Implementing Guidelines For Thyroid Nodules

1. Implementing Guidelines For Thyroid Nodules Hirotoshi Nakamura Kuma Hospital, Kobe, Japan

2. Guidelines of Japan Thyroid Association for the management of thyroid nodules (publish in 2013) (Task Force : 29 doctors in endocrinology, endocrine surgery, radiology, nuclear medicine, pathology) • １. Purpose of this guidelines • ２. Classification and incidence of the nodules • 　２-１Histological classification • 　２-２Incidence of the nodules • ３.Algorithm for approaching thyroid nodules • ４.Diagnostic approach • ４-１Clinical evaluation • ４-２Ultrasonography (US) • B-mode two-dimensional image • Doppler mode • US Elastography • ４-３Fine Needle Aspiration • ４-４ CT、MR、PET、Scintigraphy • ４-５Laboratory tests & Molecular markers ５.Management and long-term follow-up ５-１Management based on FNA diagnosis ５-２TSH suppressive therapy ５-３　Conditions for surgical treatment ５-４　Treatment for papillary carcinoma ６.Topics ６-１Adenomatous goiter ６-２Cystic lesions ６-３Functioning nodules ６-４Nodules accompanied with Graves’ disease or Hashimoto thyroiditis ６-５　Thyroid nodules during pregnancy ６-６　Thyroid nodules in childhood ７.Clinical data about thyroid nodules in major medical institutes in Japan ８.Major guidelines outside Japan

3. Incidence of thyroid nodules discovered by palpation or ultrasonography in Japan ＊ ＊ ＊ (summarized by Shimura) one of six males & one of 3.5 females ＊ ＊ ＊ Karamatsu et al. 1996 Shimuraet al. 2001 Nishi et al. 2008 Miyazaki et al. 2011 Maruchi et al. 1971 Noguchi et al. 1985 Yamashita et al. 1993 Ishikawa et al. 1995 Miki et al. 1998 Suehiro et al. 2006 Ohara et al. 1986 Saitoet al. 1991 Yanohara et al. 1991 Nakamutsu et al. 1993 Sou et al. 1994 Takebe et al. 1994

4. palpation images thyroid nodules history, physical exam TSH, (FT4)（TgAb, TPOAb, Tg, Ct） • ultrasonography cystic legion solid legion evaluation for thyroid nodules 123I- or99mTc-scintigraphy observation • Fine Needle Aspiration Biopsy Nondiagnostic • Normal/Benign Indeterminate Suspicious for malignancy Malignant A B Suspicious for nodular lesion other than follicular tumor Suspicious for follicular tumor observation / US monitoring repeated FNA surgical resection

5. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy rapid growth of a mass childhood head and neck or total body irradiation family history of thyroid cancer (MTC, PTC) or thyroid cancer syndromes (MEN 2, Cowden synd, Carney complex, familial polyposis ) cystic legion solid legion size, location, movement, consistency of the thyroid nodules cervical lymphadenopathy associated local symptoms (pain, hoarseness, dysphagia, dysphonia, dyspnea) signs of hyper- or hypo-thyroidism evaluation for thyroid nodules 123I- or Tc-scintigraphy

6. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy cystic legion solid legion Measurement of serum TSH is necessary in every patient, since TSH is an independent risk factor for predicting malignancy. If TSH is low and suppressed, a nodule may be hyperfunctioning. A hyperfunctioning nodule is usually benign. The risk of malignancy rises in parallel with TSH, even within the normal range. Higher TSH was found to be associated with advanced-stage thyroid cancer. evaluation for thyroid nodules 123I- or Tc-scintigraphy

7. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy cystic legion solid legion TgAb and TPOAb are useful to identify the existence of Hashimoto thyroiditis which is known to co-associate with thyroid nodules at high frequency. evaluation for thyroid nodules 123I- or Tc-scintigraphy

8. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy Serum Tg is not sensitive nor specific for the detection of thyroid cancer and not recommended to be measured in the initial evaluation. However, Tg measurement may be helpful in some occasions, since very high level of serum Tg has been reported in some cases of FTC. cystic legion solid legion evaluation for thyroid nodules 123I- or Tc-scintigraphy

9. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy We do not recommend serum calcitonin measurement in the initial evaluation, except for suspicious familial MTC or MEN type2. The prevalence of MTC in Japan is low and pentagastrin stimulation test is not available. cystic legion solid legion evaluation for thyroid nodules 123I- or Tc-scintigraphy

10. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy • Thyroid ultrasonography should be performed in every patient with suspected thyroid nodule(s).It provides considerable anatomic detail and its findings can be used to select nodules for FNA biopsy. cystic legion solid legion evaluation for thyroid nodules 123I- or Tc-scintigraphy

11. palpa-tion image thyroid nodules history, physical exam TSH, (FT4) （TgAb, TPOAb, Tg, Ct） • ultrasono-graphy cystic legion solid legion evaluation for thyroid nodules 123I- or Tc-scintigraphy observation • Fine Needle Aspiration Biopsy

12. US diagnostic findings suspicious findings of malignancy shape irregular, taller than wide sharpness of border poorly defined, irregular intensity of echoes hypoechoic internal structure inhomogenous calcification microcalcifications Halo incomplete or absent Doppler flow patterns central vascularity Although none of these features alone is sufficient to differentiate a malignant nodule from majority of benign nodules, a combination of these can succeed in pointing out a lesion of high risk for malignancy.

13. US criteria for FNA biopsy of solid nodules Japan Association of Breast and Thyroid Sonology solid nodule ≦5mm ＞5mm ≦10mm ＞10mm ≦20mm ＞20mm strongly suspicious suspicious finding(s) observation FNAB FNAB FNAB - - + + observation observation FNAB is recommended for solid, hypoechoic nodule in diameter larger than 10mm.

14. US criteria for FNA biopsy of cystic nodules cystic nodules Japan Association of Breast and Thyroid Sonology no solid legion presence of solid legion 20mm≧ 20mm＜ size >10mm irregular, vascular, microcalcification or (+) (-) observation observation FNAB FNAB FNAC

15. Fine Needle Aspiration Cytology （The Papanicolaou society of cytopathology. 1996) 1 Diagnostic sample should containa minimum of 6 groupings of well-preserved thyroid epithelial cells, consisting of at least 10 cells per group. Nondiagnostic Diagnostic 2 • Normal・Benign 3 Indeterminate follicular adenoma/follicular carcinoma follicular tumor any other lesions with atypia of undetermined significance FTC is difficult to be diagnosed by FNAC, since its diagnostic criteria include capsular invasion, vascular invasion and/or metastasis. Suspicious for malignancy 4 Malignant 5

16. III.Follicular lesion/Atypiaof undetermined significance The Bethesda System for Reporting Thyroid Cytopathology (Baloch et al.DiagnCytopathol, 2008) (Ali &Cibas(eds) 2009 The Bethesda System for Reporting Thyroid Cytopathology. Springer, NY) (risk of malignancy) I.Nondiagnostic <３ % • II.Benign 5-10 % 20-30 % IV.Follicular neoplasm 50-75 % V.Suspicious for malignancy 100 % VI.Malignant

17. Fine Needle Aspiration Cytology (our new modified classification) 1 Nondiagnostic favor benign Diagnostic (borderline) 2 favor malignant • Normal・Benign 3A Suspicious of follicular tumor Indeterminate A 3 Indeterminate 3B Indeterminate B Suspicious of nodular lesion other than follicular tumor Suspicious for malignancy 4 Malignant 5

18. How to manage thyroid nodules based on the results of FNA cytology ?

19. How to manage thyroid nodules based on the results of FNA cytology ? ① Nondiagnostic specimen by FNAC Diagnostic specimen should contain a minimum of 6 groupings of well-preserved thyroid epithelial cells, consisting of at least 10 cells per group. causes for nondiagnosticspecimen • cystic nodules that yield few or no follicular cells, • benign or malignant sclerotic lesions, • nodules with a thick or calcified capsule, • hypervascularor necrotic lesions, • sampling errors or faulty biopsy techniques

