Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin

1. Neoplastic Thyroid Disease: Thyroid Nodules, Goiter, and Thyroid Cancer Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Chairman, Diabetes Steering Committee, AMG/NHP, Appleton, WI Tuesday March 15, 2005 Website: www.endocrinology-online.com

2. Neoplastic Thyroid Disease • Thyroid Nodules • Goiter • Multinodular • Diffuse • Endemic • Thyroid Cancer • Well differentiated and poorly differentiated

3. Thyroid Nodular Disease • Thyroid gland nodules are common in the general population • Palpable nodules occur in approximately 5% of the US population, mainly in women • Most thyroid nodules are benign • Less than 5% are malignant • Only 8% to 10% of patients with thyroid nodules have thyroid cancer

4. Multinodular Goiter (MNG) • MNG is an enlarged thyroid gland containing multiple nodules • The thyroid gland becomes more nodular with increasing age • In MNG, nodules typically vary in size • Most MNGs are asymptomatic • MNG may be toxic or nontoxic • Toxic MNG occurs when multiple sites of autonomous nodule hyperfunction develop, resulting in thyrotoxicosis • Toxic MNG is more common in the elderly

5. Endemic Goiter • No longer a problem in the US and the developed world • Still a serious health concern in parts of the world with iodine deficiency including mountainous areas or areas with high rainfall/flooding Kaplan, E. et al. Thyroid Disease Manager “Surgery of the Thyroid Gland” Chapter 21, May 99

6. Thyroid Carcinoma • Incidence • Thyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid disease • Thyroid cancers account for only 0.74% of cancers among men, and 2.3% of cancers in women in the US • The annual rate has increased nearly 50% since 1973 to approximately 18 000 cases • Thyroid carcinomas (percentage of all US cases) • Papillary (80%) • Follicular (about 10%) • Medullary thyroid (5%-10%) • Anaplastic carcinoma (1%-2%) • Primary thyroid lymphomas (rare) • Metastatic from other primary sites (rare)

7. Initial Evaluation of a Thyroid Nodule/Mass

8. Risk factors for Malignancy • Solitary thyroid nodules in patients >60 or <30 years of age • Irradiation of the neck or face during infancy or teenage years • Symptoms of pain or pressure (especially a change in voice) • Male sex • Large Nodules (>3 or 4 cm) • Growth of nodule

9. Evaluating Thyroid Nodules • TSH measurement • Ultrasound of the thyroid • Fine needle aspiration • Radioactive iodine imaging Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33. Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Castro MR, et al. Endocr Pract. 2003;9:128-136.

10. Thyroid Ultrasonography

11. Thyroid Ultrasonography • Excellent for characterizing size and other features of nodule • Useful in localizing nodule for FNA • Cannot distinguish between benign vs. malignant

12. Thyroid Ultrasonography • Certain features may suggest greater risk of cancer: • Irregular or poorly defined borders of nodule • Lack of a "halo“ • Hypo-echogenicity • Evidence of microcalcifications • Increased blood flow • Growth and interval change on serial ultrasounds

13. RAI imaging • Formerly had been used extensively in the initial work up of nodular thyroid disease FNA is now considered the gold standard

14. RAI imaging • The problem: • Although “hot” nodules are usually never cancer, only 5% of all nodules are hyperfunctioning • The remaining 90-95% that are warm or cold could be cancer and thus require FNA

15. RAI imaging Circumstances where RAI imaging may be useful and indicated: • Suppressed TSH (more likely to have a autonomously functioning nodule) • Multiple nodules, none dominant • Other

16. Thyroid FNA • Now considered the most cost effective and sensitive/specific diagnostic test of thyroid nodules • The use of US has expanded the role of FNA in evaluating nodules and improved the validity of the results

17. Thyroid FNA Possible FNA Results • Benign: 70 -75 % • Malignant: Up to 5% • Suspicious: About 10% • Nondiagnostic: About 10 - 20%

18. Thyroid FNA Limitations • False negatives: (< 5% of FNA) more likely in large (>4cm) or small (<1cm) nodules • Suspicious FNA (Follicular and Hurhtle cell neoplasm): cannot distinguish benign vs malignant of hypercellular nodules by FNA alone, ALWAYS require surgical pathology for dx (up to 10 – 30% of these will be CA) • Non-diagnostic results: NEVER consider equivalent to benign, up to 10% of ND FNA will contain CA on resection

19. Management and Follow up

20. Management of Thyroid Nodules Depends on FNA results (see algorithm) • Benign: • False negatives rare, but be cautious in large (>4cm) or small nodules (<1cm) , repeat US in 6 to 12 months to assess for interval change • Consider surgical resection if change or suspicious • Malignant: • Surgery and RAI ablation

