1. Symposium: Postoperative Management of Thyroid Cancer
Dynamic Estimation of Prognosis in Patients with Thyroid Cancer after Surgery
Akira Miyauchi, M.D., Ph.D.
Department of Surgery
Kuma Hospital
Center for Excellence in Thyroid Care
10th AOTA Congress, Bali, Indonesia, October 22, 2012

2. Risk Assessment and Risk Stratification
1. To plan the initial treatment: the extent of surgery
2. To tailor postoperative adjunctive therapies:
RAI therapy and TSH suppressive therapy
3. To assess the patient’s risk for recurrence and mortality
4. To decide the frequency and intensity of follow-up
5. To enable accurate communication regarding a patient
among health care professionals
Risk assessment and risk stratification can be done
1. Preoperatively
2. Postoperatively
3. Following treatments
4. During follow-up

3. Risk Assessment and Risk Stratification
1. To plan the initial treatment: the extent of surgery
2. To tailor postoperative adjunctive therapies:
RAI therapy and TSH suppressive therapy
3. To assess the patient’s risk for recurrence and mortality
4. To decide the frequency and intensity of follow-up
5. To enable accurate communication regarding a patient
among health care professionals
Risk assessment and risk stratification can be done
1. Preoperatively
2. Postoperatively
3. Following major treatments
4. During follow-up

4. AJCC/UICC TNM Classification System
Tumor size
Extrathyroid extension
Node metastasis
Distant metastasis
Age
Gender
Histological findings:
aggressive variants, vascular invasion
T status
N status
cTNM Stage
M status
45 years
Extent of Surgery
pTNM Stage
Postoperative Management of the Patients:
Thyroid Ablation, TSH Suppressive Therapy,
Frequency and Intensity of Follow-up

5. AJCC/UICC TNM Classification System
Tumor size
Extrathyroid extension
Node metastasis
Distant metastasis
Age
Gender
Histological findings:
aggressive variants, vascular invasion
T status
N status
cTNM Stage
M status
45 years
Extent of Surgery
pTNM Stage
Postoperative Management of the Patients:
Thyroid Ablation, TSH Suppressive Therapy,
Frequency and Intensity of Follow-up

6. AJCC/UICC TNM Classification System
Tumor size
Extrathyroid extension
Node metastasis
Distant metastasis
Age
Gender
Histological findings:
aggressive variants, vascular invasion
T status
N status
cTNM Stage
M status
45 years
Extent of Surgery
pTNM Stage
Postoperative management of the patients:
thyroid ablation, TSH suppressive therapy,
frequency and intensity of follow-up

7. ATA Risk of Recurrence Classification
for Differentiated Thyroid Carcinoma
Low risk All of the following are present 1) No local or distant metastases 2) All macroscopic tumor has been resected 3) No invasion of locoregional tissues 4) No aggressive histology tall cell, insular, columnar cell carcinoma vascular invasion 5) If 131I is given, no uptake outside the thyroid bed
Intermediate risk
Any of the following is present
1) Microscopic invasion into the
perithyroidal soft tissue
2) Cervical lymph node metastasis or
131I uptake outside the thyroid
bed on the RxWBS done after
thyroid remnant ablation
3) Tumor with aggressive histology or
vascular invasion
High risk
Any of the following is present
1) Macroscopic tumor invasion
2) Incomplete tumor resection
3) Distant metastases
4) Thyroglobulinemia out of proportion
to what is seen on the posttreatment
scan
Cooper DS, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19: , 2009.

8. Ongoing Risk Stratification
Response to Initial Therapy Definitions
Excellent response All of the following 1) Suppressed and stimulated Tg < 1 ng/ml 2) Neck US without evidence of disease 3) Cross-sectional and / or nuclear medicine imaging negative (if performed)
Acceptable response
Any of the following is present
1) Suppressed Tg < 1 ng/ml and
stimulated Tg > 1ng and
< 10 ng/ml
2) Neck US with nonspecific changes
or stable subcentimeter lymph
nodes
3) Cross-sectional and / or nuclear
medicine imaging with nonspecific
changes, although not completely
normal
Incomplete response
Any of the following is present
1) Suppressed Tg > 1ng/ml or stimulated
Tg > 10 ng/ml
2) Rising Tg values
3) Persistent or newly identifies disease
on cross-sectional and / or nuclear
medicine imaging
Evaluate based on response to initial therapy during the first 2 years
Tuttle RM, Leboeuf R. Endocrinol Metab Clin North Am. 37:419-35, 2008.
Tuttle RM, et al. Thyroid 20:1341-9, 2010.

