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Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong

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1 Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong
Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based Approach Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong

2 Welcome and introduction
Dr June-Key Chung Professor of Nuclear Medicine Seoul National University Hospital, Korea

3 Programme Welcome and introduction Case Review: a risk-based approach
Dr Furio Pacini (Italy) Dr R. Michael Tuttle (US) Audience Q&A Dr Young-Kee Shong (Korea) Concluding remarks Luncheon served

4 Questions A voting card is in your pack – this can be used to answer questions from the presenters Q & A session – use the standing microphones

5 Case Review: a risk-based approach
Dr Furio Pacini Professor of Endocrinology University of Siena, Italy

6 Clinical case A 45 year-old medical sonographer does a neck US on herself and finds abnormal looking paratracheal nodes. They are hypoechoic with multiple echogenic foci. The thyroid gland is normal. FNAC of one of the paratracheal nodes shows highly atypical cells and serum Tg in the aspirate is 480 ng/ml.

7 Clinical case The patient undergoes a total thyroidectomy plus bilateral central and right lateral neck dissection. Pathology: classical papillary thyroid cancer in the right lower pole (3 mm); four of six central nodes are + for classical papillary cancer; lymph nodes in the right lateral nodes normal. AJCC/UICC Stage I ATA risk: intermediate. ETA risk: high

8 Risk stratification ATA Guidelines
ATA Guidelines Thyroid 2009:19:

9 Indication for RAI ablation (ATA)
ATA Guidelines Thyroid 2009:19:

10 ETA Consensus Very Low risk Low risk High risk
Unifocal intrathyroidal tumor (≤1 cm) No aggressive histology No metastases No indication Low risk High risk Intrathyroidal tumor (T1 >1 cm-T2), uni- or multifocal Aggressive histology No local or distant metastases Possible indication T3 Intrathyroidal or wiht minimal extrathyroidal invasion T4 Locoregional metastases Distant metastases Strong indication ETA Consensus Eur J Endocrinology 2006; 154: 787–803

11 Case 1 The patient received 50 mCi of 131I after administration of rhTSH (0.9 mg i.m. for two consecutive days) Basal TSH: 0.2 mU/l, TSH after rhTSH: 156 mU/l Basal Tg <1.0 ng/ml, Tg after rhTSH: 2.1 ng/ml Urinary excretion: 120 mg/l, AbTg negative Post-therapeutic whole body scan: “uptake in the thyroid bed and two lateral nodes.”

12 Case Post-therapeutic WBS: “uptake in the thyroid bed and in the right cervical region“

13 Case 12 months after ablation: rhTSH control diagnostic WBS: no uptake
Neck ultrasound: negative Basal and stimulated Tg undetectable (<1 ng/ml) The patient is considered in remission.

14 Question for the audience:
Is this patient still high risk? Yes No

15 Tuttle RM, et al. Thyroid 2010;20: 1341-9

16 512 patients PPV 95% CI NPV PVE ETA 0.384*° 0.355-0.407 0.913*°
19.1% ATA 0.392*° 0.906*° 25.4% DRS 0.728° 0.963° 62.1% * p>0.05; ° p<0.05 Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

17 Question for the audience:
What follow-up in this patient? Basal serum Tg and neck US once a year TSH-stimulated Tg

18 OUTCOME OF PATIENTS WITH TSH STIMULATED Tg  1ng/mL (Negative neck US)
Mean follow-up: 15 years Neck lymph node recurrence at US: 1 (< 0.5%). TSH in the normal range ( mU/L) in > 90%. Cailleux, JCEM, 2000. 315 patients Mean follow-up: 12 years Neck lymph node recurrences at US: 2 (0.6%). Pacini, JCEM, 2002. Excellent NPV of Tg/TSH No clinical significance of low uptake in thyroid bed Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

19 In patients with no evidence of disease:
Risk of recurrence at 20 years < 0.5% The daily dose of LT4 may be decreased to achieve a serum TSH in the low-normal range Subsequent follow-up: clinical examination, serum Tg and TSH determination, neck US once a year Is there a need for further rhTSH-stimulated Tg?

