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- 지애 십
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1 대한내분비외과학회지 : 제9권제2호 Vol. 9, No. 2, June 2009 원저 유두상갑상선미세암의임상병리학적예후인자에관한후향적분석 을지대학교의과대학을지대학교병원외과학교실 송대근ㆍ최영진ㆍ강윤중ㆍ박혜원ㆍ박주승ㆍ조병선ㆍ김창남ㆍ이민구 Clinical Characteristics and Prognostic Factors of Papillary Microcarcinoma: Results from Retrospective Analysis of 176 Patients Dae Keun Song, M.D., Young Jin Choi, M.D., Yoon Jung Kang, M.D., Hye Won Park, M.D., Joo Seung Park, M.D., Byung Sun Joe, M.D., Chang Nam Kim, M.D. and Min Koo Lee, M.D. Purpose: The clinical importance and characteristics of papillary thyroid microcarcinoma (PTC) are still under debate, and the criteria for appropriate treatment have yet to be established. In this study, we attempted to examine the appropriate extent of surgery and the desirability of prophylactic lymph node (LN) dissection through identification of factors influencing LN metastasis and capsular invasions. Methods: We reviewed the medical records of 176 consecutive biopsy-proven PTC patients. The clinical and pathological prognostic factors including LN metastasis and capsular invasion were analyzed. Chi-square test and independent sample T-test were used for statistical analysis. Results: The median age of patients was 47-years-of-age (range years). Among 108 patients who underwent central LN dissection, 38 (35.8%) patients showed LN metastasis. Univariate analysis revealed that male patients showed significantly more LN metastasis than female patients and lymphovascular invasion significantly affected LN metastasis. Twenty-eight (14.8%) patients showed capsular invasion. Tumor size, especially tumors 5 mm in diameter, and tumor multiplicity were significantly associated with capsular Invasion. Lymphatic or venous invasion also affected the occurrence of capsular invasion. Conclusion: Patients who are male, have a tumor larger than 5 mm in diameter, or multiple tumors are more likely to develop LN metastasis or capsular invasions. These factors could help us to decide the extent of thyroidectomy 책임저자 : 최영진, 대전시서구둔산동 1306 번지 , 을지대학교병원외과 Tel: , Fax: yjchoi@eulji.ac.kr 게재승인일 :2009 년 6 월 19 일 and to select patients who need prophylactic LN dissection. (Korean J Endocrine Surg 2009;9:79-84) Key Words: Papillary thyroid microcarcinoma, Lymph node metastasis, Capsular invasion 중심단어 : 유두상갑상선미세암, 림프절전이, 피막침범 Department of Surgery, Eulji Medical Center, Eulji University School of Medicine, Daejeon, Korea 서 유두상갑상선암은전체갑상선암의 70 80% 를차지하며내분비외과분야에서가장흔한종양으로 10년생존율이 90 95% 인비교적양호한예후를갖는종양으로알려져있다.(1) 유두상갑상선암의예후와관련된여러요인들이알려져있으나 (2-4) 재발에관여하는것으로알려진독립적요인들로는진단당시의연령, 피막침범여부, 종양의크기, 림프절전이여부등이있으며, 병리학적인아형이나수술시완전절제여부등과도관련이있는것으로생각되어지며,(5-7) 림프절전이여부는원격전이와도연관이있는것으로생각되어지고있다. 갑상선초음파를이용한정기검진및초음파유도하세침흡인검사증가에따라증상이없는건강한인구군에서의 1 cm 이하의갑상선결절의진단및조직학적진단이수월해짐으로인해최근수년간갑상선암의빈도, 그중에서도유두상갑상선미세암에대한진단및수술이점차늘어나고있다. 그러나유두상갑상선미세암의임상적중요성및그특성에대해서는아직도논란의여지가많으며그에따른적절한치료의기준도비교적명확하지못한실정이다. 우리는본연구를통해한기관에서일련의기간동안진단된유두상갑상선미세암의임상병리학적특성을후향적으로분석하고자한다. 그에따라림프절전이나피막침범등을포함한알려진여러예후인자들의발현을확인하고그와관련있는인자들에대한분석을통해유두상갑상선미세암의적절한수술범위및술후치료에대해고찰해보고자한다. 론 79
