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Thyroid Cancer

Thyroid Cancer. Matthew Harkenrider , MD 9/2/2010 “ Da question is: Now, did God create Da Bears, and make them superior to all teams? Or is he simply a huge fan, and Ditka made them superior to all other teams?”

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Thyroid Cancer

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  1. Thyroid Cancer Matthew Harkenrider, MD 9/2/2010 “Da question is: Now, did God create Da Bears, and make them superior to all teams? Or is he simply a huge fan, and Ditka made them superior to all other teams?” ~Bill Swerski

  2. The Thyroid Gland

  3. Anatomy • Thyroid is a gland that consists of right and left lobes, joined by an isthmus. • It extends from the level of the C5 vertebra down to the T1. • It lies anterior to the 2nd - 4th tracheal rings. • A pyramidal lobe may extend superiorly from the isthmus or from one of the thyroid lobes. • Average weight is 20 g. • The parathyroid glands lie on the posterior surface of both thyroid lobes. • The recurrent laryngeal nerves are in a cleft between the trachea and esophagus, medial to the lateral aspect of both thyroid lobes.

  4. Anatomy Contd. • Thyroid has an inner true capsule, which is thin and adheres closely to the gland. • Extensions of this capsule within the gland divide it into lobes & lobules. • The lobules are composed of follicles, the structural units of the gland, consisting of a layer of simple epithelium enclosing a colloid-filled cavity. • Epithelial cells are of 2 types: Principal cells (ie, follicular) and Parafollicular cells (ie, C, clear, light cells). • Principal cells are responsible for formation of the colloid (Iodothyroglobulin), whereas parafollicular cells produce the hormone Calcitonin, a protein central to calcium homeostasis.

  5. Histology of the thyroid gland shows the structural units of the gland and the follicles, consisting of a layer of simple epithelium enclosing a colloid-filled cavity.

  6. Lymphatic Drainage • Internal Jugular chain of Cervical Nodes • Superior thyroidal – level 2/3/6 • Inferior thyroidal – level 4/6/paratracheal • Level VI - Pre-laryngeal (Delphian) & recurrent laryngeal nodes, Pre & Para-tracheal nodes • Anterior-superior mediastinal nodes are secondary nodes to the recurrent laryngeal and pre-tracheal nodal groups.

  7. Physiology and Function • The thyroid gland manufactures two essential hormones – thyroxine (also referred to as T4) and tri-iodothyronine (also referred to as T3). • There is minimal difference between T3 and T4. The numbers refer to the amount of atoms of iodine contained in the hormones. • T3 is more potent, while T4 is released by the thyroid in larger amounts, but is mostly converted to T3 in the liver and kidneys. • TSH from pituitary regulates secretion of T3 & T4.  The effect of T3 and T4 is to :- • increase the basal metabolic rate of almost all the cells in the body • increase the fat and carbohydrate metabolism • boost protein synthesis • increase heart rate and blood flow to other organs.

  8. Thyroid CancerBackground

  9. Epidemiology • Thyroid cancer comprises about 1-2% of all malignancies and accounts for less than 0.2% of all cancer deaths in the United States. • M:F=1:3 • According to the American Cancer Society, the number of new thyroid cancer cases for 2006 was estimated to be 30,180 (7,590 men and 22,590 women), with an estimated 1,500 deaths (630 men and 870 women) from the disease.

  10. Thyroid Ca - types • Papillary – 75-80% of total. Begins in the follicular cells of the thyroid and tends to grow slowly. • Follicular – 15 %. Also begins in the follicular cells • Medullary – 5-10%.  Medullary thyroid cancer is the only thyroid cancer that begins in the Parafollicular C cells • Anaplastic – 1-2% (rare).This type begins in the follicular cells and tends to grow and spread very quickly. Other rarer types include - (Non-Epithelial origin) - <5% Sarcomas, Malignant Lymphomas(NHL) and Hemangio-endotheliomas, metastasis from other primary sites and thyroid cancer at unusual sites, ex- Struma Ovarii.

