MANAGEMENT OF THYROID CANCER Local seminar Medical Oncology department By Salah Mabruok Khalaf South Egypt Cancer Institute 2012
Epidemiology• Thyroid Cancer accounts for 1.5% of all cancers• The most common endocrine malignancy (95% of all endocrine cancers)• Sex: Female to Male Ratio 2.5:1 except anaplastic carcinoma• Age: most common after age 30
Risk Factors for Thyroid Cancer1. Neck irradiation The only well-established risk factor for differentiated thyroid cancer .2. Genetic factors 1. Papillary thyroid carcinoma may occur in several rare inherited syndromes, including i.Familial adenomatous polyposis ii.Gardners syndrome iii.Cowdens disease 2. Medullary carcinoma in MEN syndrome3. Other risk factors i. History of goiter ii. family history of thyroid disease iii. Female gender iv. Asian race.
Clinical Manifestation• Thyroid enlargement• Most patients are euthyroid and present with a thyroid nodule• Symptoms such as dysphagia, dyspnea and hoarseness usually indicate advanced disease• Cervical lymph node enlargement
Investigations• Serum TSH• Fine Needle Aspiration Cytology (FNA)• High Resolution Thyroid US- helpful in detecting non palpable nodule and solid versus cystic lesion• Thyroid Isotope Scanning- to assess functional activity of a nodule
• FNAC indicationsI. Sonar-based criteria Solid nodule 1. More than 1 cm if associated with sonographic suspious features 2. More than 1.5 cm in absence of sonographic suspicionMixed solid and cystic 1. More than 1.5 cm if associated with sonographic suspicious features 2. More than 2 cm in absence of sonographic suspicionSpongiform nodule (microcystic component > 50% of nodulesI. High risk Clinical feature RT exposure Genetic predisposition Sonographic suspicious features (hypoechoic, microcalcification, increased central vascularity, infiltrative margin or taller than wide in transverse plan)
Fine Needle Aspiration•Procedure of Choice – Fast, minimally invasive and fewrisk•Incidence of False positive: 1%•Incidence of False negative: 5%•FNA is not a tissue diagnosis•Limitation of FNA: • Cannot distinguish a benign follicular from a malignant lesion (cancer invade capsule)
Classification and Incidence of Thyroid CancerTumors of Follicular Cell Origin Differentiated Papillary 75% Follicular 10% Hurthle Cell 5% Undifferentiated Anaplastic 5%: 1-Small cell carcinoma. 2-Giant cell carcinoma.Tumors of Parafollicular cells Medullary 5% Other 1% 1-sarcomas 2-lymphomas 3-epidermoid carcinomas 4-Teratomas 5-metastasis from other cancers
Papillary Cancer The most common malignantthyroid tumor (70-80% of allcancers) Women predominance Age: 38-45 Accounts for 90% of radiationinduced thyroid cancer Prognosis directly related totumor size
• Papillary Cancer1.Histologic: 1. Psammoma bodies 2. Orphan Ann nucleus2.Multicentric: 30-50%3.Spread via Lymphatics- propensity for cervical node involvement4.Invasion of adjacent structures and distant mets uncommon
FOLLICULAR THYROID CANCER1.Usually Encapsulated2.More Common Among Older Patients3.Woman > Man4.More Aggressive & Less Curable Than Papillary5.Vascular Invasion (veins and arteries) within the thyroidgland is common6.Blood Spread (lung and bone)7.Types: 1. Follicular carcinoma 2. Follicular carcinoma variant: Minimally Invasive Hurthle Cell8.Rarely associated with radiation exposure
Hürthle Cell Neoplasms1.More aggressive than other differentiatedthyroid carcinomas (higher mets/lower survivalrates)2.Less affinity for I1313.Need to differentiate from benign/malignant4.Metastasis may be more sensitive to I131 thanprimary
Medullary Thyroid Cancer1. Usually present as a mass ± lymphadenopathy2. It can also be diagnosed by fine-needle aspiration biopsy microscopically typically.3. Family members should be screened for calcitonin elevation and/or for the RET proto-oncogene mutation4. Not associated with radiation exposure5. Residual disease (following surgery) or recurrence can be detected by measuring calcitonin
Medullary Thyroid Cancer Occurs in Four Clinical SettingsI- Sporadic1.80% of all cases of medullary thyroid cancer.2.Typically unilateral3.No associated endocrinopathies4.Peak onset 40 - 60.5.Females predominance: 3:2 ratio.6.One third will present with intractable diarrhea. Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to the hormones secreted by the tumor (calcitonin, prostaglandins, serotonin, or VIP).