20 NO NEED TO REPEAT rhTSH IN PATIENTS WITH UNDETECTABLE rhTSH STIMULATED Tg CASTAGNA, JCEM, 2008
77 patients with no evidence of disease at months. Repeated rhTSH + neck US at 2-3 years. 67 with undetectable rhTSH stimulated Tg: at 2-3 years, 67 had undetectable rhTSH stimulated Tg neck US demonstrated neck recurrence in 1 10 with detectable rhTSH stimulated Tg: at 2-3 years, 6 had undetectable rhTSH stimulated Tg 4 had detectable stimulated Tg Castagna MG, et al. JCEM 2008; 93:76–81

21 TSH-stimulated Tg repeated 5 years later
203 DTC patients fulfilling the criterion of remission after initial therapy TSH-stimulated Tg repeated 5 years later 94.6% stimulated Tg <1-2 ng/ml: no recurrence 5.4% (11 pts) stimulated Tg >2 ng/ml ( ng/ml): 3: Lymph node mets detected by US 5: mets detected by other imaging (2 in cervical nodes, 1 in the mediastinum, 2 in the lungs) 3: disease not found Rosario, PW, et al. Thyroid 2012;22:482-6

22 Application of the Risk Based Management Approach – decision-making with regard to RAI ablation
Dr R Michael Tuttle, MD Professor of Medicine Memorial Sloan Kettering Cancer Center New York

23 Changing Paradigms in the Management of Thyroid Cancer
“Traditional Paradigm” One Size Fits All Total thyroidectomy RAI remnant ablation All with same follow up “Risk Adapted Paradigm” Management recommendations based individualized risk assessment Increased Emphasis Risk of death Risk of recurrence Risk of persistent disease Risk of failing initial therapy

24 R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York
3/31/2017 Words of wisdom attributed to Mark Twain Changing management paradigms It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so.

25 What we know “for sure” 30% risk of recurrence
(Over estimate the risk of recurrence?) RAI ablation decreases recurrence by 50% (Over estimate the impact of RAI on recurrence?) RAI ablation decreases the risk of death (Over estimate the impact of RAI on survival?) RAI ablation is required for follow-up (Under estimate neck US and Tg without ablation?) Side Effects of RAI are mild and temporary (Under estimate the side effects of RAI?)

26 Risk of Structural Disease Recurrence
Risk stratification by category Risk stratification within categories* High Risk Gross extrathyroidal extension incomplete tumor resection, or distant metastases FTC, extensive vascular invasion (30-55%) pT4a gross ETE (23-40%) PTC, vascular invasion (16-30%) pN1, any LN > 3 cm (27%) Clinical N1 (22%) Intermediate Risk N1 disease, minor extrathyroidal extension vascular invasion, or aggressive histology pN1, > 5 LN involved (19%) pT3 minor ETE (3-8%) pN1, all LN < 0.2 cm (5%) pN1, < 5 LN involved (4%) Intrathyroidal 2-4 cm PTC (5-6%) Multifocal PMC (4-6%) Low Risk Intrathyroidal DTC Minimally invasive FTC (0-7%) Unifocal PMC (1-2%) *Manuscript in preparation, Randolph Thyroid 2012

27 No lymph nodes were sampled 2-3 months post-op: Tg 1 ng/mL
First Example Patient 32 yr old male Total thyroidectomy 1.9 cm unifocal Intrathyroidal PTC No lymph nodes were sampled 2-3 months post-op: Tg 1 ng/mL TSH was 1 mIU/mL Tg Ab negative Neck US is normal RAI Ablation Yes No

28 32 yr old male Total thyroidectomy, 1.9 cm intrathyroidal PTC
Risk Without RRA Recurrence 2-4% Disease Specific Mortality < 1% Distant Metastases about 1% Risks of RAI Permanent dry mouth 1-2% Blocked tear duct 1% Second cancer < 1% Potential Benefits of RAI Facilitate Staging/Follow-up +/- Recurrence No impact on mortality Tilting the Balance Toward Benefit Selective Use Lower administered activities (30 mCi) rhTSH preparation Using RAI as salvage therapy

29 Second Example Patient
R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York Second Example Patient 3/31/2017 RAI Ablation Yes No 22 year old female Total thyroidectomy & left MRN dissection 2.5 cm, multifocal, well differentiated PTC 20/32 lymph nodes positive No extrathyroidal extension No vascular invasion

30 22yr old female Total thyroidectomy, 2.5 cm intrathyroidal PTC, N1b
Risk Without RRA Recurrence 25-30% Disease Specific Mortality < 1% Distant Metastases about 5-10% What if her post-operative Tg was <0.2 ng/mL (TSH of 56 mU/L, no Tg antibodies)? Risks of RAI Permanent dry mouth 1-2% Blocked tear duct 1% Second cancer < 1% Potential Benefits of RAI Facilitate Staging/Follow-up +/- Recurrence No impact on mortality Tilting the Balance Toward Benefit Selective Use 100 mCi rhTSH?

