untitled

ISSN 1598-1703 (Print) / 2287-6782 (Online) Korean J Endocrine Surg 2012;12:252-257 ORIGINAL ARTICLE 갑상선유두미세암에서중심림프절전이를예측할수있는인자에관한분석 한림대학교의과대학외과학교실, 한림대학교성심병원유방내분비외과 안소은ㆍ김준호ㆍ이강율ㆍ임영아ㆍ이연옥ㆍ김해성ㆍ김이수 Predictive Factors of Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma So-Eun Ahn, Jun Ho Kim, Kang Yool Lee, Young-Ah Lim, Younok Lee, Hae Sung Kim and Lee Su Kim Division of Breast and Endocrine Surgery, Hallym University Sacred Heart Hospital, Department of Surgery, Hallym University College of Medicine, Anyang, Korea Purpose: Despite the excellent overall prognosis for patients with papillary thyroid microcarcinoma (PTMC), the rate of central lymph node (CLN) metastasis has been reported to be as great as 60% and the optimal surgical extent of PTMC has been controversial. The aim of this study is to identify factors for predict CLN metastasis in patients with PTMC. Methods: We conducted a retrospective study of 535 patients with PTMC who underwent total thyroidectomy with prophylactic CLN dissection between Jan. 2008 and Aug. 2011. We analyzed the association of CLN metastasis and clinicopathologic characteristics. Results: CLN metastasis was found in 181 patients (33.8%). Results of univariate analysis showed an association of younger than 45 years of age, male gender, a tumor size greater than 5 mm, bilaterality, multiplicity, extrathyroidal extension, and positivity of resection margin with CLN metastasis. Of these, results of multivariate analysis showed that age (P=0.003), gender (P=0.004), tumor size (P<0.001), extrathyroidal extension (P=0.001), and status of resection margin (P=0.002) were independent predictive factors for CLN metastasis. Conclusion: A large tumor size (>5 mm), male gender, young age (<45 yr), extrathyroidal extension, and positive resection margin were determined as the predictive factors for CLN metastasis, which occurred in approximately one third of patients with PTMC. Therefore, prophylactic CLN dissectionshould be considered in patients with PTMC who have these factors through investigation before surgery. Key Words: Papillary thyroid microcarcinoma, Lymph node metastasis, Central neck node dissection 중심단어 : 갑상선유두미세암, 림프절전이, 중심경부림프절절제술 서론갑상선유두암은전체갑상선암의 90% 이상을차지하며, 예후가매우양호한것으로알려져있다. 갑상선암의발생은수십년간급속도로증가하였고특히, 전체갑상선유두 암의 30 40% 정도를차지하는크기가 1 cm 이하인갑상선유두미세암 ( 이하, 미세암 ) 의경우, 점차그빈도가증가하고있는추세이다.(1) 일반적으로미세암은진행이느리고질병관련사망률이 1% 이하로매우양호한예후를보인다고알려져있다.(2-5) 그러나일부미세암의경우국소또는영역재발을일으키 Correspondence: Lee Su Kim Division of Breast and Endocrine Surgery, Hallym University Sacred Heart Hospital, 896, Pyeongchon-dong, Dongan-gu, Anyang 431-070, Korea Tel: +82-31-380-5930, Fax: +82-31-380-0208, E-mail: lskim0503@hallym.ac.kr Received September 19, 2012, Revised October 15, 2012, Accepted October 15, 2012 This article was presented at the 63rd Annual Congress of the Korean Surgical Society, November, 2011. Copyright 2012 Korean Association of Thyroid and Endocrine Surgeons; KATES. All Rights Reserved. cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://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. 252

