1. Thyroid Cancer 2005 Nancy Fuller, M.D. University of Wisconsin-Madison

2. 1.52 yo woman in good health; presented with back pain of a musculoskeletal nature. Exam of neck: palpable right sided thyroid nodule approx 2x3 cm; gland otherwise not enlarged and no other nodules or lymphadenopathy. Ultrasound: solid nodule; uptake scan: no excess uptake in nodule TFTs: normal A FNA was performed. DX: Hurthle cell neoplasia

3. 2. 64 yo woman with hyperlipidemia; presented for a preventive health exam with no complaints. Neck exam: 4x2 cm right sided thyroid nodule, gland otherwise normal, no lymphadenopathy. Ultrasound-solid nodule, uptake scan no excess uptake in nodule. TFTs A FNA was performed. DX: Hurthle cell neoplasia

4. 3. 28 yo woman presented after having a thyroid nodule found incidentally on a carotid ultrasound being performed as a normal control for a study. Exam: 2x2 cm right sided thyroid nodule, gland otherwise normal, no lymphadenopathy. TFTs normal Dedicated ultrasound: solid nodule; FNA performed that day because of availability of pathology support DX: Papillary thyroid carcinoma

5. Learning objectives: To learn about the epidemiology, types, behaviors, treatment and prognosis of thyroid cancer. No financial disclosures

6. Epidemiology Thyroid nodules: very common Clinically detectable thyroid carcinoma: rare: <1% of all cancers Female to male ratio- 2.5:1 Median age at dx: 45-50

7. Overall incidence is rising: In 1935: 1.3/100,000 women,.2/100,000 men By 1991: 5.8/100,000 women, 2.5/100,000 men Incidence has continued to rise in past 10 years: most rapid rate of increase in all tracked cancers

8. Reason for rise? Neck irradiation: used between 1910 and 1960 Better diagnosis? BUT: only rise is in papillary type; if better diagnosis was reason, would expect rise in all types

9. Hegedus, L. N Engl J Med 2004;351:1764-1771 Algorithm for the Cost-Effective Evaluation and Treatment of a Clinically Detectable Solitary Thyroid Nodule

10. Thyroid cancer: epithelial types Differentiated: Papillary: 70-75 % of all thyroid cancers Follicular: 15-25% Undifferentiated: Anaplastic: 2-5%

11. Thyroid cancer: non epithelial Medullary thyroid cancer Sporadic Familial MEN-2A and B Others: lymphoma, mets from breast, colon, renal and melanoma

12. Papillary thyroid carcinoma Pathogenesis: 1. Activation of tyrosine kinase receptors by rearrangement or gene amplification Results in a chimeric gene Occurs either by radiation or sporadic 2. Point mutations in BRAF gene 10X increased risk of thyroid cancer in relatives of thyroid cancer patients: suggests a genetic link

13. PTC Presentation: Solitary nodule most common Pathology: typically unencapsulated; may be cystic Papillae: 1 or 2 layers of tumor surrounding fibrovascular core Follicles and colloid are typically absent

14. PTC Psommoma bodies: scarred remnants of tumor papillae that have infarcted Present in half of papillary thyroid carcinomas

15. PTC Growth and behavior: minor to major Microcarcinoma: occult papillary carcinoma, with tumor <1cm Found in up to 50% of glands at autopsy (rarer in children) Incidental finding of no clinical importance

16. PTC Other end of spectrum: aggressive metastasis through interthyroidal lymphatic channels to form multifocal tumors Involves regional lymph nodes At diagnosis: clinically detectable nodes more common in children (50%) than adults 2-10% distant mets at dx: 2/3 pulmonary, 1/4 skeletal; also brain, kidneys, liver, adrenals

17. PTC Prognosis Most patients do not die of their disease 80-95% 10 year survival rates Patients between 20-45: best long term survival Patients older than 45 with lymph node recurrences are most likely to die from PTC

18. PTC Prognosis is poorer in patients with large tumors: one large series showed cancer related mortality of 6%/2-3.9cm, 16%/4-6.9cm and 50%7 cm and above Several variants have a worse prognosis: tall cell variant=1% of PTC; more aggressive and invasive

19. Schlumberger, M. J. N Engl J Med 1998;338:297-306 Survival Rate among 1701 Patients with Papillary or Follicular Carcinoma and No Distant Metastases at the Time of Diagnosis

20. Follicular thyroid carcinoma Characterized by follicular differentiation and encapsulation Invasion of the capsule and blood vessels is the main determinant between adenomas and carcinoma 2 main forms: minimally invasive and widely invasive Multicentricity and lymph node involvement are less frequent than in PTC

21. FTC Minimally invasive FTC behaves more like PTC Widely invasive behaves more like anaplastic thyroid carcinoma Hurthle Cell variant:more aggressive FTC is more likely than PTC to be nonresponsive to I 131.