  11. PAPILLARY Ca (PTC) • 30-40 yrs age. • 1/3 have clinical LAD at presentation • About 50% of excised nodes are positive. • Primary disease is confined to the neck in 95-99% cases at diagnosis • Distant mets are rare, (1-7%)  • 75% are multi-focal. • May have a large Follicular component – Mixed Papillary/Follicular cancers • Pathology - Arise from follicular cells of the thyroid • Psammoma bodies - round collection of Calcium • Orphan Annie Eye – empty or ground glass nuclei • Tall cell and Insular carcinomas are variants with a worse prognosis

  12. FOLLICULAR Ca (FTC) • Occurs most often in patients >50 yrs • Cannot be diagnosed on FNA due to inability to distinguish between benign follicular adenoma and carcinoma. • This type of thyroid cancer is slightly aggressive and tends to spread through the bloodstream to other parts of the body. • Most common sites are Lung and Bones. • Rare clinical LAD at presentation - 4-6% • Average tumor size is larger than Papillary Carcinoma • Direct extra-thyroidal extension is less common than PTC • Hurthle cell and primary Clear cell carcinoma are variants.

  13. Hurthle Cell Ca • Thought to be a variant of Follicular Cancer • They are usually more aggressive than Follicular or Papillary Ca’s. • Microscopically characterized by abundant eosinophilic granular cytoplasm

  14. ANAPLASTIC Ca (ATC) • Least common (<5%) • Occurs late, >60 yrs age • h/o goiter in 80% pts, suggesting that there might be a transformation from benign to malignant lesion. • Highly malignant, with rapid invasion of the adjacent structures and metastases throughout the body. • Path may reveal evidence of PTC or FTC which may represent the pre-cursor lesion. • Histology is atypical with Spindle shaped cells and Multi- nucleated Giant cells • All pts with ATC are considered Stg IV.  • Death usually occurs within 12 months of diagnosis.

  15. MEDULLARY Ca (MTC) • Medullary thyroid cancer is the only thyroid cancer that begins in the Para-follicular/C cells. • This type of thyroid cancer is easier to control if it is found and treated early, before it spreads to other parts of the body. • Two types of MTC: Sporadic(80%) & Familial(20%). • Patients with FMTC should consider familial screening tests for genetic abnormalities. • Familial MTC is bilateral, less likely to have cervical nodes involved at diagnosis and has a better prognosis • Hyper-secretes Calcitonin used as a marker of disease status.

  16. Multiple Endocrine Neoplasias (MEN) 1. MEN-2a :  (60 percent to 90 percent of MEN cases) - A high lifetime risk of medullary thyroid cancer (about 90%). - Average age of MTC diagnosis between 15 and 20 years. - 95 % have a mutation in the RET proto-oncogene (Chr 10). - 95 % have an affected parent, while 5 % are de novo. - Pheochromocytoma &  Parathyroid Adenoma, also seen. 2. MEN-2b (or 3) : (5 percent of MEN cases)- MTC, Pheochromocytoma and Marfanoidhabitus, Mucosal neuromas of tongue and lips, and Neurofibromas. 3. FAMILIAL MTC: (5 percent to 35 percent of MEN cases)- No pheochromocytoma or parathyroid disease • mutation in RET gene, age of onset of MTC later than with MEN 2A. PROPHYLACTIC THYROIDECTOMY HAS >90% CURE.

  17. Genetics • Papillary Ca - Somatic point mutations in the BRAF gene. • Medullary Ca - Gain of function mutation in RET proto-onco gene (Chr.10)

  18. Survival • Papillary and Follicular : 95-97% DSS at 20 yrs • Hurthle Cell Ca : 80% DSS at 10 yrs. • Medullary Ca : 60-80% DSS at 10 yrs. • Anaplastic Ca : 25-45% DSS at 1 yr.

  19. Radiation-Induced Thyroid Cancer • Exposure to ionizing radiation, particularly before puberty. • 25% of patients who receive as low as 0.02 Gy of external irradiation to the thyroid gland develop Goiters; 25% of these, or 7% of all individuals who receive external irradiation to the thyroid, develop cancer, usually Papillary Ca. • In the past, external irradiation was used to treat children with conditions such as acne, fungus infections of the scalp, or an enlarged thymus gland, or to shrink enlarged tonsils or adenoids.

