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1 REVIEW ARTICLE ISSN: X J Korean Thyroid Assoc 2012 November 5(2): 미분화갑상선암의치료 연세대학교의과대학외과학교실강남세브란스병원갑상선암센터 장항석 Anaplastic Thyroid Carcinoma - a Therapeutic Dilemma Hang-Seok Chang Department of Surgery, Yonsei University College of Medicine, Thyroid Cancer Center, Gangnam Severance Hospital, Seoul, Korea Anaplastic thyroid carcinoma (ATC) is a rare type of malignancy of thyroid follicular cell origin. It is one of the most aggressive human cancers, and typically associated with a fatal prognosis. Most patients are presenting as locally advanced and systemically disseminated disease. A single mode of therapy, whether it is surgery, chemotherapy, or radiotherapy, fails to afford significantly favorable outcomes. While multimodality approaches may enhance the treatment response to a small degree, such implementations of these modalities are often impractical as many patients are of old age and are unable to tolerate the intensity of treatments. As in many other types of carcinomas, radical resection may be the mainstay of therapy for ATC, but surgery itself is seldom possible for this condition. Even with aggressive surgical therapy for those invasive ATCs, there is no evidence of decreased recurrence rates, while only the post-surgical morbidity rates increase. One chemotherapeutic agent that seems to demonstrate some effect against ATC is adriamycin, which is more effective when administered in combination, and is also known to act synergistically with radiotherapy. A commonly employed treatment modality is the combination therapy of adriamycin and cisplatin administration with hyperfractionated radiation therapy. Other chemotherapeutic agents proven to be effective are taxanes such as paclitaxel and docetaxel. Despite of disappointing result of conventional radiotherapy, however, hyperfractionated radiation therapy and combined chemotherapy has been suggested to improve survival rates by some institutions, while others disagree. The dismal results of conventional treatments for ATCs have stimulated the investigation for new therapeutic methods with improved outcome. There have been a number of trials of new materials or therapeutic methods. In recent studies, some trials were partially successful or promising in vitro or in vivo. The examples of these trials are; redifferentiation therapies, molecular targeted therapies, and some other miscellaneous methods. Although the observations may suggest that some of the methods may have a therapeutic effect on ATCs, or may act as an adjunct to other primary treatment modality, the efficacy and safety have not been ascertained yet in human trials, and further confirmation through in-depth studies are required. Key Words: Anaplastic thyroid cancer, Multidisciplinary approach, Molecular targeted therapy 서론 미분화갑상선암은가장위험한암중하나로비록발병률이낮지만치명적인암으로알려졌다. 