Thyroid Cancer Management

Prof. Dr. Yusuf BÜKEY
Cerrahpasa School of Medicine Endocrine Surgery Department

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Thyroid Cancer
 Clinically uncommon (60 per million per year)  Pathologically common (up to 15 % in the U.S.A.)

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Thyroid Cancer Management
 Preoperative Diagnosis Thyroid Cancer  Peroperative Diagnosis Thyroid Cancer  Postoperative Diagnosis Thyroid Cancer  Medullary Thyroid Cancer  Anaplastic Thyroid Cancer  Cervical Lymph Nodes  Pediatric Thyroid Cancers  Completion Thyroidectomy

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Preoperative Diagnosis
 Examination of the thyroid nodule:
• consistency  hard vs. soft • size < 4.0 cm • multinodular vs. solitary nodule • multinodular  3% chance of malignancy (Goldman, 1996) • solitary nodule  5%-12% chance of malignancy (Goldman, 1996) • mobility with swallowing • mobility with respect to surrounding tissues • well circumscribed vs. ill defined borders

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Preoperative Diagnosis
 Examine for ectopic thyroid tissue  Indirect or fiberoptic laryngoscopy
• vocal cord mobility • evaluate airway • preoperative documentation of any unrelated abnormalities

 Systematic palpation of the neck
• Metastatic adenopathy commonly found:  in the central compartment (level VI)  along middle and lower portion of the jugular vein (regions III and IV)

5

Blood Tests
 Thyroid function tests
• thyroxine (T4) • triiodothyronin (T3) • thyroid stimulating hormone (TSH)

 Serum Calcium  Thyroglobulin (TG)  Calcitonin

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Imaging Modalities for Thyroid Cancer
 Radioiodine  US  CT  MRI  PET  Others

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Thyroid Ultrasound
      Objective measure of size Multinodularity Screening in radiated patients Recurrent carcinoma Cystic vs solid Ultrasound guided biopsy

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Thyroid Ultrasound
 Suspicious Nodules 0.8- 1.5 cm
• Hypoechoic lesion plus one of the following :  Microcalcifications  Irregular border  Central vascularity
(Papini et al JCEM 87: 1941, 2002)

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Longitudinal scan of a papillary thyroid cancer, showing an irregularly shaped nodule that has hypoechogenic heterogeneous internal echo and calcifications (arrows).
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A, Longitudinal scan and B, transverse scan of a metastatic lymph node from papillary thyroid cancer. The lymph node is echogenic, with a longitudinal – 11 transverse ratio of 1.3.

Thyroid Ultrasound
 Disadvantages:
 Unable to reliably diagnose true cystic lesions  Cannot accurately distinguish benign from malignant nodules  Follicular Lesions ??

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Fine-Needle Aspiration
 Currently considered to be the best first-line diagnostic procedure in the evaluation of the thyroid nodule:  Advantages:
• • • • Safe Cost-effective Minimally invasive Leads to better selection of patients for surgery than any other test (Rojeski, 1985)
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Fine-Needle Aspiration
 FNA halved the number of patients requiring thyroidectomy
(Mazzaferri, 1993)

 FNA has double the yield of cancer in those who do undergo thyroidectomy
(Mazzaferri, 1993)

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FNA Results of Thyroid Nodule
 Pathologic results are categorized as:
• positive • negative • indeterminate

 Hossein and Goellner (1993) use four categories. They pooled data from seven series and came up with the following rates:
• • • • benign  69% suspicious  10% malignant  4% nondiagnostic  17%
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FNA Results of Thyroid Nodule
 Limitations • skill of the aspirator • expertise of the cytologist • difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (follicular and Hurthle cell)  False negative results = 1%-6%
(Mazzeferri, 1993)

 False positive results = 3%-6%
(Rojeski, 1985, Mazzeferri, 1993, Hall, 1989)
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Malignant FNA
 Papillary carcinoma  Medullary carcinoma  Anaplastic carcinoma  Thyroid lymphoma  Metastatic carcinoma  Follicular carcinoma?