  20. Radiation-Induced Thyroid Cancer • Children are much more sensitive than adults. • Histology: well-differentiated type, develops slowly • Mortality rates are low - <5% die due to RT induced Ca • Risk of cancer follows a linear dose response curve without threshold. • Even when the thyroid gland is outside of the field of radiation, an increased risk of thyroid cancer has been noted following radiation treatment in childhood for Hodgkin and non-Hodgkin lymphomas, ALL, Wilm's tumor, neuroblastoma, and central nervous system tumors Inskip PD, Med PediatrOncol. 2001   • No increased risk for cancer is seen after diagnostic I131    .

  21. History • External irradiation to head, neck, or chest between infancy and early adulthood. • Family history of medullary thyroid cancer, inherited as an Autosomal Dominant condition. • Family or personal history of pheochromocytoma or hyperparathyroidism with or without mucosal neuromas, suggestive of MEN syndromes. • Still, most cases are spontaneous

  22. Clinical Manifestations/ Presentation • Painless lump in the neck - either the primary thyroid tumor or regional lymph nodes. • In some it may be clinically occult, (seen on imaging) • Pts with thyroid CA are typically EUTHYROID (normal TSH levels). • Rapid growth in suspected benign thyroid nodule • Voice change, hoarseness - suspect recurrent laryngeal nerve involvement or impingement. • Dysphagia • Difficulty breathing

  23. Prognostic Factors • Age is most important, age>45 have increased mortality. • Tumor size >4cm, higher histologic grade, Hurthle cell variety, post-op macroscopic residual disease, male sex, and presence of distant mets all constitute a poor prognosis. -Rao RS, et al. Prognostic factors in follicular carcinoma of the thyroid: a study of 198 cases. Head Neck 1996;18:118–126 - Shaha AR, et al. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995;118:1131–1136.

  24. T- Staging (AJCC 2010) • Papillary/Follicular/Medullary • T1 - Tumor ≤2 cm, Intra-thyroidal • T2 - Tumor >2 cm but not >4 cm, Intra-thyroidal • T3 - Tumor >4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid 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 vessels. • All anaplastic carcinomas are considered stage IV tumors. • T4aIntrathyroidalanaplastic carcinoma—surgically resectable • T4bExtrathyroidalanaplastic carcinoma—unresectable

  25. N & M Staging • N0 - No regional lymph-node metastasis • N1 - Regional lymph-node metastasis • N1a - Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) • N1b - Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes • M0 - No distant metastasis • M1 - Distant metastasis

  26. Thyroid CancerEvaluation & Treatment

  27. Evaluation of Thyroid Nodule • Ultrasound followed by FNA. • FNA- sensitivity- 98%, specificity-99%, and accuracy -98%. • Blood- T3,T4,TSH,Thyroglobulin levels. • Medullary CA - Calcitonin, urine and serum catecholamines.

  28. Surgery • Total thyroidectomy favored over subtotal thyroidectomy • Recurrence rate (Mazzaferri, Am J Med) • Total thyroidectomy – 7% • Subtotal thyroidectomy – 18% • Total thyroidectomy leaves a small amount of thyroid tissue behind in order to avoid morbidity from damaging adjacent structures (i.e. recurrent laryngeal nerve) • Modified radical neck dissection or limited neck dissection favored over radical neck dissection • Lower morbidity with limited dissection • No survival benefit with aggressive dissection

  29. Post Op Medical Therapy • Suppression of residual thyroid tissue with exogenous thyroid hormone (i.e. Synthroid) • Ablation of thyroid remnant with radioactive 131I • Addition of thyroid hormone replacement or 131I ablation decreases recurrence rates further • Total thyroidectomy – 7% • TT + TH or I-131 – 2.6% • TH alone – 10%

  30. Post Operative Therapy • 214 patients with follicular CA (Young, J Nucl Med) • 10 year follow up of recurrence rates • Total thyroidectomy – 33% • TT + Thyroid Hormone – 10% • TT + TH + I-131 – 6% • Only patient deaths due to disease had metastases at presentation