II-MEN II-A (Sipple Syndrome)(Multiple Endocrine Neoplasia II A).1.Sipple syndrome has  bilateral medullary carcinoma  pheochromocytoma  hyperparathyroidism.2.This syndrome is inherited in an autosomal dominant fashion. Because of this, males and females are equally affected.3.Peak incidence of medullary carcinoma in these patients is in the 30s.
III-MEN II B1.This syndrome has  medullary carcinoma  Pheochromocytoma  mucosal ganglioneuromas and Marfanoid habitus.2.Inheritance is autosomal dominant as in MEN IIA (m=f)3.Pheochromocytomas must be detected prior to any operation.4.The idea here is to remove the pheochromocytoma first to remove the risk of severe hypertensive episodes while the thyroid or parathyroid is being operated on.
IV-Inherited medullary carcinoma without associated endocrinopathies.This form of medullary carcinoma is the least aggressive.Like other types of thyroid cancers, the peak incidence is between the ages of 40 and 50.
Anaplastic cancer1)Peak onset age 65 and older Very rare in young patients1)Males more common than females by 2 to 1 ratio2)Undifferentiated3)May arise many years (>20) following radiationexposure.4)Neck mass usually large, diffuse, and very hard5)Rapidly growing, often inoperable, highly recurrent
7) Invade locally, metastasize both locally and distantly (to lungs or bones)8) Cervical metastasis are present in the vast majority (over 90%) of cases at the time of diagnosis.9) Mean survival 6 months10) Often requires the patient to get a tracheostomy to maintain their airway.
STAGING OF THYROID CANCER In differentiated thyroid carcinoma, several classification and staging systems have been introduced. However, no clear consensus has emerged favoring any one method over another• AMES system/AGES System/GAMES system• TNM system• MACIS system• University of Chicago system• Ohio State University system• National Thyroid Cancer Treatment Cooperative Study (NTCTCS)
TNM Staging• Primary tumor (T) (All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor.)TX: Primary tumor cannot be assessedT0: No evidence of primary tumorT1: Tumor ≤ 2 cm, limited to the thyroidT2: Tumor > 2 cm but ≤4 cm, limited to the thyroidT3: Tumor > 4 cm limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
• T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve• T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vesselsAll anaplastic carcinomas are considered T4 tumors.• T4a: Intrathyroidal anaplastic carcinoma—surgically resectable• T4b: Extrathyroidal anaplastic carcinoma—surgically unresectable
• Regional lymph nodes (N)(Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lNs)• NX: Regional lymph nodes cannot be assessed• N0: No regional lymph node metastasis• N1: Regional lymph node metastasis • N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian on the cricothyroid membrane (precricoid) lymph nodes) • N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes
• Distant metastases (M)• MX: Distant metastasis cannot be assessed• M0: No distant metastasis• M1: Distant metastasis
AJCC Stage GroupingsPapillary or follicular thyroid cancer • Younger than 45 years • Stage I • Any T, any N, M0 • Stage II • Any T, any N, M1 • Age 45 years and older • Stage I • T1, N0, M0 • Stage II • T2, N0, M0 • Stage III • T3, N0, M0 • T1, N1a, M0 • T2, N1a, M0 • T3, N1a, M0
Papillary or follicular thyroid cancer Age 45 years and olderStage I Stage IVA T4a, N0, M0 T1, N0, M0 T4a, N1a, M0Stage II T1, N1b, M0 T2, N0, M0 T3, N1b, M0Stage III T2, N1b, M0 T4a, N1b, M0 T3, N0, M0 Stage IVB T1, N1a, M0 T4b, any N, M0 T2, N1a, M0 Stage IVC T3, N1a, M0 Any T, any N, M1
Medullary thyroid cancer•Stage I Stage IVA • T1, N0, M0 T4a, N0, M0•Stage II T4a, N1a, M0 • T2, N0, M0 T1, N1b, M0 T2, N1b, M0•Stage III T3, N1b, M0 • T3, N0, M0 T4a, N1b, M0 • T1, N1a, M0 Stage IVB • T2, N1a, M0 T4b, any N, M0 • T3, N1a, M0 Stage IVC Any T, any N, M1
• Anaplastic thyroid cancer• All anaplastic carcinomas are considered stage IV. • Stage IVA • T4a, any N, M0 • Stage IVB • T4b, any N, M0 • Stage IVC • Any T, any N, M1
• University of Chicago system:• Class I—disease limited to the thyroid gland• Class II—lymph node involvement• Class III—extrathyroidal invasion• Class IV—distant metastases.
