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  • Thyroid cancer diagnosis and management 4C1 RI 李士寬
    • 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
    • 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
    • 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
  • Thyroid cancer
    • 1.5% of all cancer
    • Papillary carcinoma(75-85% of cases)
    • Follicular carcinoma(10-20%)
    • Medullary carcinoma(5%)
    • Anaplastic carcinoma(<5%)
  • 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
  • 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
  • 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
  • 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%
  • 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
  • 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
  • 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.
  • Treatment
    • Thyroid surgery
    • Advantage of near-total thyroidectomy :
      • can be ablated with RAI
      • can be followed with thyroglobulin levels
    • 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)
  • 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.
  • 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
  • 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%
  • Local and regional recurrences
    • Small lymph-node metastases: 131 I treatment , but abnormalities can still persist after two to three courses -> surgery
    • 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 .
  • 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
    • 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,
  • 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)
    • 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
    • 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
    • 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
  • 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.
  • Molecularly targeted treatments
    • Two main theoretical approaches:
      • inhibition of tumor growth by inhibiting cell signaling and angiogenesis
      • induction of redifferentiation of thyroid tumor tissue.
  • 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
  • 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.
  • 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.
  • 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
  • Restoring radioiodine uptake
    • Retinoic acid analogues : increase the expression of the natrium iodide symporter -> increase radioidodine uptake ,but in only a few patients.
  • 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
  • Combination treatment
    • The use of antiangiogenic drugs can enhance the efficacy of radiotherapy, radioiodine treatment, or chemotherapy.
    • MAPK and the PI3K pathways blockers.