22. Anaplastic thyroid carcinoma Undifferentiated tumor of thyroid follicular epithelium Very aggressive, with a disease specific mortality approaching 100% 2/1,000,000 annual incidence Typical patient is older than differentiated carcinoma, mean age 65 <10% under 50 60-70% women

23. ATC 20% of ATC: history of differentiated thyroid carcinoma, most papillary 10% of Hurthle cell carcinoma: has anaplastic tumor within Up to 1/2 of ATC: history of multinodular goiter

24. ATC Presentation: Nearly all present with a thyroid mass Regional or distant spread is present 90% of the time at dx Lungs, bones, brain most common mets Rapidly enlarging tumor; often causes compression symptoms like dyspnea, dysphagia, hoarseness Constitutional symptoms like fatigue, anorexia, wt loss

25. ATC 50% have palpable nodes at dx Dx: made by FNA, then CT neck and mediastinum, CXR Prognostic factors: tumor size <6 cm=25% 2 yr survival >6cm=3-15% 2 yr survival Others: older age, male sex, dyspnea at presentation No effective treatment for advanced or metastatic ATC: uniformly fatal, with median survival 3-7 mo

26. Treatment of differentiated thyroid carcinoma Surgery: goal is to remove all tumor tissue from neck Total or near total thyroidectomy because of risk of multicentricity Removal of local nodes in PTC, only palpable nodes in FTC because of lower rate of lymph node involvement

27. Treatment I 131: given post op: destroys any remaining normal thyroid tissue, and may destroy occult microcarcinomas Increases sensitivity of subsequent 1 131 total body scans 4-6 wks after surgery a total body scan off thyroid replacement with low dose 1 131; if any uptake, a treatment dose is given (2 mCi vs. 30-100 mCi) Radiation: only if surgical excision is impossible and tissue doesn’t take up I 131

28. Followup Goals of followup: Maintain adequate thyroxine treatment Detect persistent or recurrent cancer Recurrences usually occur early but may occur later so follow up for life

29. Thyroxine treatment goals: initial serum thyrotropin level 0.1 or less, serum free T3 normal Check U/S of thyroid area and nodal areas Serum thyroglobulin levels: TG produced by follicular cells-should not be detectable after total ablation; presence signifies persistent or recurrent disease 80% of patients with TG >40 have detectable foci or I 131 uptake

30. I 131 scanning: needs to be done after withdrawal of thyroxine tx, with TSH >30 needed Scanning is done 3 days after I 131 given Low risk patients with no I 131 uptake after 1 year: TSH maintained at low but detectable level (0.1-0.5)

31. Local or regional mets: occur in 5-20% Excision/I 131 tx/ Radiation tx if no I 131 uptake Distant mets: If I 131 uptake, high dose I 131 given + RT

32. Complications of treatment: I 131: nausea, sialadenitis common but mild and short duration Genetic defects: can’t be given to pregnant women Increased risk of miscarriage in pregnancies within 1 year of tx Overall relative risk of a second type of cancer only if high cumulative dose of I 131 and/or radiation

33. Medullary thyroid cancer Much less common than epithelial thyroid cancers Involves abnormalities of parafollicular C-cells Most cases are sporadic

34. MTC MEN 2 A: autosomal dominant disorder characterized by MTC, pheochromocytoma, and primary parathyroid hyperplasia MEN 2 B: same inheritance; MTC + pheochromocytoma. Occurs at a younger age; more aggressive. Familial MTC: like MEN 2 A but no other associated abnormalities

35. MTC Female to male ratio=1:1 MEN 2 A and familiar MTC: peak in index cases in 3rd decade MEN 2 B: children and teens most common age of presentation. Basal serum calcitonin: usually correlates with tumor mass and is almost always high with palpable tumor

36. MTC MTC in MEN 2 B: more aggressive Early onset Surgery often not curative Death from MTC: 50% of MEN 2 B, 10 % MEN 2 A

37. Cases: recap and current status