Ryan Hungerford, MD, ECNU Providence Medical Center May 3 rd , 2011

1. Ryan Hungerford, MD, ECNUProvidence Medical CenterMay 3rd, 2011 The evaluation and management of thyroid nodules

2. Marie de Medici By Peter Paul Rubens, 1622 Goiter considered fashionable

3. Thyroid glands are beautiful • In 1656, Thomas Wharton, English physician and anatomist, is credited with naming the thyroid gland: • “glandulae thyroideae”… • whose purpose is to beautify the neck…particularly in females to whom for this reason a larger gland has been assigned.”

4. Well, maybe some goiters aren’t quite as attractive!

5. Thyroid Nodules Benign (92-96%) Malignant (4-8%) Well-differentiated (96%) Papillary Follicular (includes Hürthle) Medullary Undifferentiated (3%) Anaplastic Miscellaneous (1%) Lymphoma, SCC, metastatic carcinoma, etc. • Adenomas (Follicular or Hurthle cell) • Focal thyroiditis • Thyroid, parathyroid, or thyroglossal cysts • Thyroid hemiagenesis • Postsurgical or postradioiodine remnant hyperplasia • Rare: teratoma, lipoma, hemangioma

6. Thyroid cancer • In general, thyroid cancer is a slow-growing, treatable, often curable, disease with a low mortality rate* • ~98% 10-year mortality for PTC • Unfortunately, recurrences are common and a non-negligible number of patients will experience: • Progressive disease with regional spread to cervical or mediastinal lymph nodes • Pulmonary or skeletal metastases • Cerebral metastases • Death (often from respiratory failure) • In 2010: • 44,670 people were diagnosed with thyroid cancer • 1,690 people died *does not apply to poorly-differentiated cancer, such as anaplastic thyroid ca

7. Thyroid cancer incidence is rising1,2 1975 2007 Incidence 11.99 cases per 100,000 Mortality 0.47 deaths per 100,000 • Incidence • 4.85 cases per 100,000 • Mortality • 0.55 deaths per 100,000 2.4 fold increase in thyroid cancer incidence 1Davies. JAMA 2006;295:2164. 2NCI Surveillance, Epidemiology and End Results (SEER)

8. RED= rising incidence Data from the National Program of Cancer Registries (NPCR) and National Cancer Institute using SEER database.

9. Conclusions: the increased incidence of thyroid cancer is due to “overdiagnosis” of subclinical disease 49% of the increased incidence attributable to small (<1cm) papillary thyroid cancers 1Davies. JAMA 2006;295:2164.

10. There is more to this story… • If the higher incidence is exclusively attributable to detection… • then it would be expected that only the number of patients with smaller tumors and early-stage disease would be increasing.

11. Larger, more aggressive tumors:Incidence also rising Morris study (Am J Surg 2009) Chen study (Cancer 2009) SEER database since 1983 Increased incidence in localized, regional and distant stage tumors Rates of distant mets have risen from 4% to 9% • SEER database since 1983 • Tumors >4cm • All showing rising incidence • About 5% annual % ↑ • Extrathyroidal extension • 0.8 per 100,000 (1983) • 1.7 per 100,000 (2006) • Lymph node mets • 1.0 per 100,000 (1983) • 2.9 per 100,000 (2006) Increasing thyroid cancer incidence not just “overdiagnosis” of subclinical disease!

12. <1cm 1.0-2.9cm 3.0-3.9cm >4cm Female 3.0-3.9cm <1cm 1.0-2.9cm >4cm Male Chen. Cancer 2009;115:3801.

13. Thyroid nodules: epidemiology • In the United States, 4 to 7% of the adult population have a palpable thyroid nodule • ~100-150 million Americans have thyroid nodules (u/s + P) • 300,000 new nodules identified in 2010! • Incidental discovery increasing1 with widespread use of CT, MRI, carotid u/s, PET 2 • More common in women, and increased incidence with age • If you are a 60 y/o female, there is a 50% chance you have a thyroid nodule • By some estimates, it is more common to have a nodule than to not have a nodule! • Only 1 of 20 clinically identified nodules is malignant • 1Am J Neuroradiol 1997;18:1423. • 2 J Nuc Med 2006;47:609.