21. Suspicious FNA • About 10% of all FNA results • CANNOT distinguish benign vs malignant of hypercellular nodules (follicular/Hurthle cell) by FNA alone • ALWAYS require surgical resection for dx • Up to 10 – 30% of these will be malignant

22. Non-diagnostic FNA • About 15% of all FNA results • NEVER consider equivalent to benign FNA • Up to 10% of ND FNA will contain CA on resection • Be very cautious of a pathology report: “consistent with benign colloid nodule”; if limited/no follicular epithelial cells noted, then this is a ND FNA rather than benign

23. Non-diagnostic FNA cont’d Three options: • Repeat FNA now- may get valid FNA on repeat up to 30 – 50% of the time • Follow-up US in 6 months, repeat FNA or resect then if any interval change • Surgical resection now- usually reserved only for patients with history suggestive of increased risk or patients who are very anxious and do not want to wait

24. LT4 Suppression of Thyroid Nodules

25. LT4 Suppression of Nodules • Although once more commonly used, it has begun to fall out of favor • Some endocrinologists still recommend LT4 suppression for a TSH between 0.1 – 0.5 • However, studies demonstrate lack of efficacy or improved outcome • There is significant risks associated with long term iatrogenic hyperthyroidism (loss of bone density, arrhythmias in the elderly, etc.)

26. LT4 Suppression of Goiter • Patients with a MNG especially could later develop an autonomously functioning nodule with subsequent thyrotoxicosis if not followed closely • Is useful for goiter suppression in patients with subclinical or overt hypothyroidism • May also have a role in goiter patients with TSHs in the upper limits of normal (>3.0) who also have + thyroid autoantibodies (controversial)

27. Thyroid Carcinoma

28. Typical Presentation of Thyroid Cancer • Painless lump • Normal thyroid function tests • Found on routine examination or by the patient • Slow growth or no growth over several months Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463.

29. Newly Diagnosed Cancer in the United States Thyroid Cancer 22 000 new cases 1400 deaths Cancer facts and figures. American Cancer Society Web site. Available at: http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf. Accessed December 10, 2003. 0 50 100 150 200 250 New Cases, Thousands

30. Types of Thyroid Cancer • Papillary (80%-85%): develops from thyroid follicle cells in 1 or both lobes; grows slowly but can spread • Follicular (5%-10%): common in countries with insufficient iodine consumption; lymph node metastases are uncommon • Medullary: develops from C-cells, can spread quickly; sporadic and familial types • Anaplastic: develops from existing papillary or follicular cancers; aggressive, usually fatal • Lymphoma: develops from lymphocytes; uncommon Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=43. Accessed December 10, 2003.

31. Papillary Thyroid Cancer • Most common type • Makes up about 80% of all thyroid carcinomas in the United States • Females outnumber males 3:1 • Highest incidence in women in midlife Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=43. Accessed December 10, 2003. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

32. Papillary Thyroid CancerCharacteristics • Unencapsulated tumor nodule with ill-defined margins • Tumor typically firm and solid • May present as nodal enlargement • Commonly metastasizes to neck and mediastinal lymph nodes • 40% to 60% in adults and 90% in children • <5% of patients have distant metastases at time of diagnosis • Lung is most common site Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000 Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

33. Follicular Thyroid Cancer • Second most common type of thyroid cancer • Solid invasive tumors, usually solitary and encapsulated • Usually stays in the thyroid gland, but can spread to the bones, lungs, and central nervous system • Usually does not spread to the lymph nodes Follicular Thyroid Cancer Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003. Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

34. Follicular Thyroid CancerDiagnosis and Prognosis • Most FTCs present as an asymptomatic neck mass • If caught early, this type of thyroid cancer is often curable • Tumors >3 cm have a much higher mortality rate Hebra A, et al. Solitary thyroid nodule. eMedicine Web site. Available at: http://www.emedicine.com/ped/topic2120.htm. Accessed December 10, 2003. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003. DeGroot LJ, et al. J Clin Endocrinol Metab. 1990;71:414-424. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY:Marcel Dekker, Inc.: 2001;239-241.

35. Hürthle Cell Cancer • A variant of follicular cancer that tends to be aggressive • Represents about 3% to 5% of all types of thyroid cancer Hürthle Cell Tumor High power magnification Aytug S, et al. Hürthle cell carcinoma. eMedicine Web site. Available at: http://www.emedicine.com/med/topic1045.htm. Accessed December 10, 2003. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY: Marcel Dekker, Inc.: 2001:239-241.