9. Re-staging Based on Response to Initial Therapy Definitions
Excellent response
Acceptable response
Incomplete response
Clinical outcome after re-staging
(n = 159)
(n = 95)
(n = 217)
No evidence of disease
96%
87% 4%
(n = 245)
153 84 8
Persistent disease, bichemical evidence 0%
13%
39%
(n = 96) 11 85
Persistent disease, structurally identifiable
57%
(n = 124)
124
Recurrent disease
(n = 6) 6
Tuttle RM, et al. Thyroid 20:1341-9, 2010.

10. Delayed Risk Stratification
Evaluated 8-12 months after the initial therapy with surgery and ablation
Low risk (Clinical Remission) All of the following are present 1) Undetectable basal and stimulated Tg 2) Negative TgAb 3) No evidence of disease on clinical examination, neck US, diagnostic 131I WBS when performed
High risk (Persistent Disease)
Any of the following is present
1) Any evidence of disease on clinical
examination, neck US or other
imaging studies
2) Detectable basal/stimulated serum Tg
Castagna MG, et al.: Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. Eur J Endocrinol.165:441-6, 2011

11. 8-12 months after initial treatment
ATA
ETA
Intermediate/high risk
Low risk
High risk
New
8-12 months after initial treatment
Remission
Diseased
Changes in risk groups according to delayed risk stratification
Castagna MG, et al. Eur J Endocrinol 165: 441-, 2011

12. Clinical outcome at the end of follow-up according to ETA, ATA, and DRS
Final outcome
Remission
Persistent disease
Recurrence
Mortality
ETA
Low risk (n 231)
211 (91.4%) *
14 (6.1%)
6 (2.5%)
0 (0%)
High risk (n 281)
173 (61.6%) #
92 (32.8%) ##
8 (2.8%)
ATA
Low risk (n 244)
221 (90.8%) *
15 (6.0%)
8 (3.2%)
Intermediate/high risk (n 268)
163 (60.8%) #
91 (33.9%) ##
6 (2.3%)
8 (3.1%)
DRS
Low risk (n 353)
341 (96.6%) *
12 (3.4%)
High risk (n 159)
43 (27.1%) #
106 (66.6%) ##
2 (4.0%)
8 (5.2%)
*P = 0.005; #P < ; ##P <
Castagna MG, et al.: Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. Eur J Endocrinol.165:441-6, 2011

13. Proposal of an Alternative Approach
Dynamic estimation of prognosis in patients with papillary thyroid carcinoma who underwent total thyroidectomy
In patients without thyroglobulin antibody (TgAb):
Postoperative serum Tg &
Thyroglobulin-doubling time (Tg-DT)
2. In patients with TgAb:
Change in serum TgAb concentration

14. Papillary and Follicular Thyroid Carcinoma
Derive from thyroid follicular cells
Produce thyroglobulin (Tg)
Serum Tg could be a tumor marker
1. Normal thyroid tissue also produces Tg.
Patients who underwent total thyroidectomy
2. Presence of TgAb interferes Tg measurements.
Patients without detectable TgAb
3. Serum Tg values vary according to TSH levels.
Serum Tg values measured at TSH < 0.1 μ IU/ml

15. Papillary and Follicular Thyroid Carcinoma
Derive from thyroid follicular cells
Produce thyroglobulin (Tg)
Serum Tg could be a tumor marker
1. Normal thyroid tissue also produces Tg.
Patients who underwent total thyroidectomy
2. Presence of TgAb interferes Tg measurements.
Patients without detectable TgAb
3. Serum Tg values vary according to TSH levels.
Serum Tg values measured at TSH < 0.1 μ IU/ml

16. Patients with Papillary Thyroid Carcinoma
1. Underwent total thyroidectomy between January 1998 and December
2004
2. Negative TgAb test results
3. 4 or more measurements of serum Tg under TSH < 0.1 μ IU/ml
426 patients (female: 349, male: 77)
Age: 14 to 81 years (mean: 51.5 years)
Follow up period: 20 to 143 months (median: 86.7 months)

17. Representative results of kinetic analyses on serial serum thyroglobulin measurements
log (y) = x
Tg-DT = years
log (y) = x
Tg-DT = years ✝
Thyroglobulin (ng/ml)
Thyroglobulin (ng/ml)
Times (years)
Times (years)
log (y) = x
Tg-DT = years
log (y) = x
Tg-DT = years
Thyroglobulin (ng/ml)
Thyroglobulin (ng/ml)
Times (years)
Times (years)
Miyauchi, A. et al.: Thyroid, 21: , 2011

18. Distribution of the Patients According to Tg-DT
Number of Patients according to Tg-DT
calculated using
Group
Tg-DT status
All available data
Only first four data 1
<1 year
17 ( 4.0%)
20 ( 4.7%) 2
1-3 years
21 ( 4.9%)
22 ( 4.9%) 3
>3 years
30 ( 7.0%)
26 ( 6.1%) 4
Negative value
69 (16.2%) 5
Not calculated
88 (20.7%) 6
Tg not detectable
201 (47.2%)
Biochemically
Persistent
Disease
Equivocal
Biochemical Rem.
Miyauchi, A. et al. Thyroid, 21: , 2011

19. Disease-specific survival
Stage 4
Stage 3
Stage 2
Stage 1 .2 .4 .6 .8 1 2 4 6 8 10 12 14
Time (years)
Survival
Tg-DT <1
Tg-DT 1-3
Tg-DT >3
Tg-DT negaive value
Tg-DT not calcutated
Tg not dettectable a c b
Disease-specific survival
TNM Stage
Tg-DT (All data)
Tg-DT (first 4 data)
Miyauchi, A. et al.: Thyroid, 21: , 2011

20. Diseae-specific survival in relation to clinical, pathological
and biological variables in patients with Tg-DT.
Variables
HR (95% CI)
P value
Multivariate
Age: > 55 vs. < 55
8.26 ( )
0.0543 NS
0.4751
Male vs. female
4.89 ( )
0.0525
0.0671
T: > 4 cm vs. < 4 cm
4.15 ( )
0.0814
0.3441
Ex: 2 vs
12.52 ( )
0.0211
0.0908
N: 1b vs a
6.64 ( )
0.0289
0.2688
M: 1 vs. 0
8.24 ( )
0.0571
0.0876
pN: 1b vs a
3.02 ( )
0.2063
0.9303
Radioiodine accumulation:
No vs. Yes
4.64 ( )
0.1619
0.8159
Tg-DT: Group 1 vs. 2 – 4
47.06 ( )
0.0005 S
0.0035
Ex: extra-thyroidal extension, Ex 0: no extension, Ex 1: minimal extension, Ex 2: massive extension. For each variable, the item on the left side showed worse outcome than that on the right. On univariate analysis, data from all patients were used, while data from only patients in Groups 1 to 4 were used for multivariate analysis, since Tg-DT was not calculated in Groups 5 and 6.
Miyauchi, A. et al.: Thyroid, 21: , 2011

21. Miyauchi, A. et al.: Thyroid, 21:707-709, 2011 TNM Stage .2 .4 .6 .8 1 2 4 6 8 10 12 14
Stage 4
Stage 3
Stage 2
Stage 1
Time (years)
Distant metastases
Tg-DT <1
Tg-DT 1-3
Tg-DT >3
Tg-DT negaive value
Tg-DT not calcutated # a c b
Miyauchi, A. et al.: Thyroid, 21: , 2011
TNM Stage
Tg-DT (All data)
Tg-DT (first 4 data) # *
Tg-DT negaive value　
Tg not dettectable

22. Loco-regional recurrence.2 .4 .6 .8 1 2 4 6 8 10 12 14
Stage 4
Stage 3
Stage 2
Stage 1
Time (years)
Recurrence
Tg-DT <1
Tg-DT 1-3
Tg-DT >3
Tg-DT negaive value
Tg-DT not calcutated
Tg not dettectable a c b
TNM Stage
Tg-DT (All data)
Tg-DT (first 4 data)
Miyauchi, A. et al.: Thyroid, 21: , 2011

23. TgAb Positive Patients with Papillary Thyroid Carcinoma
Problem: Serum Tg measurements are unreliable.
Patients who had decrease in serum TgAb concentrations following thyroid ablation had better prognosis than patients who did not, or patients who had increase in serum TgAb concentrations.
Kim WG, et a.: J Clin Endocrinol Metab 93: , 2008

24. TgAb Positive Patients with Papillary Thyroid Carcinoma
We reviewed the medical records of 225 TgAb positive patients with papillary thyroid carcinoma who underwent total thyroidectomy between April 2002 and March 2007 in Kuma Hospital and who had periodical measurements of TgAb. Most of them did not receive thyroid ablation.
We evaluated the relationship between changes in serum TgAb concentrations within 2 years and prognosis.

25. Changes in TgAb Concentration within 2 years
Decreased by >50%
Decreased by <50% or increase
Patients
181 (80.4%)
44 (19.6%)
Age (years)
Follow up period (years)

26. Outcome in Relation to Changes in TgAb Concentrations
Decreased by >50%
Decreased by <50% or increase
Patients
181 (80.4%)
44 (19.6%)
Death of the disease
0 ( 0.0%)
3 ( 6.8%)
Distant metastases
3 ( 1.7%)
5 (11.4%)
Loco-regional recurrence
5 ( 2.8%)
7 (15.9%)
No recurrence
174 (96.1%)
37 (84.1%)

27. Disease Free Survivals According to Change in TgAb Concentration
Distant metastasis free survival
Years after surgery
Loco-regional recurrence free survival
Decreased
Not decreased
カプランマイヤー法を用い低下群、非低下群の予後について検討しました。
術後5年におけるリンパ節再発を認めない生存率は、低下群、96.9％、非低下群、90.5％でした。遠隔再発を認めない生存率は、低下群98.9％、非低下群90.1％でした。
リンパ節、遠隔臓器について、無再発生存率に、両群間で有意差がみられ、非低下群は、低下群と比較して予後が悪いといえます。

28. Analysis on prognostic factors for distant metastases
Log-rank statistics P
HR (95% CI)
Male gender
3.07
0.080
2.82 ( )
0.230
Age >55 years
2.68
0.102
2.85 ( )
0.166
Tumor >4cm
4.90
0.021
1.95 ( )
0.397
N1b
5.32
0.060
2.88 ( )
0.212
Ex2
6.25
0.013
4.29 ( )
0.058
TgAb not decreased
8.01
<0.001
4.62 ( )
0.047
Univariate analysis
Multivariate analysis

29. Analysis on prognostic factors for loco-regional recurrence
Univariate analysis
Log-rank statistics P
HR (95% CI)
Male gender
1.02
0.312
1.45 ( )
0.635
Age >55 years
4.71
0.030
3.45 ( )
0.045
Tumor >4cm
1.82
0.136
1.25 ( )
0.747
N1b
5.45
0.019
3.46 ( )
0.065
Ex2
0.63
0.428
1.22 ( )
0.797
TgAb not decreased
12.9
<0.001
4.86 ( )
0.009
Multivariate analysis

30. 10874XXX 67 y-o woman with PTC Surgery TgAb PTC 1.7 cm
Total thyroidectomy with CND
Pathological Dx:
PTC, pT3, pN0, MIB1 LI 2+ (5-10%)

31. Dynamic Estimation of Prognosis for Patients with Papillary Thyroid Carcinoma
Preoperatively:
Extent of Surgery
Postoperative managements:
thyroid ablation, TSH suppressive therapy,
frequency and intensity of follow-up.
Change in serum TgAb
Tg & Tg-DT
Patients without TgAb
Patients with TgAb
cTNM Stage
Dynamic evaluation
After Total Thyroidectomy:

32. Dynamic Estimation of Prognosis for Patients with Papillary Thyroid Carcinoma
Preoperatively:
Extent of Surgery
Postoperative managements:
thyroid ablation, TSH suppressive therapy,
frequency and intensity of follow-up.
Change in serum TgAb
Tg & Tg-DT
Patients without TgAb
Patients with TgAb
cTNM Stage
Dynamic evaluation
After Total Thyroidectomy:

33. Thank you for your attention. From Kobe to the world.

35. 59 y-o woman with papillary carcinoma
Total thyroidectomy with left MND in May 2006.
Pathology: papillary thyroid carcinoma with columnar cell, solid, trabecular, and insular component

36. 59 y-o woman with PTC
Electronic medical record system in Kuma Hospital
Surgery
131I 13 mCi
131I 100 mCi
Thyroglobulin
TSH

37. 59 y-o woman with PTC
Electronic medical record system in Kuma Hospital
Surgery
131I 13 mCi
131I 100 mCi
Thyroglobulin
TSH

38. Doubling Time Calculator
59 y-o woman with PTC
Date Tg
Tg-DT (years)

39. 59 y-o woman with PTC