parathyroidectomy. 2. Treatment options for recurrent or metastatic thyroid cancer include radioactive iodine treatment, surgery, external beam radiation, and molecularly targeted therapies. 3. Molecular targeted therapies that show promise for thyroid cancer work by inhibiting pathways involved in cell signaling and angiogenesis, such as the MAPK and PI3K pathways, or by restoring radioiodine uptake.

1. Thyroid cancer diagnosis and management 4C1 RI 李士寬

2. 09-2 曾廖站 78F, 5192444 1.Thyroid cancer, follicular carcinoma, with multiple lung metastasis and skull metastasis s/p total thyroidectomy & parathyroidectomy 2. Obstructive pneumonitis 3. Urinary tract infection with fungus infection Neck mass noted for 20+ years , significant weight loss(8kg loss in 2 months) from 96/2

3. 96/4: admission at 中國附醫 CXR: trachea deviated to left side multiple lung mass over bilateral lung field CT: one 6.6x5.2x4.5 cm mass lesion containing calcification and necrotic component with treachea and esophagus deviation and multiple lung masses Bone scan: left parietal-occipital region of the skull Thyroid needle biopsy: follicular carcinoma

4. 07/21 OP: Total thyroidectomy + parathyroidectomy Operation Finding 1. Enlarged, hard, irregular, shape; yellowish, white tumor; 8X7X6cm over R’t thyroid with invasion to paraspinal muscle. Parathyroid origin was likely 2. 4X2X2cm L’t thyroid with one 1X1cm hard tumor inside

5. Thyroid cancer 1.5% of all cancer Papillary carcinoma(75-85% of cases) Follicular carcinoma(10-20%) Medullary carcinoma(5%) Anaplastic carcinoma(<5%)

6. Papillary thyroid carcinoma Most often in the twenties to forties. Incidence rinse: 1935 (1.3/100,000 for women and 0.2/100,000 for men) 1991 (5.8/100,000 for women and 2.5/100,000 for men) Cause: (1)R/T to children with head and neck benign disease between 1910 and 1960 (2) increased detection of small papillary cancers

7. Papillary thyroid carcinoma Pathogenesis : Activation of receptor tyrosine kinases (RET/PTC, TRK, MET) -> Produce chimeric proteins with tyrosine kinase activity Clinical presentation: Most: asymptomatic thyroid nodule , discovered by fine needle aspiration biopsy. Advanced disease: hoarseness,dysphagia,cough, or dyspnea Minority: lung metastasis

8. Papillary thyroid carcinoma Pathologic features: unencapsulated , calcified psammoma bodies Good prognosis: micropapillary encapsulated, solid, and follicular variants Poor prognosis:with tall cells and diffuse sclerosing variants Behavioral: Good prognosis:10 year survival rate:95% grow slowly,extend to regional lymph node(not necessarily a bad prognostic sign ) older than 50 years of age : more aggressive local spread, leading to death in over half of the patients Distant metastases: uncommon (2 to 3% of patients), lung>bone

9. Follicular carcinoma More frequency than papillary cancer in iodine deficiency area. More frequently with increasing age Early hematogenous spread to lung, bone, brain, and liver (one fifth of patients ). Lymph node involvement :less than 1%

10. Anaplastic cancer Predominantly in persons older than 70 years. One third arise in preexisting differentiated cancers Death : aggressive local invasion : progressive tracheal obstruction or massive hemorrhage Distant metastases :little clinical importance

11. Medullary carcinoma malignant tumor of calcitonin-secreting C cells Sporadically:80%, sixth and seventh decades Genetic or familial variants 20% Genetic :MEN IIa, MEN IIb Familial form: multicentric in origin and C-cell hyperplasia precedes

12. Clinical Manifestations and Diagnosis Thyroid cancer: 1/20 of thyroid nodule Rapid, painless growth Fine-needle aspiration of thyroid nodules and examination of the obtained material 123 I scan: 20% of cold nodules containing thyroid cancer.

13. Treatment Thyroid surgery Advantage of near-total thyroidectomy : can be ablated with RAI can be followed with thyroglobulin levels

14. Treat for several weeks postoperatively with liothyronine(T4).,followed by thyroid hormone withdrawl -> TSH level increase to>50 IU/L over 3-4 weeks ->scanning dose of 131 I(4-5mCi) -> ablative dose of 29 mCi of 131 I ->whole body scan(6 months after surgery) to identify possible metastatic disease Long-term supplementation with levothyroxine (maintains TSH concentrations at <0.1mU/L)

15. Whole body scan rhTSH vs.thyroid hormone withdrawal rhTSH: stimulate 131 I uptake without symptoms of hypothyroidism. Recommened for pts predicted to be at low risk of recurrence thyroid hormone withdrawal: for pts with likely residual disease.T4 switch to T3(rapidly cleared hormone) Tg measurements after rhTSH administration or when TSH level risen after thyroid hormone withdrawal.

