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Thyroid Cancer

Thyroid Cancer. Megan Mezera, MD Resident, PGY-2 James Graham Brown Cancer Center Department of Radiation Oncology. Thyroid Overview. Thyroid Anatomy. Thyroid is a gland that consists of right and left lobes, joined by an isthmus . It extends from vertebral levels C5 to T1 .

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Thyroid Cancer

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  1. Thyroid Cancer Megan Mezera, MD Resident, PGY-2 James Graham Brown Cancer Center Department of Radiation Oncology

  2. Thyroid Overview

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

  4. Anatomy cont. • Inner true capsule: 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. • Follicles consist of a layer of simple epithelium enclosing a colloid-filled cavity. • Epithelial cells are of 2 types: • Principal cells (follicular cells). • Responsible for formation of colloid (Iodothyroglobulin). • Parafollicular cells (C cells, clear cells, light cells). • Produce the hormone Calcitonin, a protein central to calcium homeostasis.

  5. Histology of thyroid gland: Follicles = structural units of the gland, consisting of a single layer of simple epithelium enclosing a colloid-filled cavity.

  6. Lymphatic Drainage • Internal Jugular chain of Cervical Lymph Nodes • Superior thyroidal – levels 2, 3, 6 • Inferior thyroidal – levels 4, 6, paratracheal • Level VI: • Pre-laryngeal (Delphian) node • Recurrent laryngeal nodes • Pre- & Para-tracheal nodes • Anterior-superior mediastinal nodes are secondary nodes to the recurrent laryngeal and pre-tracheal nodal groups. Image: Japanese Journal of Clinical Oncology. Vol. 41, Issue 8.

  7. Physiology and Function • Thyroid gland manufactures two essential hormones: • Thyroxine (T4). • Tri-iodothyronine (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, and is the more active form in the target tissues. • T4 is released by the thyroid in larger amounts, but is mostly converted to T3 in the liver and kidneys. • TSH from the pituitary regulates secretion of T3 & T4.  • Effects of T3 and T4: • Increase the basal metabolic rate of most cells in the body. • Increase fat and carbohydrate metabolism. • Boost protein synthesis. • Increase heart rate and blood flow to other organs.

  8. Thyroid CancerBackground

  9. Epidemiology • Thyroid cancer is uncommon. • 1-2% of all malignancies. • < 0.2% of all cancer deaths in the United States. • Incidence is increasing. • However, may be due to increased detection of subclinical disease by extensive use of ultrasound, FNA. • American Cancer Society estimates: • 30,180 new thyroid cancer cases estimated in 2006 (7,590 men and 22,590 women). • 1,500deaths (630 men and 870 women) from the disease. • Male:Female = 1:3 • Incidence peaks in 5th decade. • Radiation exposure is main environmental risk factor.

  10. Thyroid Cancer - types • Papillary – 75-80% • Follicular cell origin. • Tends to grow slowly. • Follicular – 15 %  • Also begins in the follicular cells. • Medullary – 5-10%  • Only thyroid cancer that originates from the Parafollicular C cells. • Anaplastic – 1-2% (rare) • Follicular cell origin. • Aggressive. Tends to grow and spread very quickly. Other rarer types (Non-Epithelial origin) – < 5% • Sarcomas • Malignant Lymphomas (NHL) • Hemangio-endotheliomas • Metastases from other primary sites • Thyroid cancer arising in unusual sites (ex: Struma Ovarii).

  11. Papillary Thyroid Carcinoma (PTC) • Age 30-40 years • 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 • Tall cell and Insular carcinomas are variants with a worse prognosis

  12. PTC – Pathology • Arise from follicular cells of the thyroid • Psammoma bodies - round collection of calcium • Orphan Annie Eye - empty or ground glass nuclei

  13. Follicular Thyroid Carcinoma (FTC) • Usually age >50 years • Tends to be slightly more aggressive than PTC. • Average tumor size is larger than PTC. • Metastatic spread to other parts of the body is more common in FTC. • Most common sites of mets are lung and bones. • Rare clinical LAD at presentation (4-6%). • Thyroglobulin can be used as a tumor marker for well-differentiated FTC. • Hurthle cell and primary Clear cell carcinoma are variants.

