Presentation on theme: "Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong"— Presentation transcript:
1Symposium Moderators: Dr June-Key Chung Dr Young-Kee Shong Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based ApproachSymposium Moderators:Dr June-Key ChungDr Young-Kee Shong
2Welcome and introduction Dr June-Key ChungProfessor of Nuclear Medicine Seoul National University Hospital, Korea
3Programme Welcome and introduction Case Review: a risk-based approach Dr Furio Pacini (Italy)Dr R. Michael Tuttle (US)Audience Q&ADr Young-Kee Shong (Korea)Concluding remarksLuncheon served
4QuestionsA voting card is in your pack – this can be used to answer questions from the presentersQ & A session – use the standing microphones
5Case Review: a risk-based approach Dr Furio PaciniProfessor of EndocrinologyUniversity of Siena, Italy
6Clinical caseA 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.
7Clinical caseThe 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 IATA risk: intermediate. ETA risk: high
8Risk stratification ATA Guidelines ATA Guidelines Thyroid 2009:19:
9Indication for RAI ablation (ATA) ATA Guidelines Thyroid 2009:19:
10ETA Consensus Very Low risk Low risk High risk Unifocal intrathyroidal tumor (≤1 cm)No aggressive histologyNo metastasesNo indicationLow riskHigh riskIntrathyroidal tumor(T1 >1 cm-T2), uni- or multifocalAggressive histologyNo local or distant metastasesPossible indicationT3 Intrathyroidal or wiht minimal extrathyroidal invasionT4Locoregional metastasesDistant metastasesStrong indicationETA Consensus Eur J Endocrinology 2006; 154: 787–803
11Case 1The 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/lBasal Tg <1.0 ng/ml, Tg after rhTSH: 2.1 ng/mlUrinary excretion: 120 mg/l, AbTg negativePost-therapeutic whole body scan: “uptake in the thyroid bed and two lateral nodes.”
12CasePost-therapeutic WBS: “uptake in the thyroid bed and in the right cervical region“
13Case 12 months after ablation: rhTSH control diagnostic WBS: no uptake Neck ultrasound: negativeBasal and stimulated Tg undetectable (<1 ng/ml)The patient is considered in remission.
14Question for the audience: Is this patient still high risk?YesNo
16512 patients PPV 95% CI NPV PVE ETA 0.384*° 0.355-0.407 0.913*° 19.1%ATA0.392*°0.906*°25.4%DRS0.728°0.963°62.1%* p>0.05; ° p<0.05Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446
17Question for the audience: What follow-up in this patient?Basal serum Tg and neck US once a yearTSH-stimulated Tg
18OUTCOME OF PATIENTS WITH TSH STIMULATED Tg 1ng/mL (Negative neck US) Mean follow-up: 15 yearsNeck lymph node recurrence at US: 1 (< 0.5%).TSH in the normal range ( mU/L) in > 90%.Cailleux, JCEM, 2000.315 patientsMean follow-up: 12 yearsNeck lymph node recurrences at US: 2 (0.6%).Pacini, JCEM, 2002.Excellent NPV of Tg/TSHNo clinical significance oflow uptake in thyroid bedCastagna MG, et al. Eur J Endocrinology 2011;165: 441–446
19In 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 rangeSubsequent follow-up: clinical examination, serum Tg and TSH determination, neck US once a yearIs there a need for further rhTSH-stimulated Tg?
20NO 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 Tgneck US demonstrated neck recurrence in 110 with detectable rhTSH stimulated Tg:at 2-3 years, 6 had undetectable rhTSH stimulated Tg4 had detectable stimulated TgCastagna MG, et al. JCEM 2008; 93:76–81
21TSH-stimulated Tg repeated 5 years later 203 DTC patients fulfilling the criterion of remission after initial therapyTSH-stimulated Tg repeated 5 years later94.6% stimulated Tg <1-2 ng/ml: no recurrence5.4% (11 pts) stimulated Tg >2 ng/ml ( ng/ml):3: Lymph node mets detected by US5: mets detected by other imaging (2 in cervical nodes, 1 in the mediastinum, 2 in the lungs)3: disease not foundRosario, PW, et al. Thyroid 2012;22:482-6
22Application of the Risk Based Management Approach – decision-making with regard to RAI ablation Dr R Michael Tuttle, MDProfessor of MedicineMemorial Sloan Kettering Cancer Center New York
23Changing Paradigms in the Management of Thyroid Cancer “Traditional Paradigm”One Size Fits AllTotal thyroidectomyRAI remnant ablationAll with same follow up“Risk Adapted Paradigm”Management recommendations based individualized risk assessmentIncreased EmphasisRisk of deathRisk of recurrenceRisk of persistent diseaseRisk of failing initial therapy
24R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York 3/31/2017Words of wisdom attributed to Mark TwainChanging management paradigmsIt ain't what you don't know that gets you into trouble.It's what you know for sure that just ain't so.
25What 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?)
