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 fieldCT: 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

123I 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 disease

Long-term supplementation with levothyroxine (maintains TSH concentrations at <0.1mU/L)

Whole body scan rhTSH vs.thyroid hormone withdrawal rhTSH: stimulate 131I 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,131I 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: 131I 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.