Thyroid Cancer Diagnosis and Management. Jerome Hershman, M.D. Internal Medicine Grand Rounds University of Missouri, Columbia October 21, 2010

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1 Thyroid Cancer Diagnosis and Management Jerome Hershman, M.D. Internal Medicine Grand Rounds University of Missouri, Columbia October 21, 2010

2 DISCLOSURE NOTHING TO DISCLOSE in regard to financial conflict

3 Epidemiology of Thyroid Cancer in 2010* Estimate 44,700 new cases in U.S. in % increase over 2009 Female/male=3. 3% of all cancers. Comparisons: Ovary 22,000, Testis 8,500, Brain 22,000, Leukemia 43,000 Prevalence: About 300,000 cases in U.S. Thyroid cancer deaths = 1,700, F/M=1.3. *Jemal A et al. CA 60:277, 2010

4 Davies L, Welch HG 2006 Increasing incidence of thyroid cancer in the United States, JAMA.

5 Chen AY, Cancer 115:3801, 2009

Type* and Survival** Type Percent 10-yr survival Papillary 81 93 Follicular Hurthle 10 3 85 76 Medullary 3 75

7 Type* and Survival** Type Percent 10-yr survival Papillary Follicular Hurthle Medullary 3 75 Anaplastic 3 14 *Hundahl et al. Cancer, cases in US in 1996 **Hundahl et al. Cancer ,856 cases in US,

8 37% 37% 26%

9 Diagnosis Currently based on fine needle aspiration biopsy (fna) of thyroid nodules in most cases Nodules detected by palpation, or more commonly nowadays by imaging neck: ultrasound, CT, MRI, or PET.

10 Thyroid FNA Classification NCI Conference 2007* Category Malignancy Risk Malignancy: Yang x 4703 Patients Benign <1% 7 FLUS** 5-10% 11 Follicular Neoplasm 20-30% 32 Suspicious for Malignancy 50-75% 65 Malignant 100% 99 Non-diagnostic 11 **Follicular lesion of undetermined significance *Baloch Z et al. Cytojournal 2008 x Cancer Cytopathol 2007; 111:306

11 A. Nodular goiter. B. Follicular nodule in Hashimoto s. C. Follicular adenoma. D. Follicular carcinoma E. Follicular variant papillary ca From Kini atlas

12 Ultrasound Characteristics Suggestive of Malignant Nodules Hypoechoic and/or heterogenous texture Irregular or blurred border Microcalcifications Amorphous coarse calcifications Taller than wider on transverse scan Intranodular vascular pattern* Invasion of surrounding tissues/structures Cervical adenopathy (pathologic)

13 Microcalcification of papillary carcinoma

14 Frates M, Alexander E, et al. JCEM, 91:3411, patients with 3483 nodules >1cm. FNA results.

15 Frates MC, Radiology 2005

16 MAP kinase pathway B-type RAF kinase is abundant protein. T1799A mutation results in BRAF(V600E) that is constitutively activated. From Xing M, Endo Rev 2007

17 BRAF V600E Mutation Found in 29 to 68% papillary thyroid ca Associated with aggressive features Extrathyroid extension Advanced Stage

18 Molecular testing of FNA aspirates to improve diagnosis of thyroid cancer

20 Nikiforov YE et al. J Clin Endocrinol Metab 94: , 2009.

21 Nikiforov YE et al. J Clin Endocrinol Metab 94: , 2009.

22 Nikiforov YE et al. J Clin Endocrinol Metab 94: , 2009.

23 174 patients undergoing thyroid surgery FNAB performed on 235 thyroid nodules Submitted for cytology and molecular analysis of BRAF, RAS, RET, and PAX8/PPARg mutations

24 Cytologic, molecular, and histologic correlation Cantara S et al. J Clin Endocrinol Metab 95: , 2010.

25 Distribution of molecular mutations according to final histology 78% Ca had mutation. Only 59% +cytology. Cantara S et al. J Clin Endocrinol Metab 95: , 2010.

26 Malignant characteristics by US: Micro- or macro calcifications Marked hypoechogenicity Irregular margin Taller than wider on transverse-section

27 Data suggest that BRAF mutation analysis is most useful and cost-effective for US-positive nodules. Nam SY et al. Thyroid 20:273,2010.