2 80 대한내분비외과학회지 : 제 9 권제 2 호 2009 방 법 Table 1. Clinicopathologic characteristics of 176 patients with papillary microcarcinoma 2001년 1월부터 2007년 8월까지을지대학병원외과학교실에서갑상선수술후유두상갑상선암으로확진된 428명중조직병리소견상유두상갑상선미세암으로진단된 176 명의환자를대상으로하였다. 미세유두상갑상선암의정의는종양의최대직경이 1 cm 이하인경우로하였으며다발성종양인경우한개의종양이라도 1 cm 이상인경우와과거엽절제술후반대편에서의갑상선질환으로갑상선완전절제술을시행받은경우는대상군에서제외하였다. 연구는후향적으로진행되었으며, 환자의특성, 종양의술전소견, 조직검사상의소견및동반질환의유무, 림프절전이여부및세부종양크기별병리조직학적특성과이에따른림프절전이여부등에대해비교하였다. 제 6판 AJCC (American Joint Committee on Cancer) 병기분류에따라대상환자를 45세미만환자와 45세이상환자군으로분류하여각환자군의차이를비교하였다. 통계방법은 SPSS 12.0 (2003 SPSS Inc. Chicago, Illinois, USA) 을이용하여 chi-square test 및독립표본 T-검정을이용하였으며 P-value가 0.05 이하인경우를의미있는것으로간주하였다. 결과 1) 일반적특성 2001년 1월부터 2007년 8월까지본원에서유두상갑상선암으로수술받은환자및그중유두상갑상선미세암으로진단된환자의연도별비율을보면 2001년 2/18 (11.1%), 2002년 4/26 (15.4%), 2003년 2/22 (9.1%), 2004년 16/40 (32.7%), 2005년 34/83 (41.0%), 2006년 53/113 (47.0%), 2007 년 84/117 (71.8%) 로점차늘어나는추세를보이고있다. 환자의평균연령은 47세 (23 80) 이며, 176명의환자중여성은 157명 (89.2%) 으로남성의 8.3배였으며, 종양의평균크기는 6.7 mm (1 10) 였고다발성을가진환자는 41명 (23.3%), 평균종양의개수는 1.3개 (1 5) 였다. 수술은 121명 (68.8%) 이전절제술을시행하였으며, 엽절제술 50명 (28.4%), 아전절제술 5명 (2.8%) 순이었고, 중심경부림프절청소술을시행한환자는 106명 (60.2%) 이었다 (Table 1). 중심경부림프절청소술을시행한환자 106명중전이가확진된환자는 38명으로림프절청소술을시행한환자의 35.8% 를보였다. 조직검사상피막침범은 26명 (14.8%) 에서보였으며, 림프관침범은 32명 (18.2%), 혈관침범은 27명 (15.3%) 으로나타났다 (Table 1). 동반질환은전체 176명의환자중 91명 (51.7%) 의환자에서보였으며, 갑상선염이 41명 (23.3%), 갑상선종 35명 (19.9%), 여포선종 7명 (4.0%) 의순이었고그밖에여포선종과갑상선 No. (%) Age (yr) Median (range) 47.3 (23 80) Gender Female 157 (89.2%) Male 19 (10.8%) Surgical resection Total thyroidectomy 121 (68.8%) Neartotal thyroidectomy 5 (2.8%) Lobectomy and isthmectomy 50 (28.4%) Central LN dissection Done 106 (60.2%) Not done 70 (39.8%) Tumor size <5 mm 30 (17%) 5 mm and <8 mm 79 (44.9%) 8 mm 67 (38.1%) Multiplicity Single 135 (76.7%) Multiple 41 (23.3%) Lymph node metastasis Negative 68 (64.2%) Positive 38 (35.8%) Capsular invasion Negative 150 (85.2%) Positive 26 (14.8%) Lymphatic invasion Negative 144 (81.8%) Positive 32 (18.2%) Vascular invasion Negative 149 (84.7%) Positive 27 (15.3%) Combined disease Negative 85 (48.3%) Positive 91 (51.7%) 염이동반된환자가 4명 (2.3%), 여포선종과갑상선종이동반된경우가 4명 (2.3%) 이었다. 갑상선전절제를시행한 121명의환자들중최종조직검사상다발성을보이거나피막침범이있거나림프절전이가확인된환자 89명 (50.6%) 에서수술후 131 I 동위원소치료를시행하였다. 2) 림프절전이와관련있는인자들 176명의유두상갑상선미세암환자중예방적또는치료적중심경부림프절청소술시행한환자는 106명이었으며, 측경부림프절청소술을시행한환자는없었다. 106명의환자중림프절전이를보인환자는 38명으로 35.8% 의전이율을보였다.
