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  1. 1. Thyroid cancer diagnosis and management 4C1 RI 李士寬
  2. 2. <ul><li>09-2 曾廖站 78F, 5192444 </li></ul><ul><li>1.Thyroid cancer, follicular carcinoma, with multiple lung metastasis and skull metastasis s/p total thyroidectomy & parathyroidectomy </li></ul><ul><li>2. Obstructive pneumonitis </li></ul><ul><li>3. Urinary tract infection with fungus infection </li></ul><ul><li>Neck mass noted for 20+ years , significant weight loss(8kg loss in 2 months) from 96/2 </li></ul>
  3. 3. <ul><li>96/4: admission at 中國附醫 </li></ul><ul><li>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 </li></ul><ul><li>Bone scan: left parietal-occipital region of the </li></ul><ul><li>skull </li></ul><ul><li>Thyroid needle biopsy: follicular carcinoma </li></ul>
  4. 4. <ul><li>07/21 OP: Total thyroidectomy + parathyroidectomy </li></ul><ul><li>Operation Finding </li></ul><ul><ul><li>1. Enlarged, hard, irregular, shape; yellowish, white tumor; 8X7X6cm over R’t thyroid with invasion to paraspinal muscle. Parathyroid origin was likely </li></ul></ul><ul><ul><li>2. 4X2X2cm L’t thyroid with one 1X1cm hard tumor inside </li></ul></ul>
  5. 5. Thyroid cancer <ul><li>1.5% of all cancer </li></ul><ul><li>Papillary carcinoma(75-85% of cases) </li></ul><ul><li>Follicular carcinoma(10-20%) </li></ul><ul><li>Medullary carcinoma(5%) </li></ul><ul><li>Anaplastic carcinoma(<5%) </li></ul>
  6. 6. Papillary thyroid carcinoma <ul><li>Most often in the twenties to forties. </li></ul><ul><li>Incidence rinse: </li></ul><ul><ul><li>1935 (1.3/100,000 for women and 0.2/100,000 for men) </li></ul></ul><ul><ul><li>1991 (5.8/100,000 for women and 2.5/100,000 for men) </li></ul></ul><ul><ul><li>Cause: </li></ul></ul><ul><ul><ul><li>(1)R/T to children with head and neck benign disease between 1910 and 1960 </li></ul></ul></ul><ul><ul><ul><li>(2) increased detection of small papillary cancers </li></ul></ul></ul>
  7. 7. Papillary thyroid carcinoma <ul><li>Pathogenesis : </li></ul><ul><li>Activation of receptor tyrosine kinases (RET/PTC, TRK, MET) -> Produce chimeric proteins with tyrosine kinase activity </li></ul><ul><li>Clinical presentation: </li></ul><ul><ul><li>Most: asymptomatic thyroid nodule , discovered by fine needle aspiration biopsy. </li></ul></ul><ul><ul><li>Advanced disease: hoarseness,dysphagia,cough, or dyspnea </li></ul></ul><ul><ul><li>Minority: lung metastasis </li></ul></ul>
  8. 8. Papillary thyroid carcinoma <ul><li>Pathologic features: unencapsulated , calcified psammoma bodies </li></ul><ul><ul><li>Good prognosis: micropapillary encapsulated, solid, and follicular variants </li></ul></ul><ul><ul><li>Poor prognosis:with tall cells and diffuse sclerosing variants </li></ul></ul><ul><li>Behavioral: </li></ul><ul><ul><li>Good prognosis:10 year survival rate:95% </li></ul></ul><ul><ul><li>grow slowly,extend to regional lymph node(not necessarily a bad prognostic sign ) </li></ul></ul><ul><ul><li>older than 50 years of age : more aggressive local spread, leading to death in over half of the patients </li></ul></ul><ul><ul><li>Distant metastases: uncommon (2 to 3% of patients), lung>bone </li></ul></ul>
  9. 9. Follicular carcinoma <ul><li>More frequency than papillary cancer in iodine deficiency area. More frequently with increasing age </li></ul><ul><li>Early hematogenous spread to lung, bone, brain, and liver (one fifth of patients ). Lymph node involvement :less than 1% </li></ul>
  10. 10. Anaplastic cancer <ul><li>Predominantly in persons older than 70 years. </li></ul><ul><li>One third arise in preexisting differentiated cancers </li></ul><ul><li>Death : aggressive local invasion : progressive tracheal obstruction or massive hemorrhage </li></ul><ul><ul><li>Distant metastases :little clinical importance </li></ul></ul>