14. Case #1: “They found a nodule in my thyroid gland” • 50 year old female presents for evaluation of neck pain following whiplash from a car accident • CT scan of the neck was performed • Radiology report: • “Right thyroid lobe contains an ill defined nodule which is inadequately evaluated by this examination. Malignancy cannot be ruled out and a dedicated US study is recommended.” • Now what?

15. Basic approach to a thyroid nodule • History • Physical • Neck Ultrasound • TSH • Decision to FNA based upon above data

16. Perform a good historyEmphasis: thyroid cancer risk factors The “sister factor” • Relevant family history • First degree relative with thyroid cancer • Especially a sibling (6x ↑ risk) or a sister if you are female (11x ↑ risk) • Family history of multiple endocrine neoplasia (MEN) 2, Carney complex, Cowden’s syndrome • Age and gender • Male gender and extremes of age (<14 or >70) associated with ↑ risk of malignancy • Radiation exposure • History of childhood head and neck irradiation (acne, tonsils, thymus, tineacapitis, etc.)1 • History of BM transplantation with whole body irradiation • Exposure to ionizing radiation from fallout (in childhood or adolescence), i.e. Chernobyl • Relevant symptoms • Rapid growth of nodule (if palpable) or palpable cervical lymph nodes • Hoarseness • The three “Ds”: dysphagia, dyspnea, dysphonia • Symptoms of thyrotoxicosis (palpitations, tremor, etc.) more s/o toxic nodule 1Otolaryngol Head Neck Surg 1996;115:403.

17. Prevalence of malignancy in relation to patients' age in years increased prevalence in patients at the extremes of age Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301

18. Nuclear fallout • Chernobyl, 1986 • Estimated that 60% of nuclear fallout landed in Belarus • Thyroid cancer incidence rose dramatically, remains elevated to present day

19. >6,000 cases of thyroid cancer diagnosed as of 2005 among children/adolescents exposed in Belarus, Ukraine, Russia The developing thyroid gland is very sensitive to radiation Chernobyl incident

20. USA Today, April 26th, 2011

21. Perform a focused physical examinationemphasis: lymph nodes • Examine neck for palpable nodule(s) and enlarged cervical lymph nodes • Particular concern if fixed, hard mass • Palpation vs. ultrasound • ~40% of nodules >2cm are MISSED by palpation!1 • Using ultrasound, about 15% of patients will have an additional non-palpable nodule >1cm, and 15% will have no nodule at all!2 • For most patients with known or suspected thyroid nodules, the physical examination is not particularly useful! 1Brander et al. J Clin Ultrasound 1992;20:37. 2Tan GH et al. Arch Intern Med 1995;155:2418.

22. Covered so far…. • History • Physical • Neck Ultrasound • TSH • Decision to FNA based upon above data

23. ATA thyroid cancer guidelines 2009;Thyroid;19:1167. Screening ultrasound not appropriate for fatigue, hypothyroidism, or elevated TPO antibodies AACE/AME/ETA Thyroid Nodule Guidelines, Endocr Pract. 2010;16(Suppl 1)

24. Nodule features by Ultrasound More likely benign More likely malignant Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard (not elastic) • Iso- or Hyperechoic • Smooth borders • Halo • Uninterrupted Peripheral or “eggshell” calcifications • Low vascularity • Soft (elastic) There is no single pathognomicfinding that confirms malignancy or benignity.

25. Normal thyroid gland

26. Normal thyroid

27. Colloid artifact Benign cyst

28. Well-defined borders

29. Irregular borders

30. Microcalcifications

31. Microcalcifications Hypoechoic

32. Taller than wide

33. Hypoechoic

34. Hypervascular

35. Not a cyst! This is a parathyroid adenoma PTH dropped from 31040 after removal

36. Nodule features by Ultrasound More likely benign More likely malignant Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard (not elastic) • Hyperechoic • Smooth borders • Halo • Uninterrupted Peripheral or “eggshell” calcifications • Low vascularity • Soft (elastic)

37. Ultrasound Elastography • Malignant lesions are associated with changes in the mechanical properties of a tissue • Elastography is a dynamic technique that uses ultrasound to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force • Has been used to differentiate cancer from benign lesions in prostate, breast, pancreas, LNs • Now being applied to thyroid nodules

39. 92 consecutive patients who underwent surgery for solitary thyroid nodules -all underwent standard thyroid ultrasound, standard risk assessment -Elastography was performed for all nodules -nodules “scored” based on how “ELASTIC” they are Rago. J Clin Endocrinol Metab 2007;92:2917-2922.