3 송대근외 : 유두상갑상선미세암의임상병리학적예후인자에관한후향적분석 81 Table 2. Clinicopathological factors associated with lymph node metastasis Variables LN negative LN positive (%) (%) Sex <0.005 Female 66 (71.0%) 27 (29.0%) Male 2 (15.4%) 11 (84.6%) Lymphatic invasion Negative 57 (71.3%) 23 (28.7%) Positive 11 (42.3%) 15 (57.7%) Vascular invasion Negative 59 (68.6%) 27 (31.4%) Positive 9 (45.0%) 11 (55.0%) Capsular invasion Negative 58 (66.7%) 29 (33.3%) Positive 10 (52.6%) 9 (47.4%) Combined disease Negative 31 (57.4%) 23 (42.6%) Positive 37 (71.2%) 15 (28.8%) P Table 3. Clinicopathological factors associated with Capsular invasion Variables Negative (%) Positive (%) P Tumor size <5 mm 28 (93.3%) 2 (6.7%) 5 mm and <8 mm 71 (89.9%) 8 (10.1%) 8 mm 51 (76.1%) 16 (23.9%) Multiplicity Negative 121 (89.0%) 15 (11.0%) Positive 29 (72.5%) 11 (27.5%) Lymphatic invasion <0.005 Negative 130 (90.3%) 14 (9.7%) Positive 20 (62.5%) 12 (37.5%) Vascular invasion <0.005 Negative 134 (89.9%) 15 (10.1%) Positive 16 (59.3%) 11 (40.7%) Combined disease Negative 71 (83.5%) 14 (16.5%) Positive 79 (86.8%) 12 (13.2%) 성별에따른림프절전이여부는남성에서 13명의환자중 11명 (84.6%) 에서전이소견이있었던데비해여성에서는 93명중 27명 (29.0%) 에서만전이소견을보여남성이림프절전이가유의하게더많은것으로나타났다 (P<0.005) (Table 2). 최종조직검사결과상림프관과혈관, 피막침범여부에따른림프절전이여부는림프관과혈관의침범이있는군이침범이없는군에비해유의하게림프절전이가많은소견을보였으나 (P=0.008, P=0.047), 피막침범여부와는유의한차이가없는것으로나타났다 (P=0.248) (Table 2). 갑상선의타질환동반여부에따른림프절전이여부는동반질환이있었던 52명의환자중 15명에서전이가보여 54명중 23명에서전이를보인비동반질환군과유의한차이를보이지않았다 (P=0.140) (Table 2). 3) 피막침범과관련있는인자들종양의크기를 5 mm 미만, 5 8 mm, 8 mm 이상으로나누었을때종양의크기가클수록피막침범이많은것으로나타났다 (P=0.017) (Table 3). 종양의평균개수는피막침범이있던군에서 1.5개, 없던군에서 1.24개로 P value=0.63으로통계적유의성이없었으나종양이 1개였던군에비해 2개이상인군에서피막침범이 11.0% vs 27.5% 로유의하게높아 (P=0.010) 다발성과는연관이있는것으로나타났다 (Table 3). 림프관침범여부에따른피막침범도는림프관침범이있는군에서 37.5% 의피막침범율을보여림프관침범이없는군에서의 9.7% 보다유의하게높게나타났으며 (P<0.005), 혈관침범여부에따른피막침범도에서도혈관침범이있는 군에서 40.7% 로혈관침범이없는군의 10.1% 보다유의하게높은결과를보였다 (P<0.005) (Table 3). 