  11. 11. Medullary carcinoma <ul><li>malignant tumor of calcitonin-secreting C cells </li></ul><ul><ul><li>Sporadically:80%, sixth and seventh decades </li></ul></ul><ul><ul><li>Genetic or familial variants 20% </li></ul></ul><ul><ul><ul><li>Genetic :MEN IIa, MEN IIb </li></ul></ul></ul><ul><ul><ul><li>Familial form: multicentric in origin and C-cell hyperplasia precedes </li></ul></ul></ul>
  12. 12. Clinical Manifestations and Diagnosis <ul><li>Thyroid cancer: 1/20 of thyroid nodule </li></ul><ul><ul><li>Rapid, painless growth </li></ul></ul><ul><li>Fine-needle aspiration of thyroid nodules and examination of the obtained material </li></ul><ul><li>123 I scan: 20% of cold nodules containing thyroid cancer. </li></ul>
  13. 13. Treatment <ul><li>Thyroid surgery </li></ul><ul><li>Advantage of near-total thyroidectomy : </li></ul><ul><ul><li>can be ablated with RAI </li></ul></ul><ul><ul><li>can be followed with thyroglobulin levels </li></ul></ul>
  14. 14. <ul><li>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 </li></ul><ul><li>Long-term supplementation with levothyroxine (maintains TSH concentrations at <0.1mU/L) </li></ul>
  15. 15. Whole body scan <ul><li>rhTSH vs.thyroid hormone withdrawal </li></ul><ul><li>rhTSH: stimulate 131 I uptake without symptoms of hypothyroidism. Recommened for pts predicted to be at low risk of recurrence </li></ul><ul><li>thyroid hormone withdrawal: for pts with likely residual disease.T4 switch to T3(rapidly cleared hormone) </li></ul><ul><li>Tg measurements after rhTSH administration or when TSH level risen after thyroid hormone withdrawal. </li></ul>
  16. 16. Follow up <ul><li>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 </li></ul><ul><li>Scan negative, Tg-positive(>5 to 10 ng/mL) ->radioiodine treatment. </li></ul><ul><li>Lung metastasis:CXR, 131 I scan,spiral CT </li></ul><ul><li>Bone metastasis:bone scintigraphy , CT , MRI </li></ul>
  17. 17. Epidemiology of incurable DTC <ul><li>85% of patients with DTC :disease-free after initial treatment </li></ul><ul><li>10–15% : recurrent disease </li></ul><ul><li>5%: distant metastases </li></ul><ul><li>Distant metastases :lungs (50%), bones (25%), lungs and bones (20%) ,10-year-survival rates ranging from 25% to 42% </li></ul>
  18. 18. Local and regional recurrences <ul><li>Small lymph-node metastases: 131 I treatment , but abnormalities can still persist after two to three courses -> surgery </li></ul>
  19. 19. <ul><li>Recurrent disease in the thyroid bed or in other soft tissue, or aerodigestive tract -> staging with endoscopies and various imaging modalities </li></ul><ul><ul><li>Disease limited to the neck :extensive surgery and external-beam radiotherapy </li></ul></ul><ul><ul><li>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 . </li></ul></ul>
  20. 20. Treatment of patients with persistent or recurrent disease <ul><li>Indications </li></ul><ul><ul><li>Abnormal clinical findings </li></ul></ul><ul><ul><li>Abnormal imaging findings </li></ul></ul><ul><ul><li>Increasing trend in serum thyroglobulin concentration </li></ul></ul><ul><li>Staging </li></ul><ul><ul><li>Neck ultrasonography, whole body scintigraphy with a large activity of radioiodine </li></ul></ul><ul><ul><li>Conventional imaging: neck and chest CT, bone MRI, [18F]FDG PET </li></ul></ul><ul><ul><li>Fine-needle biopsy or surgical biopsy in case of unusual presentation </li></ul></ul>
  21. 21. <ul><li>Treatment methods </li></ul><ul><ul><li>Surgery (when feasible) </li></ul></ul><ul><ul><li>Radioiodine treatment in presence of radioiodine uptake in tumor foci </li></ul></ul><ul><ul><li>Other local treatments (dependent on location and extent of disease): external radiation beam treatment, embolisation, radiofrequency, cement injection </li></ul></ul><ul><ul><li>New treatment methods, eg, molecularly targeted treatments, </li></ul></ul>