  31. Indications for RAI-131 • Tumor >1.0 cm • Thyroid capsule invasion • Vascular invasion • Multifocal disease • Soft-tissue invasion • Postoperative residual disease (+ margins) • Cervical or mediastinal nodal metastases • Distant metastases • Recurrent disease • Other • Eliminates any residual normal thyroid tissue • Improves reliability of future iodine uptake scans and thyroglobulin levels

  32. Induction of I-131 Uptake • Must make the residual thyroid tissue hungry for iodine • Two ways to encourage uptake of I-131 by residual thyroid tissue • Make the patient hypothyroid • Low TH levels  increases TSH  promotes I-131 uptake • Give recombinant TSH (Thyrogen) • Exogenous TSH  promotes I-131 uptake

  33. RAI Ablation • I-131 used, • Physical t½ - 8 days • Radiation Dose - Total Body : Thyroid = 1 : 300-1000 • 100-200 mCi after preparatory regimen with a target TSH of >30 or with Thyrogen (recom TSH). • Start/restart thyroid hormone replacement (Synthroid) • Diagnostic uptake scan 7-10 days after 131I • Demonstrates amount and location of thyroid tissue • If +ve then re-scan 4-6 months later and may re-dose if persistently positive. • If –ve, then follow clinically with exam and thyroglobulin levels, though some MD’s re-scan in 1 year • Never use iodinated contrast 3-6 months prior to RAI therapy.

  34. Complications of RAI ablation • Acute: Sialadenitis, xerostomia, cystitis, radiation gastritis, transient leukopenia and thrombocytopenia, transient oligo-spermia in males, thyrotoxicosis during the 1st 2 weeks from increased tumor lysis, radiation pneumonitis if pulmonary metastasis present. • Chronic: Risk of leukemia, breast and bladder Ca, bone and soft tissue Ca, with cumulative doses of >800-1000 mCi, pulmonary fibrosis. - Robino C, Br J Cancer, 2003 • No increase in cong. anomalies, however recommend that pts wait 6 mos prior to attempting pregnancy.

  35. Indications of EBRT • Primary therapy of thyroid cancer if unresectable locally, particularly if 131I does not concentrate in tumor • Bulky tumor (e.g., mediastinal dis.) large enough that it is uncontrollable by 131I alone • Malignant cervical adenopathy that may not be controlled by 131I alone • Superior vena cava syndrome • Continually recurring thyroid cancer regardless of 131I accumulation • Anaplastic CA or high risk features of Medullary CA

  36. Post Therapy Tests • Thyroid functions tests • Well Differentiated CA (Papillary/Follicular CA) • Thyroglobulin Level or ThyroglobulinAb Level • Radioactive Iodine Uptake Scan • Make the patient hypothyroid to increase TSH • Give low activity radioactive iodine (123I or 131I) • Scintigraphy detects uptake of iodine and indicates residual thyroid tissue • Medullary CA • Calcitonin Level • C Cells do not uptake iodine so RAI uptake scan is not useful

  37. Significance of Thyroglobulin • Thyroglobulin is produced by the thyroid only – glycoprotein function in the iodination of thyroid hormone • Pre-op value elevated: • differentiated thyroid cancer • follicular adenoma • other benign thyroid diseases. • An elevated thyroglobulin level cannot differentiate benign from malignant lesions pre-operatively • Athyrotic patients should not have circulating thyroglobulin (t½=65 hr) • Post-op value elevated: • indicates residual, recurrent, or metastatic differentiated thyroid cancer • correlates well with 131I imaging detection of thyroid cancer.

  38. Correlating I-131 scan and Thyroglobulin Levels • In 80% to 85% of patients, the thyroglobulin levels and 123I imaging results agree, with abnormal 123I scans seen in patients with elevated thyroglobulin levels. • In 15% to 20% of cases, the results do not agree. • Pineda et al, reported on patients with elevated thyroglobulin and negative diagnostic 131I scans. • They treated 17 patients with 131I fitting this scenario. • In half of their patients, the serum thyroglobulin level normalized after treatment . • Elevated thyroglobulin levels with normal 131I scan results is believed to reflect occult disease that is not detectable with imaging • Normal serum thyroglobulin levels occur in conjunction with an abnormal 131I scan in 1.5% of patients and probably reflect some decrease in tumor function or tumor differentiation.