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Thyroid Cancer Classification
 Papillary carcinoma
• • • • Follicular variant Tall cell Diffuse sclerosing Encapsulated

 Medullary Carcinoma  Miscellaneous
• • • • Sarcoma Lymphoma Squamous cell carcinoma Mucoepidermoid carcinoma • Clear cell tumors • Pasma cell tumors • Metastatic
• • • • Direct extention Kidney Colon Melanoma

 Follicular carcinoma
• Overtly invasive • Minimally invasive

 Hurthle cell carcinoma  Anaplastic carcinoma
• Giant cell • Small cell

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Papillary Carcinoma
 60%-80% of all thyroid cancers
(Geopfert, 1998, Merino, 1991)

 Histologic subtypes
• • • • • Follicular variant Tall cell Columnar cell Diffuse sclerosing Encapsulated (Goldman, 1996)

 Prognosis is 80% survival at 10 years  Females > Males  Mean age of 35 years
(Mazzaferri, 1994)
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Incidentaloma/Micrometastatic Disease
 Microcarcinomas - a manifestation of papillary carcinoma
• Definition - papillary carcinoms smaller than 1.0 cm • Most are found incidentally at autopsy • Autopsy reports indicate that these may be present in up to 35% of the population (Mazzaferri, 1993) • Usually clinically silent • Most agree that the morbidity and mortality from microcarcinoma is minimal and near that of the normal population • One study showed a 1.3% mortality rate (Hay, 1990)

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Incidentaloma/Micrometastatic Disease
 Lesions detected by imaging or found after surgery for unrelated indication  Thyroid nodules common in population (4-10% have palpable nodules any given time)  Female/male incidence 6.4 / 1.6%  12% detected by palpation vs. 45% by imaging  Lesions less than 1 cm-observe  Lesions 1-2cm “gray zone”  Lesions > 2cm are NOT INCIDENTAL

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Incidentaloma/Micrometastatic Disease
 Consider suspicious features:
• • • • Increased vascularity Irregular margin Central microcalcification Cervical adenopathy

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Papillary Thyroid Cancer
 Lymph node involvement is common
• Major route of metastasis is lymphatic • 46%-90% of patients have lymph node involvement
(Goepfert, 1998, Scheumann, 1984, De Jong, 1993)

• Clinically undetectable lymph node involvement does not worsen prognosis
(Harwood, 1978)

23

Incidentaloma/Micrometastatic Disease and PTC
 Pathology
• Gross - vary considerably in size - often multi-focal - unencapsulated but often have a pseudocapsule • Histology - closely packed papillae with little colloid - psammoma bodies - nuclei are oval or elongated, pale staining with ground glass appearanc - Orphan Annie cells
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Papillary Carcinoma

Algorithm for Treatment of Possible PTC

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Follicular Carcinoma
 20% of all thyroid malignancies  Women > Men (2:1 - 4:1)    Metastasis - angioinvasion and hematogenous spread 
• 15% present with distant metastases to bone and lung Lymphatic involvement is seen in 13% (Goldman, 1996) (Davis, 1992, De Souza, 1993) Mean age of 39 years (Mazzaferri, 1994) Prognosis - 60% survive to 10 years (Geopfert, 1994)

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Follicular Carcinoma
Current Classification • Minimally invasive (gross encapsulation) New classification Minimally invasive (capsule only) angioinvasive grossly encapsulated Widely invasive

Widely invasive

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Follicular Neoplasms
 Resection of lobe/isthmus with careful examination for gross invasion or nodal disease  Await final pathology of lobe/isthmus and if positive, return to OR for completion lobectomy  Subsequent I131 treatment, TSH suppression and monitoring of thyroglobulin (<2µg/l)

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Hurthle Cell Carcinoma
 Variant of follicular carcinoma  First described by Askanazy
• “Large, polygonal, eosinophilic thyroid follicular cells with abundant granular cytoplasm and numerous mitochondria” (Goldman, 1996)

 Definition (Hurthle cell neoplasm) - an encapsulated group of follicular cells with at least a 75% Hurthle cell component  Carcinoma requires evidence of vascular and capsular invasion  4%-10% of all thyroid malignancies (Sessions, 1993)