20. How to manage thyroid nodules based on the results of FNA cytology ? ① ‘Nondiagnostic’ specimen by FNAC malignant rate: about 10% repeat FNA with US guidance Re-FNA with US guidance can yield a diagnostic specimen in 50-80%. 75% of solid nodules & 50% of cystic nodules (Alexander et al. JCEM 2002) repeated nondiagnostic solid nodule(s) cystic lesion consulting US findings close observation with US surveillance surgical resection for histological diagnosis

21. How to manage thyroid nodules based on the results of FNA cytology ? ② ‘benign’nodules by FNAC (1) mostly adenomatous nodule/ adenomatous goiter nodular goiter or colloid nodule reported false negative rate : 1 ~ 11% (about ~3%?) clinically follow up with repeated US assessment at 1~2 year intervals for several years If the nodule show significant growth (>50% in volume) or suspicious US changes, to repeat FNAB is recommended.

22. Repeated FNA increased the benign probability from 90% to 98%. (Oertel et al. Thyroid 2007) Repeated FNA detected cancer in 13.2% initially diagnosed as benign nodules. (Gabales et al. Eur J Endocrinol 2009) Repeated FNA detected cancer in 15/16 nodules initially diagnosed as benign. (Kwak et al. Eur Radiol 2009) It would be advisable to repeate FNA up to three times. (Orlandi et al. Thyroid 2005) How to manage thyroid nodules based on the results of FNA cytology ? ② ‘benign’nodules by FNAC (2) Repeated FNA can increase the “benign” probability. It may be recommended to repeat FNA after a couple of years for affirmation of “benignancy”.

23. Routine suppression therapy of benign thyroid nodules in iodine sufficient populations is not recommended. (ATA-GLRecommendation F) Routine T4 treatment in patients with nodular thyroid disease is not recommended. T4 therapy may be considered in young patients who live in iodine-deficient areas. (AACE-GLGrade BLevel 3) How to manage thyroid nodules based on the results of FNA cytology ? ② ‘benign’nodules by FNAC (3) Should levothyroxine suppressive therapy be performed? Since Japanese consume sufficient amount of iodine, routine T4 treatment to suppress TSH is not recommended.

24. How to manage thyroid nodules based on the results of FNA cytology ? ③ ‘Indeterminate A’by FNAC (Suspicious of follicular tumor) follicular adenoma ? follicular carcinoma ? A-1 A-2 A-3 borderline favor benign favor malig. probability of malignancy 5〜15% probability of malignancy 15〜30% probability of malignancy 40〜60% surgical resection for histological diagnosis careful follow-up withUS monitoring every 6~18 months

25. How to manage thyroid nodules based on the results of FNA cytology ? ④ ‘Indeterminate B’by FNAC (1) (Suspicious of nodular lesion other than follicular tumor) • nodules with focal features suggestive of • PTC in an otherwise benign-appearing sample • Hashimoto thyroiditis / malignant lymphoma? A repeat FNA can result in a definitive diagnosis. Only about 20 – 25% of nodules are repeated AUS (Atypia of Undetermined Significance) in Bathesda System (Yassa et al.Cancer2007) Repeated FNA at an appropriate interval is recommended

26. How to manage thyroid nodules based on the results of FNA cytology ? ⑤Suspicious for malignancy by FNAC probability of malignancy (PTC)> 80% ⑥ Malignancy by FNAC probability of malignancy (PTC)> 99% very high probability of PTC Surgical resection total / near total thyroidectomy lobectomy

27. palpation images thyroid nodules history, physical exam TSH, (FT4)（TgAb, TPOAb, Tg, Ct） • ultrasono-graphy cystic legion solid legion evaluation for thyroid nodules 123I- or99mTc-scintigraphy observation • Fine Needle Aspiration Biopsy Nondiagnostic • Normal/Benign Indeterminate Suspicious for malignancy Malignant A B Suspicious for nodular lesion other than follicular tumor Suspicious for follicular tumor observation / US monitoring repeated FNA surgical resection

28. Thank you for your attention!