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1 REVIEW ARTICLE J Korean Thyroid Assoc Vol. 5, No. 1, May 2012 갑상선분화암의수술후추적관찰 : 갑상선글로불린검사의이용 울산대학교의과대학서울아산병원내과학교실 김태용 Postoperative Follow-Up of Differentiated Thyroid Cancer: Use of Thyroglobulin Assay Tae Yong Kim, MD, PhD Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Stimulated thyroglobulin measured 6-12 months after thyroidectomy and radioactive iodine remnant ablation is a very useful guidance for risk-stratification. Thus, this parameter should be a main variable of strategy for follow-up in such patients. Serum Tg and TgAb measurement at the time of ablation just after total thyroidectomy could give a helpful data supporting stimulated Tg measured 6-12 months after radioactive iodine remnant ablation and should be considered in your own follow-up strategies. Key Words: Thyroid, Thyroid neoplasm, Biological markers, Thyroglobulin 확립된생물표지자인혈청갑상선글로불린을이용한분화갑상선암추적관찰방침 분화갑상선암 (differentiated thyroid carcinoma, DTC) 은전세계적으로발생이증가하고있는가장흔한내분비기관의암이다. 비록 DTC가진행이느리며암에의한사망률이적지만, 재발또는잔여암의빈도가높으며이러한재발또는잔여암의존재가장기적인사망률의증가와연관이있다. 따라서, 암의재발또는잔여유무를파악하여암의진행과사망을막는동시에재발위험이낮은환자에서는불필요한검사를막는추적관찰방침이중요하다. 자극후갑상선글로불린의갑상선암재발발견에있어서의역할 혈청갑상선글로불린 (thyroglobulin, Tg) 은가장민 감한 DTC의생물학적표지자 (biomarker) 이다. Tg는정상갑상선조직또는갑상선암조직에서만생성되므로 Tg 수치를측정하는것이갑상선전절제술 (total thyroidectomy) 과방사성요오드잔여갑상선제거술 (radioactive iodine remnant ablation, RRA) 을받은 DTC 환자에서재발또는잔여갑상선암을조기에발견을가장빨리예측하는데도움을준다. 자극갑상선글로불린 (stimulated thyroglobulin, stg) 은갑상선호르몬투여중단을통한내인성 thyroid-stimulating hormone (TSH) 자극이나합성된 TSH 주사를통한외인성 TSH 자극후에측정된혈청 Tg로정의된다. 일부보고에서 RRA후 6 개월에서 1년사이에측정한 stg가잔여또는재발갑상선암을발견하는데매우유용한것으로알려져있다. 1,2) 갑상선암의재발에대한본고찰에서의정의 - 임상적정의와생화학적정의 갑상선암의임상적재발 (clinical recurrence) 은병리학적으로악성조직이확인되거나폐, 골, 뇌전이병변 논문접수일 : 2011 년 10 월 12 일 / 심사완료일 : 2011 년 12 월 7 일교신저자 : 김태용, 서울시송파구올림픽로 43 길 88, , 울산대학교의과대학서울아산병원내분비 - 대사내과 Tel: , Fax: , tykim@amc.seoul.kr 20

2 F/U of DTC Using Thyroglobulin 이확인되는경우로정의된다. 실제재발과잔여암의임상적인엄밀한감별은불가능하여흔히재발이라고하는정의에는수술전에이미있었으나임상적으로인지하지못한잔여암을포함하게된다. 추적관찰중에시행된임상적검사로시행된신체검진, 경부초음파및 computed tomography (CT) 등의영상의학적검사에서임상적재발의증거가없는경우를임상적병변없음 (no clinical evidence of disease, NCED) 이라고정의한다. 생화학적관해 (biochemical remission, BR) 는 stg가 1 ng/ml 미만인경우로정의된다. 자극갑상선글로불린이측정한계치이하인분화갑상선암환자의장기추적관찰결과 갑상선전절제술과 RRA 후 6-12개월에측정한 stg가측정한계치이하거나아주낮으면대부분갑상선암의완전또는장기간의관해를보이며재발률은매우낮다. 3-8) 서울아산병원에서수술및 RRA 후 1년에측정한 stg가 1 ng/ml 미만으로 BR 상태인 DTC 환자 1010명을대상으로한장기간의추적연구에서 1.3% 의환자만이재발하였다. 재발한환자들은모두국소적인재발로전부경부초음파로확인이가능하였다 (unpublished data). 이러한 stg가 1 ng/ml인환자에서 1-3년후에두번째 stg를측정할경우일부환자에서그수치의증가가있으며재발률이증가하는양상을보이나그수가매우적어실제임상에서유용성은제한적일것이다 (unpublished data). 따라서, RRA 후 6-12개월시점에서 BR을확인된환자에서는추가적인 stg 측정없이경부초음파추적관찰이충분할것으로사료된다. 혈청갑상선글로불린측정시갑상선글로불린자가항체의간섭 혈청에서갑상선글로불린의측정은기술적으로많은제한이있다. 현재는면역계측법 (immunometric assay, IMA) 이방사면역법 (radioimmunoassay, RIA) 보다보편적으로사용된다. 이는 IMA법이반응시간이짧고, 측정범위가넓으며, 항체가보다안정적으로표지되기때문이다. 9) 또한, IMA는방사성동위원소대신에화학발광법 (chemiluminescence assay) 을이용할수도있다. 하지만, 환자의혈청에갑상선글로불린자가항체 (thyroglobulin antibody, TgAb) 가존재하는경우 IMA법이 RIA법에비하여간섭이더심하며측정치가 실제보다낮아진다. 