  14. FTC - Pathology • Cannot be diagnosed on FNA due to inability to distinguish between benign follicular adenoma and carcinoma. • Scalloping of follicles

  15. Hürthle Cell Carcinoma • Thought to be a variant of Follicular Thyroid Ca. • Can be benign or malignant. • If no evidence of invasion, tend to act like adenomas. • If malignant, typically more aggressive than FTC or PTC. • 10-year survival 76% vs. 85% • Microscopically characterized by abundant eosinophilic granular cytoplasm.

  16. Anaplastic Thyroid Carcinoma (ATC) • Least common type (<5%). • Occurs late, >60 yrs age. • History of goiter in 80% of patients. • Possible transformation from benign to malignant lesion. • Highly malignant, with rapid invasion of the adjacent structures and metastases throughout the body. • Pathology may reveal evidence of PTC or FTC which may represent the precursor lesion. • Histology is atypical with Spindle-shaped cells and Multi- nucleated Giant cells • All pts with ATC are considered Stage IV.  • Poor prognosis: Death usually occurs within 12 months of diagnosis.

  17. Medullary Thyroid Carcinoma (MTC) • The only thyroid cancer that originates from the Para-follicular/C cells. • Two types of MTC: • Sporadic (80%) • Familial (20%) • Familial MTC: • Bilateral. • Less likely to have cervical nodes involved at diagnosis. • Better prognosis. • Patients with familial MTC should consider screening tests for genetic abnormalities – RET proto-oncogene (MEN syndromes). • Hypersecretion of Calcitoninused as a marker of disease status.

  18. MTC - Pathology • May have considerable fibrosis • Amyloid deposits • Immunohistochemical staining with anti-calcitonin antibody

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

  20. Thyroid Cancer - Genetics • Papillary Thyroid Carcinoma • Somatic point mutations in the BRAF gene. • Medullary Thyroid Carcinoma • Gain of function mutation in RET proto-onco gene located on Chromosome 10.

  21. 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.

  22. Radiation-Induced Thyroid Cancer • Exposure to ionizing radiation, particularly before puberty. • 25% of patients who receive as low as 0.02 Gy 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, fungal infections of the scalp, enlarged thymus gland, or to shrink enlarged tonsils or adenoids.

  23. Radiation-InducedThyroid Cancer cont. • Children are much more sensitive than adults. • Histology: well-differentiated, 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.

  24. 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. • Most cases are spontaneous.

  25. Clinical Manifestations & Presentation • Painless lump in the neck. • Representing either primary thyroid tumor or regional lymph nodes. • Rapid growth in suspected benign thyroid nodule. • Clinically occult in some cases (seen on imaging only). • Pts with thyroid CA are typically EUTHYROID. • Normal TSH levels. • Voice change, hoarseness. • Suspect recurrent laryngeal nerve involvement or impingement. • Dysphagia • Difficulty breathing

  26. Prognostic Factors • Age is most important factor. • Increased mortality in patients >45 years old • Tumor size >4cm • Higher histologic grade • Hurthle cell variety • Post-op macroscopic residual disease • Male sex • Presence of distant mets - 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.

  27. T- Staging (AJCC 2010) • Papillary/Follicular/Medullary Carcinomas: • 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. • T4a: Intrathyroidalanaplastic carcinoma — surgically resectable • T4b: Extrathyroidalanaplastic carcinoma — unresectable

  28. 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

  29. Thyroid CancerEvaluation & Treatment

  30. Evaluation of Thyroid Nodule • Ultrasound of thyroid with FNA. • Sensitivity 98%, Specificity 99%, Accuracy 98% • Remember: Negative FNA does not exclude FTC. • Labs: T3, T4, TSH, Thyroglobulin • Medullary Ca: • Calcitonin, CEA, calcium • Urine and serum catecholamines (screen for pheochromocytoma) • Patient and family members should be screened for RET proto-oncogene • Ultrasound, MRI, non-contrast CT of neck to evaluate adenopathy • Do not use iodinated CT contrast as this will delay 131I treatment up to 6 months

  31. 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 residual thyroid tissue 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 more aggressive dissection