26Risk of Structural Disease Recurrence Risk stratification by categoryRisk stratification within categories*High RiskGross extrathyroidal extensionincomplete tumor resection,or distant metastasesFTC, 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 RiskN1 disease,minor extrathyroidal extensionvascular invasion,or aggressive histologypN1, > 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 RiskIntrathyroidal DTCMinimally invasive FTC (0-7%)Unifocal PMC (1-2%)*Manuscript in preparation,Randolph Thyroid 2012
27No lymph nodes were sampled 2-3 months post-op: Tg 1 ng/mL First Example Patient32 yr old maleTotal thyroidectomy1.9 cm unifocalIntrathyroidal PTCNo lymph nodes were sampled2-3 months post-op: Tg 1 ng/mLTSH was 1 mIU/mLTg Ab negativeNeck US is normalRAI AblationYesNo
2832 yr old male Total thyroidectomy, 1.9 cm intrathyroidal PTC Risk Without RRARecurrence 2-4%Disease Specific Mortality < 1%Distant Metastases about 1%Risks of RAIPermanent dry mouth 1-2%Blocked tear duct 1%Second cancer < 1%Potential Benefits of RAIFacilitate Staging/Follow-up+/- RecurrenceNo impact on mortalityTilting the Balance Toward BenefitSelective UseLower administered activities (30 mCi)rhTSH preparationUsing RAI as salvage therapy
29Second Example Patient R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New YorkSecond Example Patient3/31/2017RAI AblationYesNo22 year old femaleTotal thyroidectomy & left MRN dissection2.5 cm, multifocal, well differentiated PTC20/32 lymph nodes positiveNo extrathyroidal extensionNo vascular invasion
3022yr old female Total thyroidectomy, 2.5 cm intrathyroidal PTC, N1b Risk Without RRARecurrence 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 RAIPermanent dry mouth 1-2%Blocked tear duct 1%Second cancer < 1%Potential Benefits of RAIFacilitate Staging/Follow-up+/- RecurrenceNo impact on mortalityTilting the Balance Toward BenefitSelective Use100 mCirhTSH?
31Risk of Structural Disease Recurrence My personal practice as of Nov 2012Risk stratification by categoryRisk stratification within categories*High RiskRAI givenProbably withdrawal150 mCiFTC, 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 RiskSelective userhTSH or withdrawal0 to 30 to 150 mCi depending on riskpN1, > 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 RiskUsually no RAIIf given, 30 mCi rhTSHMultifocal PMC (4-6%)Minimally invasive FTC (0-7%)Unifocal PMC (1-2%)*Manuscript in preparation,Randolph Thyroid 2012
32ACCESS Medical Group, Ltd. S317 thyroid cancer rev04 10 07 03 10/07/03New York City
33Some points on Tg level Dr June-Key Chung Professor of Nuclear Medicine Seoul National University Hospital, Korea
34Assumption of the ideal tumor marker All cancer cells express the tumor marker homogenously.All cancer cells secrete the tumor marker into the bloodrelatively equally.There is no change in the expression of tumor markeraccording to the patients and lesions.There is no change in the expression of tumor marker according to differentiation or progression of cancer.
35Facts of serum thyroglobulin 660 kDa dimeric protein, > 20 epitopesdifferent antibodies -> different concentrations in commercial kitsDifferent natureCEA, AFP: increase associated with carcinogenesisTg: normal componentImmunostaining 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.
36External QC data in Korea ItemQCConc.CV in 2012 (%)JanFebMarAprMayJunAvrTgC-12.4515.812.811.617.29.414.613.6C-227.87.712.210.611.99.011.310.5C-3126.96.36.1990.48.39.58.8T31017.56.33.03.188.8.131.52576.52.42.01.184.108.40.2065220.127.116.11.18.104.22.168T45.8622.214.171.124.19.9126.96.36.199.94.73.5CA 12530.66.74.05.55.298.34.92604.35.63.8AFP9.75.45.070.94.25.717188.8.131.52
38Immunohistochemistry results of Thyroglobulin in Papillary cancer Staining intensitiesValue (%)Thyroglobulin (n=47)0 (0%)17 (15%)230 (64%)310 (21%)J-K Chung and H Min. KTA 2012.
39Location of Thyroglobulin in Cancer tissue 왼족 종괴는 tg가 주로 세포질에 고르게 분포하나 오른쪽 종괴는 세포질의 border쪽에 강하게 발현됩니다.Cytoplasm Membrane
40Heterogenous 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
41A: Primary papillary microcarcinoma (x200) BCA: 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.
42Recurrent/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 patientsTg 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 metastasisTg positive/I-131 WBS positive group (TgP)- Tg > 2 ng/mLSix 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
43Tg 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/55TSH 89.4 Tg <1.0 TgAb <25
44Tg negative/I-131 positive case 박주석200mCi scanFunctioning metastasis to left lower neck.lung mets가 improve되면서 Tg가 negative conversion되었던 case.단, cervical LN mets는 여전히 남아있음박주석 M/17<Chest CT>CONCLUSION1. 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.FINDINGC.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 tumorM/17TSH 195 Tg <1.0 TgAb <25
45I-131 WBS: 824 WBS(-): 72 WBS(+): 752 Tg(+): 328 Tg(-): 365 *59 excludedTgAb(-) : 255 (31%)TgAb(+): 110Among 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:128Remnant:203Metastasis:52 (6.3%)
46TgP vs TgFN Metastatic site TgP TgFN Total 128 52 Cervical/Mediastinal LN91 (71.1%)45 (86.5%)Lung25 (19.5%)6 (11.5%)Bone11 (8.6%)1 (2.0%)Brain1 (0.8%)0 (0%)Total12852This 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 cancerBraverman et al.:concordance of WBS and Tg in 44%most metastatic site in Tg FN:Cervical LN and mediastinal LN*p<0.001
48Audience Q&A Panel discussion Dr Young-Kee ShongProfessor, Department of Internal Medicine, Endocrinology and MetabolismAsan Medical Center, Seoul
49Concluding remarks Dr Young-Kee Shong Professor, Department of Internal Medicine, Endocrinology and MetabolismAsan Medical Center, Seoul
50SummaryAn individualised risk stratification approach is an emerging concept to guide initial therapy and follow upRisk should be re-assessed at every follow up to guide further intervention and follow upImportance of measuring Tg and TgAb with the same assay over timePlease join us for luncheon in the Restaurant (where breakfast is served)