  39. Thyroid CancerManagement of Subtypes

  40. Management – Pap/Foll/Hurthle • Low Risk Dis: Age 15-45, no DM, no extra-thyroidal extension, and Tumor <4 cm. • Treatment • Total Thyroidectomy • Thyroid hormone replacement with good TSH suppression • +/- radioactive iodine ablation

  41. Management – Pap/Foll/Hurthle • High Risk Dis : Age<15 or >45, known regional or DM, ECE, Size > 4cm • Treatment • Total Thyroidectomy with LN sampling with dissection if positive nodes • Radioactive Iodine Ablation • If LN+, then consider EBRT following RAI. • Thyroid hormone replacement • Minimal role for chemo

  42. Management - Medullary Ca • Total Thyroidectomy with lymph node dissection • EBRT for pts with residual disease, extensive nodal involvement, T4 • Neighbor effect role for RAI – Parafollicular (C) Cells do not uptake iodine, but adjacent follicular cells do • Thyroid hormone suppression has no effect because C Cells are not regulated by TSH • Minimal for chemo

  43. Management - Anaplastic Ca • Complete surgical resection gives the only chance of cure. • If GTR not possible, then radical surgery is not indicated except for airway management. • EBRT +/- chemo used for LC and palliation. • Chemo – Doxorubicin based • EBRT – twice daily • No role for RAI ablation. • Predictors of better outcomes • Age<60 • Intra-thyroidal tumor • Combined use of surgery and EBRT

  44. Tubiana M, et al. External radiotherapy in thyroid cancers. Cancer, 1985 • Advocated postoperative irradiation for patients residual disease. • 50 Gy in 25 fractions in 5 weeks to the neck with a boost of 5 to 10 Gy to residual disease with 60Co teletherapy at the Institut Gustave-Roussy, Villejuif, France • 5-year survival rate of 94% (62 of 66) for patients with complete surgery, and 78% (76 of 97) for patients with incomplete surgery.

  45. Farahati J. Differentiated thyroid cancer. Cancer, 1996. • 238 patients with well differentiated thyroid carcinoma • 99 patients received adjuvant EBRT • Recurrence-free survival was improved with EBRT in patients • >40 years of age • Node positive

  46. Meadows KM, Amdur RJ, Morris CG. External beam radiotherapy for differentiated thyroid cancer. Am J Otolaryngol , 2006 • University of Florida: reviewed a series of 42 patients treated with external-beam radiation therapy (EBRT) between 1962 and 2003. • Most patients underwent surgery before EBRT. The volume covered included the thyroid bed, cervical lymph nodes, and upper mediastinum. • Patients in the earlier years were treated with multifieldtechniques and intensity-modulated radiation therapy (IMRT) from 2002. • Median total doses were 64.9 Gy. • Results: 4 patients (9.5%) had locoregional recurrences. Patients with gross residual disease had 70% locoregional control versus 100% with microscopic disease. • Overall survival69% for patients with gross disease, compared with 90% with microscopic disease.

  47. De Crevoisier R et al. IJROBP, 2004. • InstitutGustave-Roussy – 30 patients with anaplastic carcinoma • Treated with surgery if resectable • Doxorubicin/Carboplatin x2 cycles • EBRT 1.25 Gy BID total 40 Gy • Doxorubicin/Carboplatin x4 cycles • Surgery if initially unresectable • Complete local response – 63% • 1 year survival – 46% • 3 year survival – 23%

  48. Summary • Thyroid Cancer is a predominantly indolent cancer that affects females > males • Total thyroidectomy is the mainstay of treatment • Adjuvant TH replacement and RAI ablation are used for well differentiated carcinomas • EBRT is indicated for Medullary CA with high risk features and with chemo for Anaplastic CA

  49. Summary • Survival • Papillary and Follicular : 95-97% DSS at 20 yrs • Hurthle Cell Ca : 80% DSS at 10 yrs. • Medullary Ca : 60-80% DSS at 10 yrs. • Anaplastic Ca : 25-45% DSS at 1 yr.

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