16. Follow up whole-body scan is negative and Tg level are low -> repeat scan perform one year later ->still negative ->management with suppressive therapy and measurements of Tg every 6 to 12 months Scan negative, Tg-positive(>5 to 10 ng/mL) ->radioiodine treatment. Lung metastasis:CXR, 131 I scan,spiral CT Bone metastasis:bone scintigraphy , CT , MRI

17. Epidemiology of incurable DTC 85% of patients with DTC :disease-free after initial treatment 10–15% : recurrent disease 5%: distant metastases Distant metastases :lungs (50%), bones (25%), lungs and bones (20%) ,10-year-survival rates ranging from 25% to 42%

18. Local and regional recurrences Small lymph-node metastases: 131 I treatment , but abnormalities can still persist after two to three courses -> surgery

19. Recurrent disease in the thyroid bed or in other soft tissue, or aerodigestive tract -> staging with endoscopies and various imaging modalities Disease limited to the neck :extensive surgery and external-beam radiotherapy patients older than 40 years , poorly-differentiated tumors, no radioiodine uptake, large tumor burden, rapid progressive disease, soft tissue involvement, and high [18F]FDG uptake : develop distant metastases after treatment .

20. Treatment of patients with persistent or recurrent disease Indications Abnormal clinical findings Abnormal imaging findings Increasing trend in serum thyroglobulin concentration Staging Neck ultrasonography, whole body scintigraphy with a large activity of radioiodine Conventional imaging: neck and chest CT, bone MRI, [18F]FDG PET Fine-needle biopsy or surgical biopsy in case of unusual presentation

21. Treatment methods Surgery (when feasible) Radioiodine treatment in presence of radioiodine uptake in tumor foci Other local treatments (dependent on location and extent of disease): external radiation beam treatment, embolisation, radiofrequency, cement injection New treatment methods, eg, molecularly targeted treatments,

22. Selection of patients with metastases for treatment Candidates for radioiodine treatment Younger age Well differentiated tumour High radioiodine uptake Small metastases Location in lungs Stable or slow progressive disease Low uptake of fluorodeoxyglucose Repeated radioiodine treatment (response rate: 85%, with 96% of complete responses seen with a cumulative activity <600 mCi)

23. Candidates for other treatment modalities Older age Poorly differentiated tumor No or low radioiodine uptake Large metastases Location in bones Rapidly progressive disease High uptake of fluorodeoxyglucose Patients with initial uptake but poor or no response to radioiodine treatment and patients with no initial uptake of radioiodine, especially when disease is progressive

24. Radioiodine treatment for lung metastases : 45% of patients with radioiodine uptake and no substantial sequellae. Large bone metastases : surgery and radiotherapy , but remission is rarely achieved. local procedures such as embolisation, radiofrequency or cement injection, and treatment with biphosphonates can delay tumor progression and palliate symptoms

25. High initial [18F]FDG uptake : indicate progressive disease and resistance to radioiodine treatment -> can help to select patients who should be treated either with radioiodine or with other modalities Complete remission after treatment: only a third of patients with metastases

26. Cytotoxic chemotherapy and biotherapy absence of evidence of benefits Doxorubicin :response rates :0% to 22% , lasting only a few months Dendritic cell immunotherapy might be effective but no studies on DTC.

27. Molecularly targeted treatments Two main theoretical approaches: inhibition of tumor growth by inhibiting cell signaling and angiogenesis induction of redifferentiation of thyroid tumor tissue.

28. Targets in cell signalling and angiogenesis Papillary carcinomas : 80% :mutations of genes of mitogen-activated protein kinase (MAPK) pathway. 5–30%: RET/PTC rearrangements 10%: RAS mutations 40%: BRAF mutations Follicular carcinomas: 20–35% : RAS mutations 30% :PAX8/PPARɣ rearrangements

29. Targets in cell signalling and angiogenesis Only a few relations between gene mutations and prognosis BRAF mutations :more aggressive and less differentiated papillary tumors, and this is consistent with the inhibition of thyroid-tumor cell growth induced by the blockade of BRAF kinase.

30. Angiogenesis Thyroid cancer cells :Overexpression of tyrosine kinase receptors :fibroblast growth factor, epidermal growth factor (EGF), hepatocyte growth factor (c-Met),VEGF, insulin, and insulin-growth factor 1 Antivascular treatment blocks the growth of differentiated thyroid carcinoma in experimental models.

31. Interference with signal transduction pathways AMG 706, BAY 43-9006, ZD 64-74, and AG-013736, in DTC is being studied in phase II trials effect :inhibition of the MAPK pathway and of angiogenesis and others. BAY 43-9006 also inhibits BRAF kinase

32. Restoring radioiodine uptake Retinoic acid analogues : increase the expression of the natrium iodide symporter -> increase radioidodine uptake ,but in only a few patients.

33. Other drugs Anti-EGF receptor (EGFR) antibodies and small molecules targeting the kinase activity of the EGFR : successfully tested for inhibition of tumour growth in thyroid-cancer cell lines. COX-2 inhibitor :Cyclooxygenase-2 : overexpressed in thyroid cancer that promotes tumour progression

34. Combination treatment The use of antiangiogenic drugs can enhance the efficacy of radiotherapy, radioiodine treatment, or chemotherapy. MAPK and the PI3K pathways blockers.