1,2) 발생빈 도는매우낮으며, 전체갑상선암의약 2% 내외의빈도를보인다. 2,3) 임상적으로는갑자기자라는목의종괴를주소로하는경우가대부분이며, 주변의조직으로침습이흔하기때문에애성, 호흡곤란, 연하곤란의증상이동반되는경우가많다. 3-5) Received October 4, 2012 / Accepted October 20, 2012 Correspondence: Hang-Seok Chang, MD, PhD, FACS, Department of Surgery, Yonsei University College of Medicine, Thyroid Cancer Center, Gangnam Severance Hospital, 211, Eonju-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , surghsc@yuhs.ac Copyright c 2012, the Korean Thyroid Association. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 132

2 Anaplastic Thyroid Carcinoma - a Therapeutic Dilemma 미분화갑상선암은기존의분화갑상선암이있었던경우에발견되는경우가많고, 20-30% 의경우에는분화갑상선암이함께공존하며, 이와연관이없이발생하는경우도있다. 4,6) 진단단계에서이미원격전이가동반된경우가많고, 치료과정중에도급격한병의진행을보이기때문에대부분의치료는불가능하며, 특히수술적인치료는증상완화의목적외에는적절하지않다는의견이주를이룬다. 2,7-9) 본논문에서는미분화암의치료와최신지견에대해문헌고찰과함께논해보고자한다. 임상양상과진단 미분화암은기존의갑상선종괴나암을가지고있던고연령층에서발견될가능성이많으며, 짧은기간동안폭발적인증가를하는혹을주소로진단되는경우가많다. 2-4,8) 진단단계에서부터주변조직으로침범이확인되고, 주변의연부조직뿐만아니라기도, 식도, 신경등광범위한침범을일으키므로목의불편감, 애성, 연하곤란, 호흡장애등증상을나타낸다. 8-10) 대부분종양의크기는 3-20 cm 정도로크게자란상태로발견되며, 평균 8 cm 가량의직경을보인다. 11,12) 미분화암의위험인자에대해서는여러가지보고가있었으나, 일반적으로는진단당시연령이낮거나, 주변조직으로침범이없는경우, 원격전이가없고, 림프절전이가없으며, 갑상선외부로침범해나오지않은경우에좋은예후를기대할수있는것으로알려져있다. 3,4,7-11) 그러나이와는반대로어떠한경우에도좋은예후를기대하기어렵다는보고도있다. 1,2) 진단은특징적인임상양상을보이고주변으로침범하는소견이영상진단으로확인될경우세침흡입검사를통해확인할수있다. 3,5,6) 특징적인세포병리학적소견을보일경우비교적진단은쉽게얻을수있으나, 다른분화도가나쁜림프종, 육종등 high grade 암종과감별이중요하다. 2) 미분화암은특징적인세가지세포형을나타내는데, 방추세포형 (spindle cell type), 거대세포형 (giant cell type), 평편세포양형태 (squamoid type) 를보인다. 2,8,12) 병기를위한진단으로는경부초음파, 컴퓨터단층촬영술, 자기공명영상등을통해국소적인침범이나주변림프절침범을파악할수있으며, 원격전이를알기위해서는폐촬영, 컴퓨터단층촬영술, 전신골주사 (whole body bone scan), 양자방출단층촬영 (positron emission tomography, PET) 등이도움이된다. 3,7) 미분화암은 TNM staging system에의하면발견당시부터 4기 (stage IV) 로분류되고, 갑상선피막외부로침범이일어나지않은경우림프절전이여부에상관없이원격전이가동반되지않았다면 stage IVA로분류된다. 피막침범이일어난경우원격전이가없다면 stage IVB, 원격전이가있다면종양이나림프절병기와상관없이 stage IVC로분류된다. 13) 분자생물학적고찰 미분화갑상선암은분자생물학적변이와염색체변이등을포함하여유전적으로다양한형태의돌연변이소견을나타낸다. 14,15) 여러연구에서밝혀진바와같이미분화암에서빈번하게발견되는분자생물학적변이와신호전달체계 (signaling pathway) 의변화는미래치료적인효과를얻기위한연구의토대가될것으로기대된다. 중요한분자생물학적변화로는, BRAF v600e 돌연변이가약 25% 내외에서발견되고, RAS 돌연변이도 6-50% 에서발견되는것은미분화암이 BRAF 변이갑상선세포 ( 유두상암 ) 혹은 RAS 변이갑상선세포 ( 여포성암 ) 로부터발생한다는가설을뒷받침할수있는결과라하겠다. 10,14,15) 이결과는미분화암이분화갑상선암과동반되어발견되며, 이변화는기존의분화갑상선암에서탈분화과정 (dedifferentiation) 을거쳐발생한다는가설의증거가될수있다. 16) 이때중요한역할을하는것으로잘알려진것이종양억제인자인 p53의돌연변이다. 미분화암의 40-70% 가량에서 p53의돌연변이가관찰되며, 분화갑상선암, 저분화갑상선암 (poorly differentiated thyroid cancer), 미분화암에이르면서발현이높아지는것을보아종양의발생보다는분화도에영향을미치는것으로받아들여지고있다. RET/PTC 재배치 (rearrangement) 가있는경우유두암이발생하지만 p53 의기능이결여된경우 (knock-out) 미분화도 (anaplastic change) 의증가와침습성향 (invasiveness) 이증가하는것으로보아이들두유전자간의상호작용을미분화암이발생할수있다는연구와, 17) 저분화암에서 RET/ PTC 재배치의발현이높지않은결과를바탕으로이가설에상반되는의견이있다. 18) PI3K/Akt pathway는갑상선종양과암의발생에서중요한역할을담당하는것으로알려져있으며, 미분화암의경우높은빈도의이상발현을보인다. 19) 또한 PI3KCA의돌연변이는미분화암에서 12-23% 가량에서 133 J Korean Thyroid Assoc