안소은외 : 갑상선유두미세암에서중심림프절전이를예측할수있는인자에관한분석 253 기도하고심지어원격전이를일으켜삶의질을저하시키며사망에까지이르게하는공격적성향을갖기도한다.(2,6,7) 갑상선유두암에서갑상선전절제술과중심경부림프절절제술이일반적인일차치료로정립되어있지만, 미세암의적절한치료범위에대해서는보존적인치료가가능하다는의견에서부터육안적으로림프절전이가의심되지않아도예방적 (prophylactic) 림프절절제술까지시행해야된다는의견까지아직명확한치료범위가정해지지않아이에대해논란의여지가있다.(2,5,8,9) 하지만미세암에서 64% 에이르는림프절전이가보고된점을고려한다면,(10) 림프절절제여부는치료범위를결정하는데중요한요소로고려할필요가있다. 예방적림프절절제술을지양하는술자들은수술전, 혹은수술중검사로전이가확인된경우에만치료적으로중심경부혹은측경부림프절절제술을시행해야하고, 진행성병변 (T3 혹은 T4) 인경우에만예방적인중심경부림프절절제술을시행하도록권고했다.(11-14) 이는분화갑상선암환자중저위험군에서생존율에영향을미치지않는예방적중심경부림프절절제술은시행할필요가없으며, 불필요한광범위수술로인해유발될수있는합병증을최소화할수있다는것이다. 그러나예방적중심경부림프절절제술의장점은수술후정확한병기결정 (postoperative staging) 을할수있고, 이를토대로수술후방사성요오드치료용량결정및추적관찰이용이하다는것이다.(15) 또한중심경부림프절절제술은부갑상선기능저하나되돌이후두신경손상등의합병증이발생할가능성이증가할수있지만, 경험이많은외과의사에의해시행된다면합병증은거의없이안전하다는것이입증되었고,(16) 오히려재발후재수술로인한합병증가능성이높음이보고되었다.(11) 본저자들은갑상선유두미세암환자에게서중심경부림프절전이와관련된임상병리학적인자들을분석하여최적의치료를알아보고자하였다. 방법 2008년 1월부터 2011년 8월까지한림대학교성심병원에서갑상선암으로수술을받은환자 865명중갑상선유두미세암으로갑상선전절제술및양측중심경부림프절절제술을시행받은환자 535명을대상으로하였다. 이중 10명 (1.9%) 의환자는수술전영상의학적검사에서림프절전이가의심되어치료적림프절절제술을시행받았으며나머지 525명의환자는예방적림프절절제술을시행받았다. 최종조직검사상전형적인갑상선유두암외의다른조직학적아형은제외하였으며, 전절제술이하의수술을받았거나중심경부림프절절제술을시행하지않은경우도제 외하였다. 수술전세침흡인검사에서측경부림프절전이가진단되었거나또는초음파나컴퓨터단층촬영에서측경부림프절전이가의심되는경우에는수술중동결절검사를통한확진후변형근치적림프절절제술 (modified radical neck dissection) 을시행하였다. 대상군은중심경부림프절전이가진단된환자와림프절전이가없는환자로분류하여분석하였으며, 모든환자에있어성별, 나이, 종양의다발성 (multiplicity), 양측성 (bilaterality), 갑상선외침범 (extrathyroidal extension) 유무, 종양의크기, 위치, 측경부림프절전이유무와같은임상병리학적특징에대하여후향적연구를시행하였다. Table 1. Clinicopathologic characteristics of 535 patients with papillary thyroid microcarcinoma Parameter Total (n=535) CLNM- (n=354) CLNM+ (n=181) P value Age (yr) 48.5±10.5 49.6±10.0 46.3±11.0 <0.001 <45 204 (38.1%) 119 (33.6%) 85 (47.0%) 0.003 45 331 (61.9%) 235 (66.4%) 96 (53.0%) Gener Male 77 (14.4%) 40 (11.3%) 37 (20.4%) 0.004 Female 458 (85.6%) 314 (88.7%) 144 (79.6%) Size (mm) 6.3±2.2 6.1±2.2 6.9±2.3 <0.001 5 206 (38.5%) 155 (43.8%) 51 (28.2%) <0.001 >5 329 (61.5%) 199 (56.2%) 130 (71.8%) Bilaterality Negative 462 (86.4%) 317 (89.5%) 145 (80.1%) 0.003 Positive 73 (13.6%) 37 (10.5%) 36 (19.9%) Multiplicity Negative 410 (76.8%) 287 (81.1%) 123 (68.0%) 0.001 Positive 125 (23.4%) 67 (18.9%) 58 (32.0%) Retrieved LN 7.0±4.9 6.6±4.7 8.0±5.3 0.001 Extrathyroidal extension Negative 273 (51.2%) 199 (56.4%) 74 (41.1%) 0.001 Positive 260 (48.8%) 154 (43.6%) 106 (58.9%) Resection margin Negative 496 (94.3%) 336 (96.6%) 160 (89.9%) 0.002 Positive 30 (5.7%) 12 (3.4%) 18 (10.1%) p53 Negative 119 (23.2%) 83 (24.6%) 36 (20.6%) 0.311 Positive 394 (76.8%) 255 (75.4%) 139 (79.4%) Ki-67 index Low 498 (96.7%) 330 (97.1%) 168 (96.0%) 0.524 High 17 (3.3%) 10 (2.9%) 7 (4.0%) BRAF mutation Negative 115 (50.2%) 81 (52.9%) 34 (44.7%) 0.242 Positive 114 (49.8%) 72 (47.1%) 42 (55.3%) Lateral LN metastasis Negative 508 (95.0%) 348 (98.3%) 160 (88.4%) <0.001 Positive 27 (5.0%) 6 (1.7%) 21 (11.6%) CLNM = central lymph node metastasis.