일부임상지침들은수술후매 6-12개월간격으로혈청 Tg와 TgAb를동시에측정하며 TgAb가양성이면 IMA법대신 RIA법으로혈청 Tg를측정할것을권유하고있다. 9-11) 하지만, RIA 방법도 TgAb 존재시일부간섭이있는데, 9) 이는 TgAb 자체가매우이질적인데서기인한다. 현재까지알려진어떠한방법도 100% 정확도로샘플에존재하는 TgAb가간섭을일으킬지를예측하는것은불가하다. 가장간섭을예측하는믿을수있는인자는 RIA와 IMA 방법으로동시에 Tg를측정하여이들간에수치가다르게나타나는것이다. 9) 대개의경우 TgAb 간섭이있는경우 RIA 방법으로측정한 Tg 의수치가 IMA로측정한수치보다높게나타난다. TgAb 측정자체를이용한갑상선암의재발예측 DTC 환자의 10-25% 에서혈중에 TgAb가존재함이보고되어있는데, 이는정상인보다높은빈도이다 ) TgAb는완전관해가된환자에서는궁극적으로는감소되면서결국에는소실되게되는데, 항원의소실에서항체의소실까지걸리는기간이 3년정도로추정되고있다. 16) 비록, TgAb 수치상승이지속되거나증가하는것이갑상선암조직이존재함을의미하지만 TgAb의수치를분화갑상선암환자의예후를예측하는데사용하는것에대하여는보편적으로잘받아들여지고있지않다. 단편적으로제한된환자수와추적기간으로진행된연구들에서 TgAb 상승이지속될경우재발이높다고보고되었다 ) 하지만, 다른보고들에서는이러한연관성이없었다. 12,14,20,21) 저자들은 Tg가측정되지않으나 TgAb 수치가증가되어있는분화갑상선암환자에서 RRA 직전과 6-12개월이후측정한 TgAb 수치간의변화가환자의재발을예측하는새로운인자로사용될수있음을제시하였다. 22) TgAb 수치변화를보려면수년이상환자를추적하여야하는데, TgAb의초기변화량을이용하면수술후 1년이내에예후를조기예측할수있다. 영상의학적검사에서재발이나잔여암의증거가없으나 stg 가 2 ng/ml 이상으로증가된환자의장기예후 2009년에개정된미국갑상선학회의진료지침에따르면 stg가 2 ng/ml 이상증가한경우 Tg를분비하는 21 J Korean Thyroid Assoc

3 김태용 재발또는잔여갑상선암조직을확인하기위한진단적전신스캔 (diagnostic whole body scan, DxWBS) 을포함한영상검사시행을권유하고있다. 4,23-25) 이전의보고들에서 stg가저위험군환자의 20% 정도에서상승되어있으며이들중 1/3 정도가추적관찰시잔여또는재발암이발견되었다. 2) stg 수치가 2 ng/ml 넘는환자에서추가적인영상의학적검사를통하여잔여병소를확인하라는것은정립되어있지만, 실제로추가적인영상의학적검사에도잔여병소가확인되지않는나머지 2/3의환자들의장기추적결과및추적방침은아직명확하지않다. 영상의학검사에서재발또는잔여병소가확인되지아니하고 stg만증가한환자들에서경험적인방사성옥소치료가전통적으로시행되었다. 25) 진단전신스캔에서음성이고 Tg만상승되어있는환자를대상으로경험적인방사성옥소치료를시행시혈청 Tg가감소함이보고되어있다 ) 하지만, 진단전신스캔이외에 fluorodeoxyglucose positron emission tomography (FDG- PET) 나초음파등을추가로시행하여재발또는잔여병소가없는것이확인된환자들을대상으로한최근보고들에서는경험적인방사성옥소치료의효과가의문시되고있다. 26,29,30) 다른연구들은, 영상의학검사에서재발또는잔여병소가발견되지않고 stg만증가환환자들을경험적방사성옥소치료없이정기적인추적관찰시 stg가서서 히감소함을보고하였다. 26,31-33) 방사성옥소치료후 1 년에 30-68% 의환자가 stg가측정치이하로감소함을보고하였다. 26,27,31) 하지만, 이러한연구들은매우적은수의환자를대상으로하였으며장기간의추적관찰에서 stg의변화를보여주지는못하였다. 최근, 저자들은임상적으로재발또는잔여암의증거가없으며 RRA 시행 6-12개월후측정한 stg (stg1) 가 2 ng/ml 이상으로증가한 186명의환자의장기간추적결과에대한연구를종료하였다 (unpublished data). 추적관찰중정기적인영상의학적검사에서 NCED인환자군에는 stg 를수년간격으로반복적으로측정시수치가서서히감소함을알수있었다. stg1이 ng/ml인환자의 41% 에서자발적인 BR이관찰되었으며 stg1 측정시점부터 BR이확인되는시점의중앙기간은약 5.8년이었다. 또한, stg1과 1-3년이후에측정한 stg2 간의변화량에따라서도 BR에다다르는정도가달랐다. 즉, stg 가 50% 이상감소하는경우 BR에도달하는중앙기간이약 5년이었으며 stg가 50% 미만으로감소하거나증가하는경우는 BR에도달하는기간이약 10년이었다. 현시점에서서울아산병원에서분화갑상선암환자의방사성요오드잔여갑상선제거술후 6~12 개월후의환자관리지침 (Fig. 1) Fig. 1. Current AMC strategy for management of DTC 6-12 months after remnant ablation. Vol. 5, No. 1,

4 F/U of DTC Using Thyroglobulin 방사성옥소잔여갑상선제거술시행직전에시행한 stg 의의미 일부연구들은 RRA 시행직전에측정한 stg 수치가임상적인예후인자일수있음을보고하였다. 수술후남아있을수있는정상갑상선조직이파괴되어여기서분비되는 Tg가사라지는데 1년정도가소요되므로 RRA 시행직전에측정한 Tg는암조직에서분비된것인지정상조직에서분비된것인지알수없다. 7) 저자들은한명의외과의에의하여갑상선이철저히제거된환자군 268명에서 RRA 시행직전에측정한 Tg 수치와 RRA 이후에 6-12개월에측정한 stg 수치각각의예후인자로서의가치를연구하였다. 34) 이연구에서 RRA 시행직전의 Tg 수치는 RRA 시행 6-12개월이후의 stg와좋은상관관계를보이며특히 RRA 시행직전의 Tg 수치가 2 ng/ml 미만인경우가매우좋은예후를보임을보고한바있다. 중심단어 : 갑상선, 갑상선암, 생물표지자, 갑상선글로불린. References 1) Eustatia-Rutten CF, Smit JW, Romijn JA, van der Kleij- Corssmit EP, Pereira AM, Stokkel MP, et al. Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis. Clin Endocrinol (Oxf) 2004;61(1): ) Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88(4): ) Nascimento C, Borget I, Al Ghuzlan A, Deandreis D, Chami L, Travagli JP, et al. Persistent disease and recurrence in differentiated thyroid cancer patients with undetectable postoperative stimulated thyroglobulin level. Endocr Relat Cancer 2011;18(2):R ) Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A. Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. J Clin Endocrinol Metab 2002;87(4): ) Toubeau M, Touzery C, Arveux P, Chaplain G, Vaillant G, Berriolo A, et al. Predictive value for disease progression of serum thyroglobulin levels measured in the postoperative period and after (131)I ablation therapy in patients with differentiated thyroid cancer. J Nucl Med 2004;45(6): ) Menendez Torre E, Lopez Carballo MT, Rodriguez Erdozain RM, Forga Llenas L, Goni Iriarte MJ, Barberia Layana JJ. Prognostic value of thyroglobulin serum levels and 131I wholebody scan after initial treatment of low-risk differentiated thyroid cancer. Thyroid 2004;14(4): ) Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M. Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 2000;85(1): ) Schlumberger M, Baudin E. Serum thyroglobulin determination in the follow-up of patients with differentiated thyroid carcinoma. Eur J Endocrinol 1998;138(3): ) Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13(1): ) Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154(6): ) Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16(2): ) Pacini F, Mariotti S, Formica N, Elisei R, Anelli S, Capotorti E, et al. Thyroid autoantibodies in thyroid cancer: incidence and relationship with tumour outcome. Acta Endocrinol (Copenh) 1988;119(3): ) Rubello D, Girelli ME, Casara D, Piccolo M, Perin A, Busnardo B. Usefulness of the combined antithyroglobulin antibodies and thyroglobulin assay in the follow-up of patients with differentiated thyroid cancer. J Endocrinol Invest 1990;13(9): ) Kumar A, Shah DH, Shrihari U, Dandekar SR, Vijayan U, Sharma SM. Significance of antithyroglobulin autoantibodies in differentiated thyroid carcinoma. Thyroid 1994;4(2): ) Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, et al. Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83(4): ) Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone M, Masserini L, et al. Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 2003;139(5 Pt 1): ) Rubello D, Casara D, Girelli ME, Piccolo M, Busnardo B. Clinical meaning of circulating antithyroglobulin antibodies in differentiated thyroid cancer: a prospective study. J Nucl Med 1992;33(8): ) Adil A, Jafri RA, Waqar A, Abbasi SA, Matiul H, Asghar AH, et al. Frequency and clinical importance of anti-tg autoantibodies (ATG). J Coll Physicians Surg Pak 2003;13(9): ) Chung JK, Park YJ, Kim TY, So Y, Kim SK, Park DJ, et al. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf) 2002;57(2): ) Quevedo I, Campino C, Rodriguez Portales JA, Arteaga E, Lopez JM, Campusano C, et al. [Anti thyroglobulin antibodies 23 J Korean Thyroid Assoc

