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Implementing Guidelines For Thyroid Nodules Hirotoshi Nakamura Kuma Hospital, Kobe, Japan Guidelines of Japan Thyroid Association for the management of thyroid nodules (Task Force : 29 doctors in endocrinology, endocrine surgery, radiology, nuclear medicine, pathology) １. Purpose of this guidelines ２. Classification and incidence of the nodules ２-１ Histological classification ２-２ Incidence of the nodules ３.Algorithm for approaching thyroid nodules ４. Diagnostic approach ４-１ Clinical evaluation ４-２ Ultrasonography (US) B-mode two-dimensional image Doppler mode US Elastography ４-３ Fine Needle Aspiration ４-４ CT、MR、PET、Scintigraphy ４-５ Laboratory tests & Molecular markers ５. Management and long-term follow-up ５-１ Management based on FNA diagnosis ５-２ TSH suppressive therapy ５-３ Conditions for surgical treatment ５-４ Treatment for papillary carcinoma ６. Topics ６-１ Adenomatous goiter ６-２ Cystic lesions ６-３ Functioning nodules ６-４ Nodules 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 Incidence of thyroid nodules discovered by palpation or ultrasonography in Japan nodules method region Japan gender ＊ palpation outside Japan ultrasono graphy Japan ＊＊ outside Japan cancer rate of cancer n rate n rate n of nodules cancer/ nodules male 88858 0.64% 128664 0.08% 569 14.4% female 289973 1.64% 469070 0.18% 4752 11.3% male 9080 0.76% female 9990 3.10% male 16811 16.6% 37459 0.26% 2795 1.9% female 21907 28.1% 38524 0.66% 6164 3.2% male 45500 20.1% female 40658 26.7% (summarized by Shimura) one of six males & one of 3.5 females ＊ 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 Karamatsu et al. 1996 Shimuraet al. 2001 Nishi et al. 2008 Miyazaki et al. 2011 palpation images thyroid nodules history, physical exam ultrasonography cystic legion TSH, (FT4)（TgAb, TPOAb, Tg, Ct） solid legion evaluation for thyroid nodules 123I- or99mTcscintigraphy observation Fine Needle Aspiration Biopsy Nondiagnostic Normal/Benign Indeterminate B Suspicious for nodular lesion other than follicular tumor repeated FNA A Suspicious for malignancy Malignant Suspicious for follicular tumor observation / US monitoring surgical resection palpation thyroid nodules history, physical exam ultrasonography image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） rapid growth of a mass cystic headsolid childhood and neck or total body irradiation legion family history legion of thyroid cancer (MTC, PTC) or thyroid cancer syndromes (MEN 2, Cowden synd, Carney complex, familial polyposis ) size, location, movement, consistency of the thyroid nodules cervical lymphadenopathy evaluation for 123I- or Tcassociated local symptoms (pain, hoarseness, dysphagia, scintigraphy dysphonia, dyspnea) thyroid nodules signs of hyper- or hypo-thyroidism palpation thyroid nodules history, physical exam ultrasonography image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） Measurement of serum TSH is necessary in every patient, since cystic solid TSH is an independentlegion risk factorlegion 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.evaluation for 123I- or TcHigher TSH was found to be associated with advanced-stage scintigraphy thyroid nodules thyroid cancer. palpation thyroid nodules history, physical exam ultrasonography cystic legion image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） 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 Tcscintigraphy palpation thyroid nodules history, physical exam ultrasonography image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） cystic solid Serum Tg is not sensitive nor specific for the detection of thyroid legion legion 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. evaluation for thyroid nodules 123I- or Tcscintigraphy palpation thyroid nodules history, physical exam ultrasonography image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） cystic solid legion legion 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. evaluation for thyroid nodules 123I- or Tcscintigraphy palpation thyroid nodules history, physical exam ultrasonography image TSH, (FT4) （TgAb, TPOAb, Tg, Ct） Thyroid ultrasonography cystic solid should be legion patient legion performed in every with suspected thyroid nodule(s).It provides considerable anatomic detail and its findings can be used to select nodules for FNA biopsy. evaluation for 123I- or Tcscintigraphy thyroid nodules palpation history, physical exam thyroid nodules ultrasonography cystic legion TSH, (FT4) （TgAb, TPOAb, Tg, Ct） solid legion evaluation for thyroid nodules observation image 123I- or Tcscintigraphy Fine Needle Aspiration Biopsy 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. US criteria for FNA biopsy of solid nodules solid nodule Japan Association of Breast and Thyroid Sonology ≦5mm ＞5mm ≦10mm ＞10mm ≦20mm observation strongly suspicious suspicious finding(s) observation ＞20mm FNAB + - + FNAB observation FNAB FNAB is recommended for solid, hypoechoic nodule in diameter larger than 10mm. US criteria for FNA biopsy of cystic nodules Japan Association of Breast and Thyroid Sonology cystic nodules presence of no solid legion 20mm≧ solid legion size >10 mm or irregular, vascular, microcalcification 20mm＜ (-) observation FNAC FNAB observation (+) FNAB Fine Needle Aspiration Cytology （The Papanicolaou society of cytopathology. 1996) 1 Nondiagnostic Diagnostic 2 Normal・Benign 3 Indeterminate Diagnostic sample should contain a minimum of 6 groupings of wellpreserved thyroid epithelial cells, consisting of at least 10 cells per group. follicular adenoma/follicular carcinoma follicular tumor any other lesions with atypia of undetermined significance 4 Suspicious for malignancy 5 Malignant FTC is difficult to be diagnosed by FNAC, since its diagnostic criteria include capsular invasion, vascular invasion and/or metastasis. 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) I.Nondiagnostic (risk of malignancy) II.Benign <３ % III.Follicular lesion/Atypiaof undetermined significance 5-10 % IV.Follicular neoplasm 20-30 % V.Suspicious for malignancy 50-75 % VI.Malignant 100 % Fine Needle Aspiration Cytology (our new modified classification) 1 Nondiagnostic favor benign Diagnostic (borderline) 2 Normal・Benign favor malignant 3A Indeterminate A 3 Indeterminate 3B Indeterminate B 4 Suspicious for malignancy 5 Malignant Suspicious of follicular tumor Suspicious of nodular lesion other than follicular tumor How to manage thyroid nodules based on the results of FNA cytology ? 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 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) surgical resection for histological diagnosis cystic lesion close observation with US surveillance consulting US findings 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. 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. Repeated FNA increased the benign probability from 90% to (Oertel et al. Thyroid 2007) 98%. 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 (Kwak et al. Eur Radiol 2009) diagnosed as benign. It would be advisable to repeate FNA up to three times. (Orlandi et al. Thyroid 2005) It may be recommended to repeat FNA after a couple of years for affirmation of “benignancy”. How to manage thyroid nodules based on the results of FNA cytology ? ② ‘benign’nodules by FNAC (3) Should levothyroxine suppressive therapy be performed? 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) Since Japanese consume sufficient amount of iodine, routine T4 treatment to suppress TSH is not recommended. 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 favor benign A-2 A-3 borderline favor malig. probability of malignancy probability of malignancy probability of malignancy 5〜15% 15〜30% 40〜60% careful follow-up withUS monitoring every 6~18 months surgical resection for histological diagnosis 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 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 palpation images thyroid nodules history, physical exam ultrasono-graphy cystic legion TSH, (FT4)（TgAb, TPOAb, Tg, Ct） solid legion evaluation for thyroid nodules 123I- or99mTcscintigraphy observation Fine Needle Aspiration Biopsy Nondiagnostic Normal/Benign Indeterminate B Suspicious for nodular lesion other than follicular tumor repeated FNA A Suspicious for malignancy Malignant Suspicious for follicular tumor observation / US monitoring surgical resection Thank you for your attention!