254 대한내분비외과학회지 : 제 12 권제 4 호 2012 통계학적분석은 SPSS version 17.0 (SPSS Inc. Chicago, Illinois, USA) 을사용하였으며양군간의임상병리학적특성에대한비교분석은 Chi-square test을통하여단변량분석을시행하였고, 이를바탕으로로지스틱회귀분석 (logistic regression analysis) 을통해다변량분석을시행하여림프절전이와연관된인자를찾고자하였다. P<0.05인경우를통계학적으로의미있는것으로해석하였다. 결과갑상선유두미세암환자 535명중여자는 458명 (85.6%), 남자는 77명 (14.4%) 이었고평균나이는 48.5±10.5세 ( 범위 22 77) 였다. 종양의평균개수는 1.3개였으며평균크기는 6.3±2.2 mm이었다. 종양의다발성은 125명 (23.4%) 에서있었고, 양측성은 73명 (13.6%) 에서관찰되었다. 중심경부림프절전이가있는환자는 181명 (33.8%) 이었으며, 평균전이림프절개수는 3.9±2.5개 ( 범위 1 10) 였다. 측경부림프절전이가진단되어변형근치적림프절절제술을시행한환자는총 27명 (5%) 이었다. 갑상선외침범소견을보인환자는모두 260명 (48.8%) 이었으며 30명의환자에서는절제연양성소견을보였다. BRAF 돌연변이분석이가능했던 299명의환자중 BRAF 돌연변이양성은 114명으로약 49.8% 를차지하였다 (Table 1). 갑상선유두미세암의중심경부림프절전이의위험인자에대한단변량분석에서나이가 45세미만환자의경우 41.7% 에서림프절전이를보인반면, 45세이상에서는 29% 만이림프절전이를보였다 (P=0.003). 남성의경우여성에비해림프절전이율이높았으며 (48.1% vs. 31.4%, P=0.004), 종양의크기가 5 mm를초과한군에서역시림프절전이율이높았다 (24.8% vs. 39.5%, P<0.001). 또한양측성 (P=0.003) 및다발성병변 (P=0.001), 종양의갑상선외침범 (P=0.001), 절제연양성 (P=0.002) 등이림프절전이와연관이있었다 (Table 2). p53 발현, Ki-67 labeling index, BRAF 변이는두군간에큰차이를보이지는않았다. 이를토대로다변량분석을시행하였으며남성 ( 비교위험도, 2.300; P=0.002), 45세미만의나이 ( 비교위험도, 1.654; P=0.011), 5 mm 이상의종양크기 ( 비교위험도, 1.75; P=0.007), 갑상선외침범 ( 비교위험도, 1.585; P=0.022) 및절제연양성 ( 비교위험도, 2.573; P=0.023) 등이중심경부림프절전이의독립적인위험인자로나타났다 (Table 2). 고찰갑상선유두미세암은비교적좋은예후에도불구하고약 8% 에서재발을일으키는것으로알려져있다.(17) 일반적으로예방적중심경부림프절절제술이갑상선유두암의예후에미치는영향은거의없는것으로알려져있으나일부보고에서는경부림프절전이여부가국소또는영역재발및전신전이와관련된중요한위험인자라고하였다.(17,18) 미세암에서중심경부림프절및측경부림프절전이율은각각 20 60% 와 3 30% 정도로보고되며,(10,19) 본연구에서도이와유사한림프절전이율을확인할수가있었다. 또한측경부림프절전이를보인 27명의환자중 6명의환자는 (22.2%) 중심경부림프절전이없이바로측경부림프절전이를보인도약림프절전이 (skip metastasis) 를보였다. 미세암에서예방적인중심경부림프절절제술시행여부에대해서는많은논란이있다. 일반적으로예방적중심경부림프절절제술이예후에미치는영향이미비하고림프절절제술에따른합병증의증가등을이유로임상적으로림프절전이가확인된경우에서만치료적림프절절제술을권고하고있다.