36. Hürthle Cell Cancer Prognosis • May be benign or malignant, based on demonstration of vascular or capsular invasion • Malignancies tend to have a worse prognosis than other follicular tumors and rarely respond to 131I therapy • Tend to be locally invasive Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Mazzaferri EL. Thyroid carcinoma: papillary and follicular. In: Mazzaferri, EL, Samaan N, eds. Endocrine Tumors. Cambridge, MA: Blackwell; 1993:278-333.

37. Anaplastic Thyroid Cancer • Extremely aggressive and exceptionally virulent • Composed wholly or in part of undifferentiated cells Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Sherman SI. Lancet. 2003;361:501-511. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.

38. Anaplastic Thyroid Cancer (Continued) • Tumor is typically hard, poorly circumscribed, and fixed to surrounding structures • Often occurs in the elderly population (mean age: 65 years) • 3-fold greater risk in iodine-deficient areas Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

39. Medullary Thyroid Cancer • Tumor arising from the calcitonin-secreting C-cells of the thyroid gland • Mortality rate of 10% to 20% at 10 years Medullary (C-cell) Carcinoma Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Sherman SI. Lancet. 2003;361:501-511. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: http://www.vmmc.org/dbCancer/sec180604.htm. Accessed December 10, 2003.

40. Medullary Thyroid CancerTypes • 70% to 80% of cases are sporadic disease (median age=51 years) • 20% to 30% are part of 3 familial autosomal dominant syndromes (MEN-2A, MEN-2B, or familial non-MEN medullary thyroid cancer [median age=21 years]) Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: http://documents.cancer.org/196.00/196.00.pdf. Accessed December 10, 2003.

41. Medullary Thyroid CancerMetastases • Cervical lymph node metastases occur early • Tumors >1.5 cm are likely to metastasize, often to bone, lungs, liver, and the central nervous system • Metastases usually contain calcitonin and stain for amyloid Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: http://www.vmmc.org/dbCancer/sec180604.htm. Accessed December 10, 2003. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003. Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: http://documents.cancer.org/196.00/196.00.pdf. Accessed December 10, 2003.

42. Primary Thyroid Lymphoma • A rare type of thyroid cancer • Affects fewer than 1 in 2 million people • Constitutes 5% of thyroid malignancies Large Cell Lymphoma of the Thyroid Braverman LE, Utiger RD, eds. Werner & Ingbar’sThe Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Cabanillas F. Thyroid lymphoma. eMedicine Web site. Available at: http://www.emedicine.com/med/topic2271.htm. Accessed December 10, 2003.

43. Primary Thyroid LymphomaCharacteristics and Diagnosis • Develops in the setting of pre-existing lymphocytic thyroiditis • Often diagnosed because of airway obstruction symptoms • Tumors are firm, fleshy, and usually pale Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Ansell SM, et al. Semin Oncol. 1999;26:316-323.

44. Newly Detected and Fatal Cases of Thyroid Cancer Deaths by 2010 (N=1426) Thyroid Cancer Cases Diagnosed in 2000 (N=18 000 ) Anaplastic 11% Hürthle 4% Anaplastic 1% Papillary 50% Hürthle 12% Follicular 14% Follicular 27% Papillary 80% Robbins R, et al. Adv Intern Med. 2001;46:277-294.

45. Recurrence and Death After Diagnosis of Thyroid Cancer N=1355 Mazzaferri EL, et al. Am J Med. 1994;97:418-428.

46. Etiology of Thyroid Cancers • Usually unknown • Radiation exposure • Medical uses during childhood in the 1950s • Current medical uses in cancer therapy • Nuclear accidents Ron E, et al. Radiat Res. 1995;141:259-277. Tuttle RM, et al.Semin Nucl Med. 2000;30:133-140.

47. Genetic Basis of Thyroid Cancer • Papillary and follicular thyroid cancer • Usually sporadic • Approximately 5% of patients have other family members with thyroid cancer • Rare genetic syndromes in which thyroid cancer is associated with other benign and malignant neoplasms Alsanea O, et al. Curr Opin Oncol. 2001;13:44-51.

48. Management and Follow up of Thyroid Carcinoma

49. Thyroid Cancer Risk Stratification Intermediate Risk Low Risk High Risk >45 years Age <45 years Male Gender Female >4 cm Size <2 cm Mixture of Features Intraglandular Extraglandular Extent High Grade Low Distant Metastases Absent Present Treated, % 39 39 22 Death Rate, % <1 53 13 Shaha AR, et al. Acta Otolaryngol. 2002;122:343-347. Shaha AR. Cancer Control. 2000;7:240-245.

50. Thyroid Cancer Initial Treatment Strategy Diagnosis of Thyroid Cancer Surgery Intermediate and High Risk Low Risk Lobectomy Isthmusectomy Total Thyroidectomy Shaha AR. Cancer Control. 2000;7:240-245. Kinder BK. Curr Opin Oncol. 2003;15:71-77.