31 Risk of Structural Disease Recurrence
My personal practice as of Nov 2012 Risk stratification by category Risk stratification within categories* High Risk RAI given Probably withdrawal 150 mCi FTC, extensive vascular invasion (30-55%) pT4a gross ETE (23-40%) PTC, vascular invasion (16-30%) pN1, any LN > 3 cm (27%) Clinical N1 (22%) Intermediate Risk Selective use rhTSH or withdrawal 0 to 30 to 150 mCi depending on risk pN1, > 5 LN involved (19%) pT3 minor ETE (3-8%) pN1, all LN < 0.2 cm (5%) pN1, < 5 LN involved (4%) Intrathyroidal 2-4 cm PTC (5-6%) Low Risk Usually no RAI If given, 30 mCi rhTSH Multifocal PMC (4-6%) Minimally invasive FTC (0-7%) Unifocal PMC (1-2%) *Manuscript in preparation, Randolph Thyroid 2012

32 ACCESS Medical Group, Ltd. S317 thyroid cancer rev04 10 07 03
10/07/03 New York City

33 Some points on Tg level Dr June-Key Chung
Professor of Nuclear Medicine Seoul National University Hospital, Korea

34 Assumption of the ideal tumor marker
All cancer cells express the tumor marker homogenously. All cancer cells secrete the tumor marker into the blood relatively equally. There is no change in the expression of tumor marker according to the patients and lesions. There is no change in the expression of tumor marker according to differentiation or progression of cancer.

35 Facts of serum thyroglobulin
660 kDa dimeric protein, > 20 epitopes different antibodies -> different concentrations in commercial kits Different nature CEA, AFP: increase associated with carcinogenesis Tg: normal component Immunostaining results showed that Tg expression was heterogenous and variable in PTC, and related to cellular differentiation in FTC. The expression of Tg might decrease in metastatic tissue of lymph node. Almost all cancers in Korea are PTCs, which often are de-differentiated and negative in Tg expression. In thyroid cancer cells, Tg molecule can be modified inhibiting secretion to the blood, or cannot be measured by some kits.

36 External QC data in Korea
Item QC Conc. CV in 2012 (%) Jan Feb Mar Apr May Jun Avr Tg C-1 2.45 15.8 12.8 11.6 17.2 9.4 14.6 13.6 C-2 27.8 7.7 12.2 10.6 11.9 9.0 11.3 10.5 C-3 70.1 7.1 8.7 10.4 8.3 9.5 8.8 T3 101 7.5 6.3 3.0 3.7 3.2 2.6 4.4 157 6.5 2.4 2.0 1.7 1.8 1.5 2.7 255 6.9 3.4 2.9 2.2 1.2 2.1 3.1 T4 5.86 13.8 3.6 4.5 6.1 9.98 5.3 2.5 2.8 7.9 4.7 3.5 CA 125 30.6 6.7 4.0 5.5 5.2 98.3 4.9 260 4.3 5.6 3.8 AFP 9.7 5.4 5.0 70.9 4.2 5.7 177 5.8 5.1 4.6

37 Thyroglobulin Content in Thyroid Tissue
Metastatic lymph nodes ±8.42 mg/g Hurthle adenoma ± mg/g Papillary thyroid carcinoma ± mg/g Follicular thyroid carcinoma ±24.33 mg/g Anaplastic thyroid carcinoma 1.63±0.48 mg/g Normal mg/g A. Czarnywojtek. Archivum Immunologiae et Therapiae Experimentalis, 2002, 50,

38 Immunohistochemistry results of Thyroglobulin in Papillary cancer
Staining intensities Value (%) Thyroglobulin (n=47) 0 (0%) 1 7 (15%) 2 30 (64%) 3 10 (21%) J-K Chung and H Min. KTA 2012.