(10,20) 그러나많은수의미세암환자에서수술전검사를통해림프절전이를확인하는것이어렵고,(20,21) 이렇게임상적으로림프절전이가없는환자의 30 50% 가수술후최종조직검사에서림프절전이가진단되는것으로보고되고있다.(10,22,23) 본저자들의경우에서도수술전초음파검사상중심경부림프절전이가의심되었던환자는단지 10명 (1.9%) 에불과하였다. 또한예방적 Table 2. Univariate and multivariate logistic regression for central CLN metastasis Independent variable Univariate Multivariate OR (95% CI) P value OR (95% CI) P value Age ( 45 vs. <45 yr) 1.749 (1.213 2.521) 0.003 1.654 (1.121 2.441) 0.011 Gender (female vs. male) 2.017 (1.237 3.288) 0.004 2.300 (1.375 3.846) 0.002 Size ( 5 vs. >5 mm) 1.985 (1.350 2.921) <0.001 1.752 (1.163 2.640) 0.007 Bilaterality (negative vs. positive) 2.127 (1.291 3.504) 0.003 1.415 (0.698 2.871) 0.336 Multiplicity (negative vs. positive) 2.020 (1.340 3.044) 0.001 1.638 (0.912 2.941) 0.099 ETE (negative vs. positive) 1.851 (1.286 2.633) 0.001 1.585 (1.067 2.353) 0.022 RM (negative vs. positive) 3.150 (1.482 6.697) 0.002 2.573 (1.141 5.802) 0.023 ETE = extrathyroidal extension; RM = resection margin.

안소은외 : 갑상선유두미세암에서중심림프절전이를예측할수있는인자에관한분석 255 중심경부림프절절제술의장점은수술후정확한병기결정 (postoperative staging) 을할수있고, 이를토대로수술후방사성요오드치료용량결정등에도움이된다는것이다.(15) 특히경험이많은외과의에의해시행된다면예방적중심경부림프절절제술로인한합병증은거의없으며, 안전하다는것이보고되었다.(16) 따라서미세암에서중심경부림프절전이를예측할수있는임상병리학적특징들에대한분석이수술의범위를결정하는데있어서도움이될것으로생각된다. 지금까지미세암에있어서중심경부림프절전이를예측할수있는인자들에대한많은연구들이있어왔지만, 연구자에따라조금씩다른결과들을보여주고있다. 본연구의경우타연구에비해비교적많은수의환자수를포함하고있으며모든환자에게서갑상선전절제술및양측중심경부림프절절제술을시행했기에보다정확한림프절전이율및관련인자에대한분석이가능하였다. 2008년부터 2011년까지갑상선암으로수술받은총 865명의환자중미세암은 535명으로 61.4% 를차지하였다. 이는기존의다른보고들보다는다소높은빈도로서저자들의경우타논문들에비해비교적최근의자료를가지고연구한결과로생각되며최근갑상선유두미세암의발생이증가하고있는경향을확인할수있는결과이다.(24,25) 본연구에서는 45세미만의젊은환자, 남성, 5 mm 초과의종양크기, 갑상선외침범및절제연양성은미세암에서중심경부림프절전이의독립적인예측인자임을확인할수있었다. 종양의다발성과양측성, BRAF 돌연변이를포함한여러면역화학염색결과들은중심경부림프절전이를예측할수있는인자는아니었다. 