3 Hang-Seok Chang 관찰되고 copy gain은 38-61% 에서나타나는등 Akt 활성화를통해미분화암의발생에기여하는것으로생각된다 ) 그외분자생물학적관찰로는 PTEN 변이가 12% 정도에서나타나고, 이로인해 Akt pathway의적절한조절이되지않는문제가발생한다. 21) 또한 Wnt signaling pathway를조절하는종양억제인자인 axin의돌연변이역시미분화암의발생에영향을미치는것으로알려져있으며, 22) Wnt signaling과세포간유착 (cell-cell adhesion), 기저막 (basement membrane) 침범에영향을미치는 β-catenin의변이는미분화암의공격적인침범과관련이있다. 23) 이러한분자생물학적연구의결과미분화암의발생과연관된정보를확보할수있으며, 진단과예후및이를표적으로한새로운분자생물학적표적치료 (molecular targeted therapy) 가가능하다. 예후인자 미분화암은조기에발견되어병기가낮은경우, 예를들어종양의크기작고갑상선외부로침범이일어나지않고원격전이가없는경우 (stage IVA), 45세미만의젊은연령층, 완벽한수술적절제가가능한경우좋은예후를보이는것으로보고한연구들이있는가하면, 어떠한경우에도좋은예후를보이지않는다는실망스러운연구가대부분으로아주초기를제외하고는거의예후가불량한것으로잘알려져있다. 2,3,7,12) 미분화암의치료 미분화암은매우드문질환이며치료도중에도병이진행되고사망에이르는등예후가좋지않기때문에대규모의연구결과도없고예후를알수있을만한근거도희박한편이다. 현재까지확실한증거중심의치료지침 (evidence-based treatment guideline) 은확립된바가없고단편적인연구결과에의존하는수밖에없다. 2,10) 단일요법 (single mode therapy) 의경우에는수술이나항암화학요법, 혹은방사선요법모두치료효과를내기에는부적합한것으로밝혀졌고, 다병합요법 (multimode therapy) 은어느정도생존율향상과생존기간연장의효과가있는것으로알려졌다. 그러나이러한다병합요법은실제로적용하기어려움이많은데, 환자들의연령이대부분고연령층이고, 치료중에도전이가 일어나는등질환이급속히악화되기때문에치료의강도를이겨내기힘든이유때문이다. 2) 다른암과마찬가지로미분화갑상선암의치료에서도완벽한수술적절제가가장중요하며, 가능한경우치료의효과도높일수있고, 생존율향상도기대할수있다. 그러나수술이대부분의경우에적합하지않은데, 미분화암의경우발견당시부터경부나흉부의중요기관과혈관등으로침범이일어난경우가대부분이며, 원격전이도많은수에서동반되어수술자체가불가능한경우가많기때문이다. 1-3,11,24) 아주작은미분화암에서완벽한수술적절제가가능한경우향상된생존율을보였다는보고들이있는가하면, 25-27) 어떠한수술적치료를해도생존율은차이가없다는의견도있다. 2,28,29) 특히기도나식도, 인후등으로침범이일어난경우에는적극적인수술적치료로이들기관을절제하는수술은부작용의발생만높이고삶의질을저하시킬뿐생존기간연장에는도움이되지않으므로반대하는의견이주를이룬다. 1-3,25-29) 항암화학요법제치료는거의대부분효과가없는것으로알려져있으며특정약물한가지로치료효과를높일수있는가능성은매우희박하다. 이는미분화갑상선암세포주에서 multidrug resistance-associated protein과 multiple drug resistance (MDR) mrna, P-glycoprotein이과발현하는것을관찰함으로써증명되었다 ) Doxorubicin은가장많이사용되는약제로서특히방사선치료와함께사용할때방사선치료의효과를상승시키는 (radiosensitizer) 역할을하는것으로알려져있으나이와는반대로그효능에의문을제기하는보고들도많은실정이다. 2,25,33,34) Taxane 계통의약제들 (paclitaxel, docetaxel) 역시미분화암에서가능성있는약제로인정되고있으며, 실제로도생존기간향상에도움이되는것으로보고되었다. 특히방사선치료와병합하였을때효과적이라고알려졌지만, 아직생존율을획기적으로연장시켰다는보고는없다. 30,35,36) 방사선치료는수술이불가능한경우나국소적으로통증이심한경우완화치료 (palliative treatment) 의목적으로사용된다. 그러나방사선치료단독으로는거의효과를기대할수없고항암화학요법과병합이더욱효과적이며, 완벽한수술적절제가가능할경우다병합요법의효과는더욱증가될수있다. 2) 그러나이러한경우에도생존율향상에는도움이되지못하고, 원격전이에대한치료효과는없는것으로알려졌다. 37) Intensity-modulated radiation therapy (IMRT) 는주변조직의손상을최소화하고종양에높은에너지를전달할 Vol. 5, No. 2,