39 Location of Thyroglobulin in Cancer tissue
왼족 종괴는 tg가 주로 세포질에 고르게 분포하나 오른쪽 종괴는 세포질의 border쪽에 강하게 발현됩니다. Cytoplasm Membrane

40 Heterogenous Expression of Tg
Anaplastic carcinoma의 tg 염색 사진은 없고, poorly differentiated carcinoma를 보내드립니다. 세포질에 염색이 되기는 하나 얼룩덜룩하게 heterogenous하게 염색이 되는 것을 알 수 있습니다. Anaplastic carcioma에서는 tg 발현이 거의 없다고 할 수 있습니다. Poorly differentiated carcinoma

41 A: Primary papillary microcarcinoma (x200)
B C A: Primary papillary microcarcinoma (x200) B: Tg immunostaining of primary tumor, strong positive (x400) C: Tg immunostaining of lymph node, focal positive (x200) Fig.1 Papillary microcarcinomas were detected in right thyroid gland (A, x200), which revealed strong thyrogloblulin positivitiy in immunohistochemistry (B, X400). However, the metastatic lymph node showed more solid growth pattern and only focal positivity (C, x400) for thyroglobulin. The lung biopsy was diagnosed as primary well-differentiated adenocarcinoma (D, X200). ID: 이 환자는 2년 폐선암이 발생하였으나 (D) 조직학적 소견상 갑상선 유두암 (A,B,C) 과는 매우 다른 형태를 보여 전이암과는 관계가 없을 가능성이 매우 높았던 증례입니다.

42 Recurrent/metastatic thyroid carcinoma: false negative Tg, positive I-131 scan
Subject - Differentiated thyroid carcinoma - ’01.1~’04.12 post-Therapy I-131 WBS (≥ 30 mCi) - Consecutive 824 patients Tg negative/I-131 WBS positive group (TgFN) - Tg ≤ 2 ng/mL (Tg-plus, BRAHMS, Germany) - Tg Ab ≤ 100 U/mL (HENNINGtest® anti-Tg, BRAHMS, Germany) TSH-stimulation state (TSH ≥ 30 μIU/ml) - I-131 WBS: remnant and/or functioning metastasis Tg positive/I-131 WBS positive group (TgP) - Tg > 2 ng/mL Six hundred and twenty four (624) consecutive patients (age 48.4 13.4, M:F=126:498) who underwent therapeutic I-131 WBS after total thyroidectomy due to differentiated thyroid carcinoma from 2003 to 2004 were retrospectively studied. I-131 WBS was interpreted visually and reported to be positive or negative. Tg negative was defined as serum level under 2 ng/mL and Tg antibody level under 200 U/ml, with combined TSH-stimulation state (TSH≥30). Tg false negative was defined as Tg negative with I-131 WBS positive. 한편, Tg true positive was defined as Tg positive with I-131 WBS positive. Park EK, Chung JK et al, Eur J Nucl Med Mol Imaging, 2009;36:172-9

43 Tg negative/I-131 positive case
(김춘자 ) This slide is one of the representative case of false negative Tg level with true positive I-131 WBS. A 55-year-old female patient underwent therapeutic I-131 WBS, who previously had total thyroidectomy due to differentiated thyroiod carcinoma. On WBS, she had remnant thyroid activity and functioning metastases to cervical lymph nodes and lung, however, Tg level was less than 1.0 and Tg antibody was also less than 25. On Neck CT, which was performed for further evaluation, multiple small lymphadenopathy was seen in level II of bilateral internal jugular chanins, suggesting metastatic lymphadenopathy. (Lung metastasis was not confirmed at that time since neck CT did not cover lung area where that focal lung lesion on I-131 WBS was supposed to be.) Those metastatic lesions in neck and lung disappeared after series of radioactive iodine therapy and Tg has never been positive during the whole course of treatment. (참고: radioactive iodine 치료 (350mCi x 6회)에 의해 완전히 사라짐. Tg는 끝까지 <1.0 이었음. TgAb도 끝까지 <25 ~ 73.) F/55 TSH 89.4 Tg <1.0 TgAb <25