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Hurthle Cell Carcinoma
 Women > Men  Lymphatic spread seen in 30% of patients
(Goldman, 1996)

 Distant metastases to bone and lung is seen in 15% at the time of presentation

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Management Hurthle Cell Carcinoma
 Total thyroidectomy is recommended because:
1) Lesions are often multifocal 2) They are more aggressive than WDTCs 3) Most do not concentrate iodine

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Prognosis DTC
 Based on age, sex, and findings at the time of surgery (Geopfert, 1998)  Several prognostic schemes represented by acronyms have been developed by different groups:
• AMES (Lahey Clinic, Burlington, MA) • GAMES (Memorial Sloan-Kettering Cancer Center,
New York, NT)

• AGES (Mayo Clinic, Rochester, MN)

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Thyroid Carcinoma Classification
 Papillary, Follicular and Medullary Carcinoma
• • • • T1 - ≤ 2cm intrathyroidal T2 - > 2 to 4 cm intrathyroidal T3 - > 4 cm or minimal extension T4a – subcutaneous, larynx, trachea, esophagus, recurrent laryngeal nerve • T4b – prevertebral fascia, mediastinal vessels, carotid artery

 Anaplastic/ undifferantiated Carcinoma
• T4a – tumor limited to thyroid • T4b – tumor beyond thyroid capsule

 All types
• N1a - Level VI N1b – other regional
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Staging for Differentiated Thyroid Cancer
 In differentiated thyroid carcinoma, several classification and staging systems have been introduced. However no 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)

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University of Chicago system – An easy to remember staging system for papillary carcinoma is the Clinical Class scheme proposed by De Groot colleague the University of Chicago  Class I  disease limited to thyroid gland  Class II  Lymph node involvement  Class III  extrathyroidal invasion  Class IV  distant metastases

35

National Thyroid Cancer Treatment Cooperative Study (NTCTCS)

The NTCTCS created a staging approach that was applied prospectively to a registry of patients drawn from 14 cooperating institutions . Clinicalpathologic staging was based upon:

• • • • • • •

patient age at diagnosis tumor histology tumor size intrathyroidal multifocality extraglandular invasion metastases tumor differentiation

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Prognosis DTC
Low risk group
- men younger than 40 years and women younger than 50 years regardless of histologic typ - recurrence rate -11% - death rate - 4%

Intermediate risk group
- men older than 40 years and women older than 50 years who have papillary carcinoma - recurrence rate - 29% - death rate - 21%

High risk group
- men older than 40 years and women older than 50 years who have follicular carcinoma - recurrence rate - 40% - death rate - 36% (Cady and Rossi, 1988

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Medullary Thyroid Carcinoma
 10% of all thyroid malignancies  1000 new cases in the U.S. each year  Arises from the parafollicular cell or C-cells of the thyroid gland
• derivatives of neural crest cells of the branchial arches • secrete calcitonin which plays a role in calcium metabolism

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Medullary Thyroid Carcinoma
 Tumor of C- cells  75 % sporadic  25% hereditary  Do not concentrate iodine  Produce calcitonin

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Medullary Thyroid Carcinoma
 Developes in 4 clinical settings:
• • • • Sporadic MTC (SMTC) Familial MTC (FMTC) Multiple endocrine neoplasia IIa (MEN IIa) Multiple endocrine neoplasia IIb (MEN IIb)

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Medullary Thyroid Carcinoma
Sporadic MTC:
• • • • • • 70%-80% of all MTCs (Colson, 1993, Marzano, 1995) Mean age of 50 years (Russell, 1983) 75% 15 year survival (Alexander, 1991) Unilateral and Unifocal (70%) Slightly more aggressive than FMTC and MEN IIa 74% have extrathyroid involvement at presentation
(Russell, 1983)

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Medullary Thyroid Carcinoma
Familial MTC:
• • • • • • Autosomal dominant transmission Not associated with any other endocrinopathies Mean age of 43 Multifocal and bilateral Has the best prognosis of all types of MTC 100% 15 year survival
(Farndon, 1986)