PROGNOSISPrognostic schemes: GAMES scoring (PAPILLARY &FOLLICULAR CANCER)•G Grade•A Age of patient when tumor discovered•M Metastases of the tumor (other than Neck LN)•E Extent of primary tumor•S Size of tumor (>5 cm)•The patient is then placed into a high or low riskcategory
Prognostic Risk Classification for Patients with Well-Differentiated Thyroid Cancer (GAMES ) Low Risk High Risk• Grade Well Differentiated Poorly Differentiated• Age <40 >40• Mets None Regional or Distant• Extent No local extension, Capsular invasion, intrathyroidal, extrathyroidal• Sex Female Male
MACIS Scoring•Developed by the Mayo Clinic for staging.•It is known to be the most accurate predictor of apatients outcome with papillary thyroid cancer (M =Metastasis, A = Age, I = Invasion, C = Completenessof Resection, S = Size)•MAICS Score 20 year Survival < 6 = 99% 6-7 = 89% 7-8 = 56% > 8 = 24%
Stage I and II Papillary and FollicularI-Total thyroidectomy:• Rationale? Bilateral cancers are common (30-85%) improved effectiveness for I131 ablation lowers dose needed for I131 ablation allows f/u with thyroglobulin levels decreased recurrence in all groups improved survival in high risk pts. Decreased risk of pulmonary mets• Disadvantage?higher incidence of hypoparathyroidism, but this complication may be reduced when a small amount of tissue remains on the contralateral side.
II-Lobectomy:• Rationale? Most patients are low risk and excellent prognosis Role of adjuvant treatment not defined Complications of Total Occult multicentric tumor not clinically significant Most local recurrences treated with surgery Excellent outcome with lobectomy in low risk patients• Disadvantage?• approximately 5% to 10% of patients will have a recurrence
Indications for total Thyroidectomy OR lobectomy: (all present)• Age 15 y - 45 y• No prior radiation• No distant metastases• No cervical lymph node metastases• No extrathyroidal extension• Tumor < 4 cm in diameter• No aggressive variant
When complete total thyroidectomy after lobectomy:• Aggressive variant• Macroscopic multifocal disease• Positive isthmus margins• Cervical lymph node metastases• Extrathyroidal extensionAggressive=Tall cell, columnar cell, insular, oxyphilic, or poorly differentiated features
• Node removal ?• Selective node removal can be performed, and radical neck dissection is usually not required.• This results in a decreased recurrence rate, but has not been shown to improve survival.