환자의나이는갑상선유두암에서이미잘알려진예후인자이지만, 미세암에서의예후인자적가치는확실하지않다.(10,18,19,26) So 등 (26) 은 45세미만의미세암환자에게서 45세이상의환자보다다소높은림프절전이율을보였지만통계학적인의의는없다고보고하였다. 그러나본연구에서는다변량분석결과 45세미만에서는 41.7% 가림프절전이를보인반면 45세이상에서는 29% 만이림프절전이를보였다 (P=0.001). Zhang 등 (24) 도 1,066명의미세암환자를분석한결과 45세미만의젊은나이가경부림프절전이의예측인자임을확인하였다. 본연구에서는남성의경우높은림프절전이율을보인반면, Roh 등 (23) 은성별과림프절전이와관계가없다고보고하기도하였다. 하지만기존의많은연구에서성별에따른림프절전이의차이를보고하고있다.(24,26) 일반적으로갑상선유두암에서경부림프절전이는종양의크기에따라증가하는것으로알려져있다. Lim 등 (22) 은종양의크기가 5 mm을초과하는경우림프절전이율이증가한다고보고하였고본연구에서도같은결과를보여주었다. 많은미세암에대한연구에서 5 mm를기준으로림프절 전이율에대한분석을시도하였으나, Zhang 등 (24) 은다변량분석결과 6 mm를기준으로하였을때보다정확한림프절전이율의차이를발견할수있다고보고하기도하였다. 다발성병변은갑상선유두암에서중심경부림프절전이의위험인자로알려져있다.(2,24) 특히 Chow 등 (2) 은다발성병변이경부림프절전이와관련되어있을뿐아니라다발성병변이존재할경우경부림프절의재발이 5.6배증가한다고하였다. 그러나본연구에서는 535명의환자중다발성병변을보인환자는 125명 (23.4%) 이었으며, 중심경부림프절전이의독립적인예측인자는아니었고, 또한종양의양측성여부도마찬가지결과를보였다. 갑상선외침범은갑상선유두암에서중요한예후인자이다. 본연구에서는총 260명 (48.8%) 의환자에게서갑상선외침범소견을보였으며이환자에게서높은림프절전이율을보였다. 저자들은림프절전이와 BRAF 돌연변이, p53 발현등과의관계에대해서연구하였다. 기존의보고에따르면갑상선유두암환자의약 45% 에서 BRAF 돌연변이가발견되고이는나쁜예후인자로알려져있다.(27) 미세암에서도 BRAF 돌연변이는갑상선외침범, 경부림프절전이, 높은 TNM 병기와관련되어있다는보고가있다.(28) 하지만본연구에서는 BRAF 돌연변이에대한분석이가능했던 229명의환자중 BRAF 돌연변이를보였던경우는 114명 (49.8%) 이었으며, BRAF 음성인환자에비해다소높은림프절전이율을보였으나통계학적인의의는발견하지못하였다 (36.8% vs. 29.6%, P=0.242). 또한일부연구에서는 p53 발현이갑상선유두암에서림프절전이와관련이있다는보고가있었으나,(29) 저자들의경우 p53 발현을보인 394명 (76.8%) 의환자에서경부림프절전이와의관련성을발견할수는없었다. 본연구에서는수술후추적기간이길지않아갑상선유두미세암의림프절전이와예후와의관계에대해서는알수없었으나, 임상적으로중심경부림프절전이가없었던환자의많은수에서수술후림프절전이를확인할수가있었고, 기존에잘알려져있었던갑상선유두암의예후인자들과림프절전이는밀접한관련이있음을확인하였다. 따라서보다많은수의환자와장기간의추적관찰을통해갑상선유두미세암에서중심경부림프절전이가가지는의의에대해정확한정보를얻을수있을것으로생각한다. 비록저자들은양측중심경부림프절절제술에따른합병증에대한분석을하지는못하였지만갑상선유두미세암의치료에있어서 45세미만, 남성, 종양의크기가 5 mm 이상, 갑상선외침범등의소견이보이는경우임상적으로림프절전이소견이없다하더라도적극적인중심경부림프절절제술을고려해야된다고생각한다.