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Medullary Thyroid Carcinoma
 Multiple endocrine neoplasia IIa (Sipple’s Syndrome):
• MTC, Pheochromocytoma, parathyroid hyperplasia • Autosomal dominant transmission • Mean age of 27 • 100% develop MTC (Cance, 1985) • 85%-90% survival at 15 years
(Alexander, 1991, Brunt, 1987)

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Medullary Thyroid Carcinoma
 Multiple endocrine neoplasia IIb (Wermer’s Syndrome, MEN III, mucosal syndrome):
• Pheochromocytoma, multiple mucosal neuromas, marfanoid body habitus • 90% develop MTC by the age of 20 • Most aggressive type of MTC • 15 year survival is <40%-50%
(Carney, 1979)

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Medullary Thyroid Carcinoma
Diagnosis
 Labs:
1) basal and pentagastrin stimulated serum calcitonin levels (>300 pg/ml) 2) serum calcium 3) 24 hour urinary catecholamines (metanephrines, VMA, nor-metanephrines) 4) carcinoembryonic antigen (CEA) Fine-needle aspiration Genetic testing of all first degree relatives • RET proto-oncogene
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 

Medullary Thyroid Carcinoma (Management)
 Recommended surgical management
• total thyroidectomy • central lymph node dissection • lateral jugular sampling • if suspicious nodes - modified radical neck dissection

 If patient has MEN syndrome
• remove pheochromocytoma before thyroid surgery

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Medullary Thyroid Carcinoma (Management)
 Postoperative management
 disease surveillance
• serial calcitonin and CEA 2 weeks postop 3/month for one year, then… Twice a year

 If calcitonin rises metastatic work-up surgical excision if metastases - external beam radiation
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Anaplastic Carcinoma of the Thyroid
 Highly lethal form of thyroid cancer  Median survival <8 months (Jereb, 1975, Junor, 1992)  1%-10% of all thyroid cancers (Leeper, 1985, LiVolsi,
1987)

 Affects the elderly (30% of thyroid cancers in patients >70 years) (Sou, 1996)  Mean age of 60 years (Junor, 1992)  53% have previous benign thyroid disease (Demeter,
1991)

 47% have previous history of WDTC (Demeter, 1991)

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Anaplastic Carcinoma (Management)
 Most have extensive extrathyroidal involvement at the time of diagnosis
• surgery is limited to biopsy and tracheostomy

 Current standard of care is:
• maximum surgical debulking, possible • adjuvant radiotherapy and chemotherapy
(Jereb and Sweeney, 1996)

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Management
 Surgery is the definitive management of thyroid cancer, excluding most cases of ATC and lymphoma  Types of operations:
• lobectomy with isthmusectomy
- minimal operation required for a potentially malignant thyroid nodule

• total thyroidectomy
- removal of all thyroid tissue

- preservation of the parathyroid glands • subtotal thyroidectomy
- anything less than a total thyroidectomy

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Management Papillary and Follicular
 Subtotal vs. total thyroidectomy

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Arguments for Total Thyroidectomy
 Radioactive iodine may be used to detect and treat residual normal thyroid tissue and local or distant metastases  Serum thyroglobulin level is a more sensitive marker for persistent or recurrent disease when all normal thyroid tissue is removed  In up to 85% of papillary cancer, microscopic foci are present in the contralateral lobe. Total thyroidectomy removes these possible sites of recurrence  Recurrence develops in 7% of contralateral lobes (1/3 die)  Risk (though very low [1%]) of dedifferentiation into anaplastic thyroid cancer is reduced  Survival is improved if papillary cancer greater than 1.5cm or follicular greater than 1cm  Need for reoperative surgery associated with higher risk is lower
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Arguments against Total Thyroidectomy
 Total thyroidectomy may be associated with higher complication rate than subtotal thyroidectomy 50% of recurrences can be controlled with surgery  Fewer than 5% of recurrences occur in the thyroid bed  Tumor multicentricity has little clinical significance  Prognosis of low risk patients (age, grade, extent, size) is excellent regardless of extent of resection