28 When to repeat FNA Repeat if specimen unsatisfactory Do not repeat if benign Repeat if lesion grows

29 Surgical Management of Differentiated Thyroid Cancer Total/near total thyroidectomy Central lymph node compartment dissection

30 Surgery for Follicular Lesion Lobectomy vs near-total thyroidectomy Latter eliminates need for 2nd surgery if lesion is follicular cancer Frozen section may determine whether it is follicular variant of papillary ca, and then near-total can be done Near-total for benign lesion results in definite hypothyroidism I generally recommend lobectomy, but leave it up to surgeon s judgement.

31 Staging of Differentiated Thyroid Cancer TNM staging system uses Tumor size: T1<2 cm, T2: 2-4cm, T3:>4cm T4 tumor outside capsule Lymph Nodes Distant metastasis Age <45 years is good, > 45 years bad Stages are 1 to 4 and correlate with prognosis

32 Radioiodine-131 Ablation of Remnants Indicated for aggressive tumors, large lesions, incomplete resection, positive nodes, intermediate to advanced stage Not worthwhile for T1 papillary ca (<2 cm) unless nodes positive or tumor is aggressive variant: tall cell

33 131 I Ablation Prepare by thyroid hormone withdrawal or recombinant TSH My protocol for withdrawal: use 25 mcg T3 bid post-op for 6 to 8 weeks, withdraw for 2 weeks while patient is on low iodine diet. Then give 100 mci 131 I. I favor therapy as outpatient if circumstances permit it. Do post-therapy scan 7 days after 131 I. Start suppressive T4 48 hr after 131 I, and give 25 mcg T3/day also for first week.

34 Pacini, Ladenson et al. JCEM: 91, 926, mci 131 I ablative dose after rhtsh vs no T4

35 Follow-up Management Serum Tg q 4 to 6 months with anti-tg Neck ultrasound annually Stimulated Tg, either by rhtsh or withdrawal if recurrence is likely. I combine 131 I total body scan with either of above.

36 T4 suppression TSH goal depends on stage and age Suppress to <0.1 mu/l for stages 3, 4. Stage 1 or 2 (low risk of recurrence: Keep TSH <normal for 5 years, then bring to lower limit of normal. Avoid symptomatic thyrotoxicosis and high T3 level. Warn patient about atrial fibrillation and osteoporosis as possible consequences

37 Sensitive Tg assay obviates need for rhtsh in follow-up Smallridge RC et al. JCEM 2007; 92:82-7.

38 Recurrent Neck Disease Surgery 131 I External radiation

Surgical resection of persistent PTC in cervical lymph nodes achieves biochemical complete remission (BCR) in one-fourth of patients, sometimes requiring

39 Surgical resection of persistent PTC in cervical lymph nodes achieves biochemical complete remission (BCR) in one-fourth of patients, sometimes requiring several surgeries. No biochemical or clinical recurrences occurred during follow-up. In patients who do not achieve BCR, Tg levels were significantly reduced.

Results of I-131 treatment for metastases Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of

40 Results of I-131 treatment for metastases Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy.* Patients with distant metastases treated at Institute Gustave-Roussy, France during *Durante C, et al. J Clin Endocrinol Metab Aug;91:2892-9

41 Durante, Schlumberger, et al. JCEM, patients.

42 Treatment for Metastatic Differentiated Thyroid Cancer New chemotherapy is available for cancers that do not take up 131 I and cannot be treated with surgery or external beam radiation.

44 Tyrosine Kinase Inhibitors (TKI) Most affect multiple kinases. VEGF-R is common target. Clinical trials have been completed for several TKIs. Therapy often results in stable disease, but none are cured.

46 Sorafenib (Nexavar) Approved for renal cell and hepatic cancer Rx Targets BRAF, VEGFR1, VEGFR2, PDGF

48 60 y/o w follicular ca After 16 wks Rx 59 y/o w pap ca After 33 wks Rx

49 N Engl J Med 2008;359:31-42.

51 Summary Papillary thyroid cancer is increasing. Molecular analysis of FNA specimens improves accuracy of diagnosis. Therapy with surgery, 131 I ablation, and T4 suppression cures most patients. Patients with advanced metastatic disease may achieve stable disease or partial remission with TKI therapy.

52 Thank you for your attention

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