갑상선의타질환동반여부에따른피막침범도는동반질환이있는군과없는군에서 13.2% 와 16.5% 로유의성을보이지않았다 (P=0.540) (Table 3). 다시정리하면림프절전이에영향을주는인자는성별 ( 남자 ), 림프관침범, 혈관침범이며, 피막침범에영향을주는인자는종양의크기 (>5 mm), 종양의다발성, 림프관침범, 혈관침범이있다. 고찰유두상갑상선암은전체갑상선암의 80% 이상을차지하고다른종류의암에비해상대적으로원격전이나암으로인한사망이드물어진행이거의없는종양으로생각되어진다.(13) 그중에서도유두상갑상선미세암은전체갑상선암의 30 35% 를차지할정도로높은빈도를보이며본연구에서와같이점점진단율및빈도수가증가되고있으나그중요성및치료의방법과범위에대해서는아직도논란의여지가많다.(8,11,12,14,15) 현재까지알려진여러예후인자로는림프절전이여부와다발성, 그리고일부에서는일차수술시수술의범위등이관여한다고알려져있으나 (12,15-19) 갑상선암의진행이워낙장기적진행을보이므로이에대한확실한결론은없다. 유두상갑상선미세암의경과와예후는비교적양호한것으로생각되어지나, 최근의일부연구에서 162명의환자를대상으로 9년간추적관찰한결과변화가없는환자가 70% 였음에도국소재발율은 15% 나나타났다.(20)
4 82 대한내분비외과학회지 : 제 9 권제 2 호 2009 일부의학자들은유두상갑상선미세암의평균진단연령과전체유두상갑상선암의평균진단연령이거의비슷한점및우연히진단되는유두상갑상선미세암의비율과부검시우연히발견되는유두상갑상선미세암의비율이거의비슷한점등을들어유두상갑상선미세암이양성의특성을지니며, 거의진행하지않기때문에공격적인치료가불필요하다고주장하기도하나,(1) 최근일부학자들에서는진단당시이미국소림프절전이와원격전이등이동반된환자들이있고심지어유두상갑상선미세암으로인한사망자까지있음을들어좀더적극적인치료를주장하기도한다.(2-4) 갑상선의양성질환으로수술한환자에서우연히진단되는유두상갑상선미세암이 20 24% 로보고되고있고, 부검상우연히발견되는경우도 30 40% 로보고되고있는데이수치가보편적인유두상갑상선미세암의진단율과별다른차이를보이지않는다. 또한 1.5 cm 이하의갑상선암에서는암에의한사망률이증가되지않는점등을보아 (12,15,18,21) 이에대한적극적인치료에대해회의적인연구결과도있는반면,(9,22) 일부연구에서는 10 20% 이상의림프절전이와국소재발을보이며,(8,15,16,21,23) 원격전이나사망에관계되는경우도보고되고있다.(5,11,15,24) 따라서유두상갑상선미세암에서별다른진행이없는임상양상과공격적인임상양상사이의차이에영향을주는요소들에대한좀더적극적인연구와체계화가필요하다. 유두상갑상선미세암에서방사성옥소동위원소치료의효과에대해서도아직논란의여지가많다. Pelizzo 등은갑상선절제술후방사선동위원소치료를시행한환자군에서는재발이없었던반면시행하지않은환자군에서는 2% 의재발률을보고했고, Chow 등도방사성동위원소치료군이비치료군에비해유의하게재발율이낮음을보고했다 (3.7% vs 9.8%).(10-12) 그러나대부분의연구결과가후향적이고추적기간이길지않아확정적이지못하고최근의여러연구들에서방사선동위원소치료여부에관계없이재발율에차이가없었다는보고들도있어,(10-12) 아직은명확한방사선동위원소치료의적응군이없으나대부분고위험군에서의방사선동위원소치료의필요성에대해서는동의하고있다. 본연구에서우리는유두상갑상선미세암의예후에영향을미칠수있는림프절전이와피막침범과관련된인자에대해알아보고이에따른수술의범위와예방적림프절절제술의필요성, 술후방사성동위원소치료의필요성에대해알아보고자하였다. 본연구에서는 38명 (35.8%) 의환자에서림프절전이를보였으며특히남성의경우여성보다유의하게림프절전이율을보였다. 