Thyroid cancer diagnosis and management4C1 RI

09-2 78F, 51924441.Thyroid cancer, follicular carcinoma, with multiple lung metastasis and skull metastasis s/p total thyroidectomy & parathyroidectomy2.Obstructive pneumonitis3.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 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 + parathyroidectomyOperation Finding1. Enlarged, hard, irregular, shape; yellowish, white tumor; 8X7X6cm over Rt thyroid with invasion to paraspinal muscle. Parathyroid origin was likely2. 4X2X2cm Lt thyroid with one 1X1cm hard tumor inside

Thyroid cancer1.5% of all cancerPapillary carcinoma(75-85% of cases)Follicular carcinoma(10-20%)Medullary carcinoma(5%)Anaplastic carcinoma(

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 carcinomaPathogenesis : Activation of receptor tyrosine kinases (RET/PTC, TRK, MET) Produce chimeric proteins with tyrosine kinase activityClinical presentation: Most: asymptomatic thyroid nodule , discovered by fine needle aspiration biopsy.Advanced disease: hoarseness,dysphagia,cough, or dyspneaMinority: lung metastasis

Papillary thyroid carcinoma

Pathologic features: unencapsulated , calcified psammoma bodiesGood 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 noduleRapid, painless growthFine-needle aspiration of thyroid nodules and examination of the obtained material123I 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 131I(4-5mCi) ablative dose of 29 mCi of 131I whole body scan(6 months after surgery) to identify possible metastatic diseaseLong-term supplementation with levothyroxine (maintains TSH concentrations at

Whole body scanrhTSH vs.thyroid hormone withdrawalrhTSH: stimulate 131I uptake without symptoms of hypothyroidism. Recommened for pts predicted to be at low risk of recurrencethyroid 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 laterstill negative management with suppressive therapy and measurements of Tg every 6 to 12 monthsScan negative, Tg-positive(>5 to 10 ng/mL) radioiodine treatment.Lung metastasis:CXR,131I scan,spiral CT Bone metastasis:bone scintigraphy , CT , MRI

Epidemiology of incurable DTC85% of patients with DTC :disease-free after initial treatment 1015% : 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: 131I treatment , but abnormalities can still persist after two to three coursessurgery

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 diseaseIndications Abnormal clinical findingsAbnormal imaging findingsIncreasing trend in serum thyroglobulin concentrationStaging Neck ultrasonography, whole body scintigraphy with a large activity of radioiodineConventional imaging: neck and chest CT, bone MRI, [18F]FDG PETFine-needle biopsy or surgical biopsy in case of unusual presentation

Treatment methodsSurgery (when feasible)Radioiodine treatment in presence of radioiodine uptake in tumor fociOther local treatments (dependent on location and extent of disease): external radiation beam treatment, embolisation, radiofrequency, cement injectionNew treatment methods, eg, molecularly targeted treatments,

Selection of patients with metastases for treatment Candidates for radioiodine treatmentYounger ageWell differentiated tumourHigh radioiodine uptakeSmall metastasesLocation in lungsStable or slow progressive diseaseLow uptake of fluorodeoxyglucoseRepeated radioiodine treatment (response rate: 85%, with 96% of complete responses seen with a cumulative activity

Candidates for other treatment modalitiesOlder agePoorly differentiated tumorNo or low radioiodine uptakeLarge metastasesLocation in bonesRapidly progressive diseaseHigh uptake of fluorodeoxyglucosePatients 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 benefitsDoxorubicin :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 angiogenesisinduction 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.530%: RET/PTC rearrangements 10%: RAS mutations40%: BRAF mutations Follicular carcinomas:2035% : RAS mutations 30% :PAX8/PPAR rearrangements

Targets in cell signalling and angiogenesisOnly 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.

AngiogenesisThyroid 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 uptakeRetinoic 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 treatmentThe use of antiangiogenic drugs can enhance the efficacy of radiotherapy, radioiodine treatment, or chemotherapy. MAPK and the PI3K pathways blockers.