Thyroid carcinoma after lobectomy for benign lesionsI-Completion of thyroidectomy: III- follow up:• > 4 cm • Negative margins• Positive margins • No contralateral lesion• Extra-thyroidal invasion (T3 or T4( • < 1 cm in diameterII- Completion of Thyroidectomy or follow • No suspicious lymph up: node• Clinically suspicious lymph node, contralateral lesion, or perithyroidal node• Aggressive variant• Macroscopic multifocal disease• ≥1 cm in diameter
POSTSURGICAL EVALUATION AFTER THYROIDECTOMY I-No gross Residual Disease in neck: • Follow up (TSH + thyroglobulin measurement + antithyroglobulin antibodies) II- Gross Residual Disease in neck: • Resectable >>>>>>>> Surgery • Irresectable >>>>>>>> Total body radioiodine scan: Inadequate uptake >>>>>>RT Adequate uptake >>>>> Radioiodine treatment or RT No scan performed >>>>>Radioiodine treatment or RT • Total body radioiodine scan is done after adequate TSH stimulation (thyroid withdrawal or recombinant rhTSH stimulation)
Postoberative I131?a postoperative course of therapeutic (ablative) doses of I131 results in a decreased recurrence rate among high-risk patients with papillary and follicular carcinomas.Indications: (any present)• Age < 15 y or > 45 y• Radiation history• Known distant metastases• Bilateral nodularity• Extrathyroidal extension• Tumor > 4 cm in diameter• Cervical lymph node metastases• Aggressive variant
Pretherapy whole body iodine scan:•If performed, a pretherapy scan should use a low dose of 131 I(1 to 5 mCi) or 123I. • To detect residual thyroid tissue, thyroid cancer, and metastatic foci • To reduce the potential for sublethal radiation stunning of thyroid tissue that prevents optimal uptake of future 131I therapy.•Stunning is defined as a reduction in uptake of the I therapy 131dose induced by a pretreatment diagnostic dose
Dose of RAI•The dosing of 131I for ablation is somewhat controversial.•Low-dose ablation with less than 30 mCi administered onan outpatient basis: • For low-risk young patients•High-dose ablation with100 to 200 mCi • For high-risk patients•300 mCi • For all patients with metastatic disease that treated with repeated therapeutic doses of 131I
Replacement therapy?•Postoperative treatment with exogenous thyroid hormonein doses sufficient to suppress thyroid-stimulating hormone(TSH) with development of thyrotoxic manifestations;decreases incidence of recurrence.•Administration of Thyroid Hormone To suppress TSH and growth of any residual thyroid To maintain patient euthyroid o Maintain TSH level 0.1uU/ml in low risk pts o Maintain TSH Level < 0.1uU/ml in high risk pts
Stage III Papillary and FollicularA. Surgery•Total thyroidectomy plus removal of involved lymph nodes orother sites of extrathyroid disease.B. Adjuvant therapy•I131 ablation following total thyroidectomy if the tumordemonstrates uptake of this isotope.•External-beam radiation therapy if I131 uptake is minimal•Replacement therapy for all patients.
Stage IV Papillary and Follicular1) Adequate uptake of I131 • I1311) Inadequate uptake or not sensitive to I131 i. Localized lesions 1) Radiation therapy 2) Resection of limited metastases dont uptake of I131. ii. Disseminated disease 1) TSH suppression with thyroxine is effective. 2) Chemotherapy has been reported to produce occasional complete responses of long duration. 3) Clinical trials testing new approaches to this disease.
Medullary Thyroid Cancertreatment• Thyroidectomy: • total thyroidectomy + routine central and bilateral modified neck dissections ..Why?• External radiation therapy: • palliation of locally recurrent tumors, without evidence that it provides any survival advantage. • Radioactive iodine has no place in the treatment of patients with MTC.• Palliative chemotherapy: • Palliative chemotherapy has been reported to produce occasional responses in patients with metastatic disease. • No single drug regimen can be considered standard. • Some patients with distant metastases will experience prolonged survival and can be observed until they become symptomatic.
Anaplastic Thyroid Cancer• Surgery: • Tracheostomy is frequently necessary. • If the disease is confined to the local area, which is rare, total thyroidectomy is warranted to reduce symptoms caused by the tumor mass.• Radiation therapy: • Used in patients who are not surgical candidates or whose tumor cannot be surgically excised.