5 김태용 in the follow up of patients with differentiated thyroid cancer: residual or relapsing disease markers?]. Rev Med Chil 2002; 130(2): ) Gorges R, Maniecki M, Jentzen W, Sheu SN, Mann K, Bockisch A, et al. Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy. Eur J Endocrinol 2005;153(1): ) Kim WG, Yoon JH, Kim WB, Kim TY, Kim EY, Kim JM, et al. Change of serum antithyroglobulin antibody levels is useful for prediction of clinical recurrence in thyroglobulin-negative patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2008;93(12): ) Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84(11): ) Pacini F, Molinaro E, Lippi F, Castagna MG, Agate L, Ceccarelli C, et al. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86(12): ) Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11): ) Pacini F, Agate L, Elisei R, Capezzone M, Ceccarelli C, Lippi F, et al. Outcome of differentiated thyroid cancer with detectable serum Tg and negative diagnostic (131)I whole body scan: comparison of patients treated with high (131)I activities versus untreated patients. J Clin Endocrinol Metab 2001;86(9): ) Pineda JD, Lee T, Ain K, Reynolds JC, Robbins J. Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 1995;80(5): ) Koh JM, Kim ES, Ryu JS, Hong SJ, Kim WB, Shong YK. Effects of therapeutic doses of 131I in thyroid papillary carcinoma patients with elevated thyroglobulin level and negative 131I whole-body scan: comparative study. Clin Endocrinol (Oxf) 2003;58(4): ) Fatourechi V, Hay ID, Javedan H, Wiseman GA, Mullan BP, Gorman CA. Lack of impact of radioiodine therapy in tg-positive, diagnostic whole-body scan-negative patients with follicular cell-derived thyroid cancer. J Clin Endocrinol Metab 2002;87(4): ) Kim WG, Ryu JS, Kim EY, Lee JH, Baek JH, Yoon JH, et al. Empiric high-dose 131-iodine therapy lacks efficacy for treated papillary thyroid cancer patients with detectable serum thyroglobulin, but negative cervical sonography and 18F-fluorodeoxyglucose positron emission tomography scan. J Clin Endocrinol Metab 2010;95(3): ) Baudin E, Do Cao C, Cailleux AF, Leboulleux S, Travagli JP, Schlumberger M. Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients. J Clin Endocrinol Metab 2003;88(3): ) Chao M. Management of differentiated thyroid cancer with rising thyroglobulin and negative diagnostic radioiodine whole body scan. Clin Oncol (R Coll Radiol) 2010;22(6): ) Kloos RT. Thyroid cancer recurrence in patients clinically free of disease with undetectable or very low serum thyroglobulin values. J Clin Endocrinol Metab 2010;95(12): ) Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC, et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2005;90(3): Vol. 5, No. 1,

Kaes025.hwp

Kaes025.hwp 고위험군유두상갑상선암환자에대한방사성옥소최대허용선량측정법및치료법의검증 Verification of Measurement Methods and Therapeutic Efficacy of Maximum Permissible Dose of I-131 in High Risk Patients with Differentiated Papillary Thyroid Cancer