40. Elasto study findings • 92 cases, all proceeded to surgery, known histologic diagnosis • 34% malignant • 66% benign • Elastography • Score 1-2identified in 49 patients: all benign • Score 3identified in 13 patient: 1 malignancy, 12 benign • Score 4-5identified in 30 patients: all malignant • Conclusions • If your thyroid nodule is very elastic (score 1-2), it is most likely benign • If your thyroid nodule is very firm (score 4-5), it is most likely cancer • Elastography is of tremendous clinical value, particularly when added to other standard US sonographic features • Limitations: can’t be used on cystic/solid nodules or calcified nodules Rago. J Clin Endocrinol Metab 2007;92:2917-2922.

41. Elastic: Score 1 Hard: Score 5

42. Should I do any lab testing for a thyroid nodule? • TSH for everybody! • If low, don’t biopsy! (To be reviewed in next few slides) • TPO and TG antibodies usually NOT necessary • But, TPO abs may help determine the explanation for other sonographic findings (ex: Hashimoto’s) • ↑ TG abs associated with thyroid cancer, hypothesis: thyroid inflammation is tumorigenic or abnormal TG expressed by tumor cells triggers immune response • Calcitonin • Elevated in Medullary Thyroid Cancer (3-5% of thyroid malignancies) and C-cell hyperplasia and may help detect MTC at an earlier stage • Some recommend universal calcitonin screening in patients with nodules • American Thyroid Association (2009) guidelines: recommendation I • AACE, AME, European Thyroid Association: “consider” • Always measured if family history of MTC or MEN2 • Thyroglobulin • Not useful, no relationship to thyroid malignancy • Universal consensus among all professional societies (ATA, AACE, AME, ETA) • Do NOT measure! A serum TSH is indicated in all patients with thyroid nodules

43. AACE/AME/ETA Thyroid Nodule Guidelines, Endocr Pract. 2010;16(Suppl 1). ATA guidelines for management of thyroid nodules and thyroid cancer, Thyroid, 2009;19(11):1167.

44. Why is the TSH so useful? • It helps determine if the nodule is likely to be a “toxic” adenoma • These are autonomous, hyperfunctioning nodules, aka “hot” nodules • They are [almost] always benign! • Thus, FNA is usually* unnecessary • If the TSH is low, patient should be sent for a radionuclide study first and/or referredto endo Important: thyroid uptake and scan is not appropriate for MOST patients with thyroid nodules! *if nodule is smaller (<1.5 or so) with suspicious features, FNA may still be indicated

45. Does TSH correlate with risk of malignancy in a patient with a nodule? • Prospective study of 1,183 patients with palpable thyroid enlargement • All had FNA and/or surgery • TSH measured at presentation, then compared to FNA and/or surgical findings Boelaert K. J Clin Endocrinol Metab 2006;91(11):4295.

46. Risk of thyroid cancer increases as TSH rises Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301

47. Estimated probability of malignancy in 40 y/o female with a solitary thyroid nodule Why? TSH has a trophic effect on thyroid cancer growth, likely mediated by TSH receptors on tumor cells. TSH suppression is an independent predictor of relapse-free survival from differentiated thyroid cancer. TSH Risk of cancer_ 0.3 8% 0.5 8.4% 1.0 9.4% 3.0 14.6% 5.0 21.9% 6.0 26.4% Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301

48. Test: true or false? • The larger the nodule, the more likely it is to be cancer. • A patient with a solitary nodule is more likely to have cancer than a patient with multiple nodules (multinodular goiter). • Treatment with levothyroxine will shrink thyroid nodules.

49. Nodule features by Ultrasound More likely benign More likely malignant Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard/not elastic • Hyperechoic or isoechoic • Smooth borders • Halo • Uninterrupted Peripheral or “eggshell” calcifications • Low vascularity • Soft/elastic No mention of size!

50. Malignancy rate was not lower (was actually higher) in nodules <1cm 520 consecutive thyroid nodules evaluated from 2003-2006. Group 1: subcentimeter nodules (N=247) Group 2: supracentimeter nodules (N=273) Ultrasound and FNA for all patients; malignant or suspicioussurgery Berker. Thyroid 2008;18:603-608.