여성에비해현저하게적은분포를보인남성환자중림프절청소술을시행했던 13명중에 11명에서전이를보여상대적으로높은전이율을나타냈고, 이결과 는유두상갑상선미세암의경우확률은적지만측경부림프절이나종격동림프절전이등국소진행상태를보이거나, 원격전이가동반되는등원발종양의크기와상관없이공격적인형태로발현되는경우가있으므로, 유두상갑상선미세암에대해특히남성에대해서적극적인치료가필요하다는주장을뒷받침해준다. 또한조직검사상림프관침범과혈관침범이있는경우에유의하게림프절전이를보였으므로병리조직검사상림프관과혈관침범이있는경우에좀더적극적인치료를해야할것으로사료된다. 피막침범에영향을주는인자로는종양의크기, 다발성, 림프관침범, 혈관침범이있는데, 림프절전이에영향을주는인자로서의피막침범은의미가없는것으로나타났다. 그렇다고해서피막침범자체가예후인자로서의미가없다고는할수없으므로피막침범이있는경우에도적극적인치료가필요할것으로사료된다. 그리고예후인자로서의림프관침범은림프절전이와피막침범둘다의미가있으므로조직검사상림프관침범이있는경우좀더광범위한수술및림프절절제술, 술후방사성동위원소치료가필요할것이다. 유두상갑상선미세암에서의다발성은연구에따라 20 46% 로보고되고있으며그중약 40% 에서림프절전이를보이며,(8,12,23) 재발율도 8.6% 로단일유두상갑상선미세암의 1.2% 에비해높다.(18) 이러한다발성은우연히발견된경우보다수술전미세세침흡입검사상에서유두상갑상선미세암으로의심됐던환자들에서더높게나타나며, 양측성또한우연종에비해높게나타난다.(11,12,25) 본연구에서는다발성이있는환자의경우, 피막침범이의미있게높은결과를보여술전, 또는수술중다발성이의심된경우아전절제술이나전절제술이필요하리라생각된다. 종양의크기에따른임상양상의차이또한보고마다약간씩차이가있다. Mazzaferri 등은 1.5 cm를기준으로그이하의크기에서는종양의재발이없었으나그이상의크기에서는종양의크기와재발율이비례한다고보고하였고,(13) Pellegriti 등도 1 cm 이하의암에서는그이상인경우보다덜공격적인임상양상을보인다고하였다.(25) 일부연구들에서 1 cm 이하의유두상갑상선미세암에서는재발이나공격적성향이종양의크기와관계가없음을보고하였다.(11,12,15,19) 그러나이를좀더세분화하여시행한일부연구들에서 5 mm를기준으로했을때양군간에림프절전이나피막침범과같은임상양상의차이가없다고보고한논문들도있었던반면,(10) Kasai와 Sakamoto는 5 mm 이하군에비해이상군에서의미있게림프절전이가많음을보고하기도했다.(17) 일부연구에서는 8 mm를기준으로했을때 8 10 mm 사이의암이 8 mm 이하의암에비해진단당시림프절전이및원격전이가더많고, 추적관찰기
5 송대근외 : 유두상갑상선미세암의임상병리학적예후인자에관한후향적분석 83 간동안재발율이더많았다.(26) 이는본연구에서도 10 mm 이하종양을다시크기별로세분화하여피막침범여부와의관계를비교한결과에서종양의크기가 5 mm 이상인경우가그이하군에비해피막침범이의미있게많은결과를보여같은유두상갑상선미세암일지라도크기를세분화하여그에맞는적절한치료가필요하리라생각되어진다. 또한유두상갑상선미세암에서조직검사상동반질환이있는경우, 특히그레이브스병이있는경우종양의임상양상이더공격적이라고보고한논문이나하시모토갑상선염이동반된경우림프절전이가오히려적다는보고도있으나 (25) 본연구에서는동반질환의유무, 질환의종류등과림프절전이여부, 피막침범여부사이에유의한상관은없는것으로나타났다. 유두상갑상선미세암에서적절한수술범위에대해서는아직도논란이많다. 과거에는수술전세침흡인검사나수술중동결조직검사에서이미진단된경우라도아전절제술이나근전절제술만으로충분하며, 림프절청소술은필요없고, 수술후최종조직검사결과상갑상선암으로진단된경우단일종양으로갑상선내에국한되어있다면엽절제술만으로충분하며더이상의수술은필요치않다고보고한경우도있으나,(5,14,24,27) Hay 등의 Mayo clinic의 50년간연구결과에서는엽절제술만시행한군이근전절제술이나전절제술을시행한군에비해확연히높은재발율을보고하면서유두상갑상선미세암에서도엽절제술보다는근전절제술이나전절제술을시행해야한다고주장한다.