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Indications for Total Thyroidectomy
1)

2) 4) 5) 6)

Patients older than 40 years with papillary or follicular carcinoma Anyone with a thyroid nodule with a history of irradiation Patients with bilateral disease Patients with neck lap. Patients had Tm 2cm

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Papillary/Differentiated Carcinoma
Node Dissection:
 Up to 80% of patients found to have asymptomatic positive nodes during series of prophylactic neck dissections 1,2  Clinically significant disease only develops in less than 10% of patients with microscopic lymph node metastases 1,3,4  Central node dissection should be carried out if central nodes are enlarged and positive by frozen section  Ipsilateral modified neck dissection has been shown to reduce regional recurrence without improving survival if enlarged cervical node is positive by preop FNA or intraoperative frozen5

1 Am J Surg 122:464-471,1971 2 World J Surg 18:359-367,1994. 3 Surg Clin North Am 67:251-261,1987. 4 Cancer 26:1053-1060, 1970 5 Textbook of Endocrine Surgery, WB Saunders, 1997, p90.

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Node Dissection
 Managing lymphatic involvement
• pericapsular and tracheoesophageal nodes should be dissected and removed in all patients undergoing thyroidectomy for malignancy • Overt nodal involvement requires exploration of mediastinal and lateral neck • if any cervical nodes are clinically palpable or identified by MR or CT imaging as being suspicious a neck dissection should be done (Goldman, 1996) • Prophylactic neck dissections are not done (Gluckman)

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LYMPHATIC DRAINAGE
Superior

Lateral

Lateral

Posterior

Inferior

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Lateral Group

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Central Group
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Incision

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Outline of modified Mac Fee incision
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Indications of Lymph Node Dissection
•All thyroid cancers with palpable pathologic lymph node •Positive frozen section •High risk patients(prophylactic) •Pediatric thyroid cancer •Medullary thyroid cancer •Extrathyroid head and neck malignancy
62

Central Lymph Node Dissection:
 Central compartment =the region bounded by the jugular veins, the hyoid bone, and the sternal notch  All central nodes removed at time or procedure  Removal of Central Nodes important in medullary and Hurthle Cell Ca
• Microscopic spread is high • Do not take up I131 and cannot be ablated

63

Lateral Lymph Node Dissection
 Diseased nodes lateral to the jugular vein = modified radical neck dissection  Removal of LN’s anterior and posterolateral to the internal jugular vein from the mastoid to subclavian vessels inferiorly and laterally to spinal accessory nerve (Level 2-5)  Sparing the internal jugular vein, spinal accessory nerve, and sternocleidomastoid muscle
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Complications of Surgery
 Hypocalcemia -devascularization of parathyroid
• about 5%, which resolves in 80% of these cases in about 12 months

 Recurrent Laryngeal Nerve Injury either traction induced or division.
• less than 3%

 Bleeding
• wound hematomas

67

Standard Initial Treatment
Total Thyroidectomy

Remove the thyroid with all cancerous tissue

Radioactive Iodine Treatment

Destroy any microscopic residual thyroid tissue

Without any functional thyroid tissue Completely dependent on exogenous levothyroxine 68

Pediatric Papillary Carcinoma Incidence
4 cases per million per year (children) vs 50 cases per million per year (adults)

69

Pediatric Papillary Carcinoma
 PTC and FVPTC – 90 % of all childhood thyroid cancers  1.4 % of all pediatric head and neck tumors  7 % of all pediatric head and neck tumors

70

Pediatric Papillary Carcinoma
Age
5–9 10-14 15-19

 Female to Male Ratio
1:6 1:1 5 : 2 (peak incidence)

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Completion Thyroidectomy
 Postoperative reveal of DTC  Incomplet surgery  Folicular lesion  High grade patients  Neck lymphadenopathy

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Total thyroidectomy is the treatment of choice for virtually all patients with thyroid cancer when it can be done safely. No study documents that lesser operations have better results than total thyroidectomy, whereas numerous studies suggest that patients treated by total thyroidectomy have fewer recurrences and better survival. Orlo H. Clark
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