44 Tg negative/I-131 positive case
박주석 200mCi scan Functioning metastasis to left lower neck. lung mets가 improve되면서 Tg가 negative conversion되었던 case. 단, cervical LN mets는 여전히 남아있음 박주석 M/17 <Chest CT> CONCLUSION 1. Subcutaneous nodule in left anterior lower neck at the scapular level.      --> Can not exclude metastasis. 2. No definite evidence of mediastinal lymphadenopathy or lung metastasis. FINDING C.I.: Papillary thyroid carcinoma. Left anterior lower neck scapular level 에서 subcutaneous soft tissue nodule 이 보이고 있음. 핵의학에서 시행한 scan 에 uptake 된 portion 과 matching 되는 부분으로 생각되며 metastasis 의 가능성을 완전히 배제할 수 없겠음. 하지만 significant 한 mediastinal lymphadenopathy 나 lung metastasis 의 evidence 없으며 scan 에서 cover 된 상복부에는 left kidney 에 cyst 로 생각되는 low attenuated nodule 이 있음. PET : F-18 FDG iv injection 후 cerebellum이하 pelvis까지 전신영상을 얻음. 전신영상에서 left lower neck에 mild hypermetabolism이 관찰되며, maxSUV는 1.9로 측정됨. I-131 scan에서 관찰되는 부위와 일치하는 소견임. -R/O residual tumor M/17 TSH 195 Tg <1.0 TgAb <25

45 I-131 WBS: 824 WBS(-): 72 WBS(+): 752 Tg(+): 328 Tg(-): 365
*59 excluded TgAb(-) : 255 (31%) TgAb(+): 110 Among 624 patients who performed I-131 WBS in 2003 to 2004, majority patients demonstrated positive results. Among 562 patients with I-131 WBS positive, 317 patients also demonstrated positive Tg level. Surprisingly, 208 patients, which is 37%, demonstrated negative Tg level. For your information, 37 patients were excluded who was not in a sufficient hypothyroid status as we defined or whose lab result was not available. In these 208 patient group, 177 patients were definite TG false negative cases whose Tg Ab level was also negative. This is 28.4% in total. We further investigated this Tg false negative group and could find out that they could be separated into two distinct groups. 124 of them had only remnant thyroid activity, and 53 of them had functioning metastasis to extrathyroidal organs. Patient group with functioning metastases consisted of 49 cases of cervical/mediastinal lymph node metastases, 3 cases of lung metastases and 1 case of bone metastasis on I-131 WBS. Metastasis: 128 Remnant: 203 Metastasis: 52 (6.3%)

46 TgP vs TgFN Metastatic site TgP TgFN Total 128 52
Cervical/Mediastinal LN 91 (71.1%) 45 (86.5%) Lung 25 (19.5%) 6 (11.5%) Bone 11 (8.6%) 1 (2.0%) Brain 1 (0.8%) 0 (0%) Total 128 52 This slide demonstrates significantly different metastatic profile of Tg true positive cases (where Tg level and I-131 whole body scan are all positive) versus Tg false negative cases (p<0.001). Metastatic sites are mostly regional-cervical and mediastinal lymph nodes while metastases to other distant sites such as lung, bone or brain are relatively smaller in Tg false negative cases comparing Tg true positive cases. Others) Falk et al.:Tg FN: 4.2% of total thyroid cancer Braverman et al.:concordance of WBS and Tg in 44% most metastatic site in Tg FN:Cervical LN and mediastinal LN *p<0.001

47 I mCi I mCi I mCi I mCi TSH 88 Tg 3.3, Tg Ab<60 TSH 212 Tg <1.0, Tg Ab<25 TSH 219 Tg <1.0, Tg Ab<25 TSH 158 Tg <1.0, Tg Ab<25

48 Audience Q&A Panel discussion
Dr Young-Kee Shong Professor, Department of Internal Medicine, Endocrinology and Metabolism Asan Medical Center, Seoul

49 Concluding remarks Dr Young-Kee Shong
Professor, Department of Internal Medicine, Endocrinology and Metabolism Asan Medical Center, Seoul

50 Summary An individualised risk stratification approach is an emerging concept to guide initial therapy and follow up Risk should be re-assessed at every follow up to guide further intervention and follow up Importance of measuring Tg and TgAb with the same assay over time Please join us for luncheon in the Restaurant (where breakfast is served)


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