(20) 림프절절제술의경우, 수술전이미림프절전이가의심된경우나, 림프절종대가보였던환자에게서의제거에대해서는대체적으로별다른이견이없으나, 그렇지않은환자군에서의예방적절제술에대해서는아직명확한결론이없다. Nobuyuki 등이 259명의환자를대상으로시행한림프절곽청술의결과림프절종대가있었던환자들에게서는림프절청소술이의미가있었으나, 예방적림프절절제술은수술후재발율이나예후에별다른영향을주지않았으며청소술을시행하지않은군과의비교에서도재발율에차이가없었다.(27) 본연구에서는 176명의환자중 106명의환자에서중심경부림프절청소술을시행하였으며그중 37 명에서양성소견을보여 34.9% 의전이율을보였다. 그러나추적관찰기간이짧으므로림프절청소술을시행한환자와비시행환자, 전이가있었던환자와없었던환자사이의재발율및예후의차이에대해서는좀더장기적인추적관찰이필요하리라생각된다. 술후 131 I 동위원소치료의필요성에대해서도아직은명확하지않다. Baudin이나최근의 Sawka 등은 131 I 동위원소치료가환자의재발에영향을끼치지않는다는결과를보고했고,(10) Mayo clinic의연구에서도수술후 131 I 동위원소치료에대해불필요함을주장하지만 (15) Chow 등은수술후 131 I 동위원소치료시행환자가비시행환자에비해재발이적 음을발표했다.(11) Roti 등은유두상갑상선미세암환자의대부분에게술후 131 I 동위원소치료를시행하였고약 1.7% 의재발율을보여부분갑상선절제술후 131 I 동위원소치료는시행하지않은다른여러연구들의재발율 ( %) 과별다른차이를보이지는않았으나그럼에도불구하고유두상갑상선미세암에서갑상선전절제, 또는근전절제술후 131 I 동위원소치료를시행하는것이가장안전한치료이며추적관찰에도용이함을주장하였다.(26) Pelizzo의연구에서도 131 I 동위원소치료시행환자가비시행환자에비해재발이적은결과를보고하면서갑상선전절제술을시행한환자의경우잘발견되지않는전이를진단하는데있어최소한전신 131 I 동위원소검사가진단적도구로써유용할수있음을들어반드시시행할것을주장하였다.(10) 본연구에서는갑상선전절제술을시행했던 121명의환자중최종조직검사상다발성을보이거나피막침범이있거나림프절전이가확인된환자에서술후 131 I 동위원소치료를시행하였다. 이는유두상갑상선미세암에서다발성, 피막침범, 림프절전이가있는경우측경부림프절전이및원격전이의위험성, 그리고재발의위험성이있을것이라는예상에기인하고있으며최근의연구결과에서연령에관계없이방사성요오드로잔여조직을제거한경우에재발률이현저하게감소하며특히 40세이상에서는사망률이현저하게감소한다는결과에기초한것이다. 결 급격한의료산업의발전으로특별한증상이없는일반인들에게서정기검진을통한갑상선내의결절의발견이증가되고이에대한세침흡인검사의정확도가높아짐에따라 1 cm 이하의미세갑상선종양에대한진단율과수술이최근급격하게증가되고있다. 특히유두상갑상선암의대부분을차지하는유두상갑상선미세암에서이종양의장기적인예후에영향을줄수있는공격적인성향을설명할수있는임상적, 조직학적특성이중요해졌다. 유두상갑상선미세암이진단된모든환자들에게과도하게공격적인치료를시도하는것은무리가있으나향후환자의예후에영향을주리라예상이되는요소들에대해서는적극적인치료가필요할것이다. 본연구에서는특히, 남성인경우와종양의크기가 5 mm 이상인경우, 다발성을가진경우에림프절전이나피막침범에영향을미치는것으로나타났으며, 조직학적으로림프선침범이나, 혈관침범등이확인된경우에도추후예후에영향을줄수있는요소가될것으로생각됐다. 따라서환자에게이런요소들이확인된경우좀더적극적인수술이필요할것으로보이며, 수술후방사선동위원소치료도좀더적극적으로고려해야할것으로생각된다. 그러나여러다른연구들과마찬가지로갑상선암의진행이매우느린데비해연구를위한추적관찰기간이 론
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