4 Anaplastic Thyroid Carcinoma - a Therapeutic Dilemma 수있는방법으로병합요법으로사용했을때더욱효과적인것으로알려져있으며, 전통적인과분할요법 (hyperfractionated radiational therapy) 의방법에도입을해도적은손상으로치료를할수있는것으로알려져있다. 37,38) 이러한단일요법은거의효과를기대하기힘들지만, 다병합요법은좀더효과적이며, 잘선택된증례에서는생존율연장까지도기대할수있는것으로알려졌다. 2,27) 특히초기에발견되어완벽한수술적절제가가능할경우치료효과가높은것으로알려져있는데, 최근의여러연구에서는 stage IVA의경우는적극적인수술과다병합치료를통해좋은결과를얻었으나 stage IVB와 IVC는거의차이가없는것으로보고되었다. 33,39,40) 현재까지는수술, 항암화학요법과방사선치료를포함한다병합요법을시행하여도미분화암의치료성적은개선이되지않고있으며, 이로인하여새로운치료법의필요성이강조되고있다. 2,10) 최근에는미분화암에대한분자생물학적연구가활발히진행되고있으며, 이를바탕으로새로운표적치료가개발되고있다. 현재주목받고있는분자생물학적표적은세포내신호전달체계이상을초래하는물질들인데, 대표적인것으로는 BRAF 돌연변이, RAS-RAF-MAPK pathway의활성화, p53 돌연변이, tyrosine kinase 수용체발현증가 (EGF, VEGF, PGF receptors) 등이있다. 10,41) 현재까지효과가기대되는약제로는 EGFR과 VEGF의단일클론항체 (monoclonal antibody) 인 cetuximab과 bevacizumab 가있는데이들은종양의성장과혈관생성 (angiogenesis) 을효과적으로억제하는것으로알려져있으며, 기존의항암제인 doxorubicin, irinotecan 등과병용하였을때더욱효과가증가하는것으로보고되었다. 42,43) 또한 EGFR과 VEGF를동시에통제할수있는 dual kinase inhibitor인 AEE788 역시기대가되는약물로미분화암세포주에서 6-8배강력한억제효과를보였으며, 단독사용혹은 paclitaxel, cetuximab 등과병용할경우더욱효과적인것으로보고되었다 ) 또한 BRAF와 VEGFR-2, PDGF-beta kinase의 multikinase inhibitor인 sorafenib은종양의혈관형성을억제하고혈관내막세포 (endothelial cell) 의 apoptosis를조장하여실험동물에서종양성장을억제하고생존기간을연장하는효과를보였다. 47) 그외 NIS (sodium-iodide symporter) 의기능을복원하여방사성요오드치료의효과를높이기위한여러연구가진행되고있지만아직임상에서활용할수있 는단계에는이르지못하였다. 또한과거탈분화과정에서소실되거나저하된미분화암세포의요오드섭취능을복원하기위한여러가지약물에대한연구가이루어졌는데, 이들중 valproic acid, retinoids 등의약물에의한성과가보고된바있으나현재는회의적인의견이대부분이다. 2,10) 결론 미분화갑상선암은드물지만치명적인암으로서현재까지어떠한치료방법을동원하더라도예후는불량하다. 아주초기에발견된경우적극적인수술과추가치료를포함한다병합요법이도움이되는경우도있지만아직뚜렷한치료방침이정해지기는어려운상황이다. 향후분자생물학적연구를통해미분화암의생성과진행의지식을축적한다면새로운치료법을발견할가능성이있으며, 이를위해서는대규모의임상적결과와증거를확보하는것이중요하다. 중심단어 : 미분화갑상선암, 다병합요법, 분자생물학적표적치료. References 1) Ain KB. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin Surg Oncol 1999;16(1): ) Chang HS, Nam KH, Chung WY, Park CS. Anaplastic thyroid carcinoma: a therapeutic dilemma. Yonsei Med J 2005; 46(6): ) Are C, Shaha AR. Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006;13(4): ) Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program Cancer 1997;79(3): ) Us-Krasovec M, Golouh R, Auersperg M, Besic N, Ruparcic-Oblak L. Anaplastic thyroid carcinoma in fine needle aspirates. Acta Cytol 1996;40(5): ) Rivera M, Sang C, Gerhard R, Ghossein R, Lin O. Anaplastic thyroid carcinoma: morphologic findings and PAX-8 expression in cytology specimens. Acta Cytol 2010;54(5): ) Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005;103(7): ) Carcangiu ML, Steeper T, Zampi G, Rosai J. Anaplastic thyroid carcinoma. A study of 70 cases. Am J Clin Pathol 1985;83(2): ) Lang BH, Lo CY. Surgical options in undifferentiated thyroid carcinoma. World J Surg 2007;31(5): J Korean Thyroid Assoc

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy