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
　　　２-１　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

3. one of six males & one of 3.5 females
Incidence of thyroid nodules discovered by palpation or ultrasonography in Japan
method
region
gender
nodules
cancer
rate of cancer n
rate
n of nodules
cancer/　nodules
palpation
Japan
male
88858
0.64%
128664
0.08%
569
14.4%
female
289973
1.64%
469070
0.18%
4752
11.3%
outside Japan
9080
0.76%
9990
3.10%
ultrasonography
16811
16.6%
37459
0.26%
2795
1.9%
21907
28.1%
38524
0.66%
6164
3.2%
45500
20.1%
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

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

5. evaluation for thyroid nodules
palpa-tion
thyroid nodules
image
history,
physical exam
ultrasono-graphy
TSH, (FT4) 　 （TgAb, TPOAb, Tg, Ct）
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. evaluation for thyroid nodules
palpa-tion
thyroid nodules
image
history,
physical exam
ultrasono-graphy
TSH, (FT4) 　 （TgAb, TPOAb, Tg, Ct）
Measurement of serum TSH is necessary in every patient, since TSH is an independent risk factor for predicting malignancy.
cystic legion
solid legion
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. evaluation for thyroid nodules
palpa-tion
thyroid nodules
image
history,
physical exam
ultrasono-graphy
TSH, (FT4) 　 （TgAb, TPOAb, Tg, Ct）
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. evaluation for thyroid nodules
palpa-tion
thyroid nodules
image
history,
physical exam
ultrasono-graphy
TSH, (FT4) 　 （TgAb, TPOAb, Tg, Ct）
cystic legion
solid legion
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.
evaluation for thyroid nodules
123I- or Tc-　scintigraphy

9. evaluation for thyroid nodules
palpa-tion
thyroid nodules
image
history,
physical exam
ultrasono-graphy
TSH, (FT4) 　 （TgAb, TPOAb, Tg, Ct）
cystic legion
solid 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 Tc-　scintigraphy

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

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

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

15. Fine Needle Aspiration Cytology
（The Papanicolaou society of cytopathology. 　1996) 1
Nondiagnostic
Diagnostic sample should contain　a minimum of 6 groupings of well-preserved thyroid epithelial cells, consisting of at least 10 cells per group.
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. 4
Suspicious for malignancy 5
Malignant

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

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

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

19. ① Nondiagnostic specimen by FNAC
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. consulting US findings
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
surgical resection for histological diagnosis
close observation with US surveillance
consulting US findings

21. ② ‘benign’nodules by FNAC (1)
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. ② ‘benign’nodules by FNAC (2)
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 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)
It may be recommended to repeat FNA after a couple of years for affirmation of “benignancy”.

23. ② ‘benign’nodules by FNAC (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?
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.

24. ③ ‘Indeterminate A’by FNAC
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
favor benign
borderline
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 24

25. Repeated FNA at an appropriate interval is recommended
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. Surgical resection ⑤Suspicious for malignancy by FNAC
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. evaluation for thyroid nodules
palpation
images
thyroid nodules
history, physical exam
ultrasono-graphy
TSH, (FT4)（TgAb, TPOAb, Tg, Ct）
cystic legion
solid legion
evaluation for thyroid nodules
123I- or99mTc-　scintigraphy
observation
Fine Needle Aspiration Biopsy
Nondiagnostic
Normal/Benign
Indeterminate
Suspicious for malignancy
Malignant B A
Suspicious for nodular lesion other than follicular tumor
Suspicious for follicular tumor
repeated FNA
observation / US monitoring
surgical resection

28. Thank you for your attention!