Anaplastic Thyroid Cancer• Chemotherapy: • Produce partial remissions in some patients. • Approximately 30% of patients achieve a partial remission with doxorubicin. • The combination of doxorubicin plus cisplatin appears to be more active than doxorubicin alone and has been reported to produce more complete responses.Treatment options under clinical evaluation: • The combination of chemotherapy plus radiation therapy in patients following complete resection may provide prolonged survival but has not been compared to any one modality alone.
Recurrent Thyroid Cancer• Recurrence rate for differentiated thyroidis about 10-30% • 80% develop recurrence with disease in the neck alone, and • 20% develop recurrence with distant metastases. The most common site of distant metastasis is the lung.• The prognosis for patients with clinically detectable recurrences is generally poor, regardless of cell type.
Treatment of recurrent thyroid cancerThe selection of further treatment depends on manyfactors, including Cell type Uptake of I131 Prior treatment Site of recurrence Individual patient considerations
Treatment of recurrent thyroid cancer• Adequate I131 uptake • Localized • Surgery with or without I131 ablation can be useful in controlling local recurrences, regional node metastases, or, occasionally, metastases at other localized sites. • I131 ablation • RT • Disseminated • I131 ablation • Systemic chemotherapy for tumor not sensitive to I131. Chemotherapy has been reported to produce occasional objective responses, usually of short duration.
Treatment of recurrent thyroid cancer• Inadequate I131 uptake or insensitive to I131 • Localized • Surgery with or without I131 ablation can be useful in controlling local recurrences, regional node metastases, or, occasionally, metastases at other localized sites. • RT • Disseminated • Systemic chemotherapy
Systemic chemotherapy• Doxorubicin alone• Cisplatin and doxorubicin (better)• BAP: Cisplatin, doxorubicin and bleomycin• CVD: cyclophosphamide, vincristine, and dacarbazine• Dacarbazine and 5-fluorouracil
• Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy.• Two cycles of doxorubicin (60 mg/m(2)) and cisplatin (120 mg/m(2)) were delivered before RT and four cycles after RT.• RT consisted of two daily fractions of 1.25 Gy, 5 days per week to a total dose of 40 Gy to the cervical lymph node areas and the superior mediastinum).• Improve OS and decrease RR.
BAP regimen• Schedule • BAP regimen which consisted of bleomycin (B) 30 mg a day for three days, adriamycin (A) 60 mg/m2 iv in day 5, and cisplatinum (P) 60 to mg/m2 iv in day 5.• Cell type • Several histologic types of thyroid carcinoma responded, but the best responses were observed in medullary and anaplastic giant- cell carcinomas.• Effectiveness • BAP regime can achieve reasonable palliation, and probably increases survival, in poor-prognosis thyroid cancers.
CVD regimen• Schedule • cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), and dacarbazine (600 mg/m2 daily for 2 days in each cycle) every 3 weeks.• Cell type • Medullary thyroid carcinoma.• Effecetiveness • CVD chemotherapy has moderate activity and is well tolerated in patients with advanced MTC.
Dacarbazine and 5-fluorouracil• Schedule • 5 day intravenous courses of dacarbazine (DTIC) (250 mg/sqm) and 12 hour infusion 5-fluorouracil (450 mg/sqm), given every 4 weeks. Six cycles• Cell type • MTC• Effectiveness • Treatment of advanced thyroid carcinoma with DTIC and 5-FU appeared to have significant activity and was well tolerated.
Take home messages• FNAC is not adequate for definite diagnosis of follicular carcinoma• Because the mixed papillary-follicular variant tends to behave like a pure papillary cancer, it is treated in the same manner and has a similar prognosis.• Thyroglobulin as a marker of follow up is useful only in absence of any thyroid tissue in differentiated thyroid cancer.• Once medullary carcinoma is diagnosed, familial predisposition should be checked up• If I131 is indicated, stunning effect should be avoided
Take home messagesAll except rule•All risk factors of differentiated thyroid cancers are notestablished except Radiotherapy•All types are caused by RT except medullary•All types commonly occur before age of 50y exceptanaplastic•All types are commoner in females than in males exceptanaplastic (M > F) and familial MTC (M=F)•All types rarely associated with genetic syndrome exceptmedullary
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