  22. 22. Selection of patients with metastases for treatment <ul><li>Candidates for radioiodine treatment </li></ul><ul><ul><li>Younger age </li></ul></ul><ul><ul><li>Well differentiated tumour </li></ul></ul><ul><ul><li>High radioiodine uptake </li></ul></ul><ul><ul><li>Small metastases </li></ul></ul><ul><ul><li>Location in lungs </li></ul></ul><ul><ul><li>Stable or slow progressive disease </li></ul></ul><ul><ul><li>Low uptake of fluorodeoxyglucose </li></ul></ul><ul><ul><li>Repeated radioiodine treatment (response rate: 85%, with 96% of complete responses seen with a cumulative activity <600 mCi) </li></ul></ul>
  23. 23. <ul><li>Candidates for other treatment modalities </li></ul><ul><ul><li>Older age </li></ul></ul><ul><ul><li>Poorly differentiated tumor </li></ul></ul><ul><ul><li>No or low radioiodine uptake </li></ul></ul><ul><ul><li>Large metastases </li></ul></ul><ul><ul><li>Location in bones </li></ul></ul><ul><ul><li>Rapidly progressive disease </li></ul></ul><ul><ul><li>High uptake of fluorodeoxyglucose </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  24. 24. <ul><li>Radioiodine treatment for lung metastases : 45% of patients with radioiodine uptake and no substantial sequellae. </li></ul><ul><li>Large bone metastases : surgery and radiotherapy , but remission is rarely achieved. </li></ul><ul><ul><li>local procedures such as embolisation, radiofrequency or cement injection, and treatment with biphosphonates can delay tumor progression and palliate symptoms </li></ul></ul>
  25. 25. <ul><li>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 </li></ul><ul><li>Complete remission after treatment: only a third of patients with metastases </li></ul>
  26. 26. Cytotoxic chemotherapy and biotherapy <ul><li>absence of evidence of benefits </li></ul><ul><li>Doxorubicin :response rates :0% to 22% , lasting only a few months </li></ul><ul><li>Dendritic cell immunotherapy might be effective but no studies on DTC. </li></ul>
  27. 27. Molecularly targeted treatments <ul><li>Two main theoretical approaches: </li></ul><ul><ul><li>inhibition of tumor growth by inhibiting cell signaling and angiogenesis </li></ul></ul><ul><ul><li>induction of redifferentiation of thyroid tumor tissue. </li></ul></ul>
  28. 28. Targets in cell signalling and angiogenesis <ul><li>Papillary carcinomas : </li></ul><ul><ul><li>80% :mutations of genes of mitogen-activated protein kinase (MAPK) pathway. </li></ul></ul><ul><ul><li>5–30%: RET/PTC rearrangements </li></ul></ul><ul><ul><li>10%: RAS mutations </li></ul></ul><ul><ul><li>40%: BRAF mutations </li></ul></ul><ul><li>Follicular carcinomas: </li></ul><ul><ul><li>20–35% : RAS mutations </li></ul></ul><ul><ul><li>30% :PAX8/PPARɣ rearrangements </li></ul></ul>
  29. 29. Targets in cell signalling and angiogenesis <ul><li>Only a few relations between gene mutations and prognosis </li></ul><ul><ul><li>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. </li></ul></ul>
  30. 30. Angiogenesis <ul><li>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 </li></ul><ul><li>Antivascular treatment blocks the growth of differentiated thyroid carcinoma in experimental models. </li></ul>
  31. 31. Interference with signal transduction pathways <ul><li>AMG 706, BAY 43-9006, ZD 64-74, and AG-013736, in DTC is being studied in phase II trials </li></ul><ul><li>effect :inhibition of the MAPK pathway and of angiogenesis and others. </li></ul><ul><li>BAY 43-9006 also inhibits BRAF kinase </li></ul>
  32. 32. Restoring radioiodine uptake <ul><li>Retinoic acid analogues : increase the expression of the natrium iodide symporter -> increase radioidodine uptake ,but in only a few patients. </li></ul>
  33. 33. Other drugs <ul><li>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. </li></ul><ul><li>COX-2 inhibitor :Cyclooxygenase-2 : overexpressed in thyroid cancer that promotes tumour progression </li></ul>
  34. 34. Combination treatment <ul><li>The use of antiangiogenic drugs can enhance the efficacy of radiotherapy, radioiodine treatment, or chemotherapy. </li></ul><ul><li>MAPK and the PI3K pathways blockers. </li></ul>