  32. Post-Operative Therapy • Suppression of residual thyroid tissue with exogenous thyroid hormone (i.e. Levothyroxine) • Ablation of thyroid remnant with radioactive 131I • Addition of post-op thyroid hormone replacement or 131I ablation decreases recurrence rates vs. surgery alone. • Total thyroidectomy alone: 7% • TT + Thyroid Hormone or I-131: 2.6% • Thyroid Hormone alone: 10%

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

  34. Radioactive 131I (RAI) • Taken up by follicular cells • Can be used to treat papillary, follicular (including Hürthle subtype), and some medullary cancers • C-cells do not take up RAI, but may consider for inoperable MTC as nearby follicular cells will take up RAI and may kill adjacent MTC cells in thyroid • Will not treat MTC-involved LN or distant mets

  35. Indications for RAI • Tumor size >1.0 cm • Thyroid capsule invasion • Vascular invasion • Multifocal disease • Soft tissue invasion • Post-operative residual disease (+ margins) • Cervical or mediastinal nodal metastases (N1b) • Distant metastases • Recurrent disease • Other • Eliminates any residual normal thyroid tissue • Improves reliability of future iodine uptake scans and thyroglobulin levels for disease monitoring

  36. Induction of 131I Uptake • Must make the residual thyroid tissue “hungry” for iodine • Two ways to encourage uptake of 131I by residual thyroid tissue • Make the patient hypothyroid • Low TH levels  increases TSH  promotes 131I uptake • Goal TSH >30 • Give recombinant TSH (rhTSH, Thyrogen) • Exogenous TSH  promotes 131I uptake • Tolerated better by patients as does not induce hypothyroidism • Patients must remain on low-iodine diet prior to treatment

  37. RAI Ablation • 131I is used • Physical t½ = 8 days • Radiation Dose: Total Body:Thyroid = 1:300-1000 • 100-200 mCi after preparatory regimen with a target TSH >30 or with Thyrogen (rhTSH). • 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-treat 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.

  38. Complications of RAI ablation • Acute: • Sialadenitis, xerostomia, cystitis, radiation gastritis, transient leukopenia and thrombocytopenia, transient oligo-spermia in males, thyrotoxicosis during the 1st two weeks from increased tumor lysis, radiation pneumonitis if pulmonary metastasis present. • Chronic: • Risk of leukemia with cumulative doses >800 mCi • Breast and bladder Ca with >1000 mCi • Bone and soft tissue Ca with >800-1000 mCi • Pulmonary fibrosis in patients with diffuse pulm mets - Robino C, Br J Cancer, 2003 • No increase in infertility, miscarriages, prematurity, or congenital anomalies. However, recommend that pts wait 6 months prior to attempting pregnancy.

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

  40. Post-Therapy Follow-up Tests • Thyroid function panel • 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

  41. 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 for detection of thyroid cancer.

  42. Correlating 131I 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 on 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.

  43. Thyroid CancerManagement of Subtypes

  44. Management – Papillary/Follicular/Hürthle • Low Risk Disease: • Age 15-45 • No distant mets • No extra-thyroidal extension • Tumor size <4 cm • Treatment: • Total Thyroidectomy • Thyroid hormone replacement with good TSH suppression • +/- radioactive iodine ablation

  45. Management – Papillary/Follicular/Hürthle cont. • High Risk Disease: • Age <15 or >45 • Known regional or distant mets • Extra-capsular extension • Tumor size >4 cm • Treatment: • Total Thyroidectomy with LN sampling • LN dissection if positive nodes • Radioactive Iodine Ablation • If LN+, then consider EBRT following RAI. • Thyroid hormone replacement • Minimal role for chemo

  46. Management – Medullary Thyroid Carcinoma • Total Thyroidectomy with lymph node dissection • EBRT indications: • Residual disease • Extensive nodal involvement • T4 • Neighbor effect role for RAI • Parafollicular (C) Cells do not uptake iodine, but adjacent follicular cells do and may concentrate adequate dose in the area • Thyroid hormone suppression has no effect because C Cells are not regulated by TSH • Minimal role for chemo

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

  48. Tubiana M, et al. External Radiotherapy in Thyroid Cancers. Cancer, 1985 • Advocated post-operative irradiation for patients with residual disease. • 50 Gy in 25 fractions over 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 • 94% (62 of 66) for patients with complete surgery • 78% (76 of 97) for patients with incomplete surgery

  49. 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 • LN+

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