256 대한내분비외과학회지 : 제 12 권제 4 호 2012 결 갑상선유두미세암에서예방적중심경부림프절절제술에대해서는논란이많다. 저자들은양측중심경부림프절절제술을시행한비교적많은수의미세암환자에게서수술전검사에서는발견하지못했던림프절전이를확인할수가있었고, 특히 45세미만의젊은나이, 남성, 0.5 cm 이상의종양크기, 종양의갑상선외침범등의소견이보일경우높은중심경부림프절전이율를확인할수가있었다. 따라서미세암의중심경부림프절절제술의결정에있어서이러한임상병리학적소견들을고려할것을권고하는바이다. 론 REFERENCES 1) Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al; American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29. 2) Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer 2003;98:31-40. 3) Bramley MD, Harrison BJ. Papillary microcarcinoma of the thyroid gland. Br J Surg 1996;83:1674-83. 4) Franssila KO, Harach HR. Occult papillary carcinoma of the thyroid in children and young adults. A systemic autopsy study in Finland. Cancer 1986;58:715-9. 5) Orsenigo E, Beretta E, Fiacco E, Scaltrini F, Veronesi P, Invernizzi L, et al. Management of papillary microcarcinoma of the thyroid gland. Eur J Surg Oncol 2004;30:1104-6. 6) Cappelli C, Castellano M, Braga M, Gandossi E, Pirola I, De Martino E, et al. Aggressiveness and outcome of papillary thyroid carcinoma (PTC) versus microcarcinoma (PMC): a mono-institutional experience. J Surg Oncol 2007;95:555-60. 7) Liou MJ, Lin JD, Chung MH, Liau CT, Hsueh C. Renal metastasis from papillary thyroid microcarcinoma. Acta Otolaryngol 2005;125:438-42. 8) Arora N, Turbendian HK, Kato MA, Moo TA, Zarnegar R, Fahey TJ 3rd. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 2009;19:473-7. 9) Mercante G, Frasoldati A, Pedroni C, Formisano D, Renna L, Piana S, et al. Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid 2009;19:707-16. 10) Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237:399-407. 11) White ML, Gauger PG, Doherty GM. Central lymph node dissection in differentiated thyroid cancer. World J Surg 2007; 31:895-904. 12) Wang TS, Dubner S, Sznyter LA, Heller KS. Incidence of metastatic well-differentiated thyroid cancer in cervical lymph nodes. Arch Otolaryngol Head Neck Surg 2004;130:110-3. 13) Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node dissection for papillary microcarcinoma of the thyroid. World J Surg 2004;28:498-501. 14) Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber RS. Patterns of lateral neck metastasis in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 2004;130:857-60. 15) Mazzaferri EL, Doherty GM, Steward DL. The pros and cons of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma. Thyroid 2009;19:683-9. 16) Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320-30. 17) Hay ID, Hutchinson ME, Gonzalez-Losada T, McIver B, Reinalda ME, Grant CS, et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 2008;144:980-7. 18) Pisanu A, Reccia I, Nardello O, Uccheddu A. Risk factors for nodal metastasis and recurrence among patients with papillary thyroid microcarcinoma: differences in clinical relevance between nonincidental and incidental tumors. World J Surg 2009;33:460-8. 19) Kwak JY, Kim EK, Kim MJ, Son EJ, Chung WY, Park CS, et al. Papillary microcarcinoma of the thyroid: predicting factors of lateral neck node metastasis. Ann Surg Oncol 2009;16: 1348-55. 20) Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Clinical significance of metastasis to the central compartment from papillary microcarcinoma of the thyroid. World J Surg 2006;30:91-9. 21) Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro BS, Sherman SI, Vassilopoulou-Sellin R, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 2003;134:946-54. 22) Lim YC, Choi EC, Yoon YH, Kim EH, Koo BS. Central lymph node metastases in unilateral papillary thyroid microcarcinoma. Br J Surg 2009;96:253-7. 23) Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol 2008;15: 2482-6. 24) Zhang L, Wei WJ, Ji QH, Zhu YX, Wang ZY, Wang Y, et

안소은외 : 갑상선유두미세암에서중심림프절전이를예측할수있는인자에관한분석 257 al. Risk factors for neck nodal metastasis in papillary thyroid microcarcinoma: a study of 1066 patients. J Clin Endocrinol Metab 2012;97:1250-7. 25) Cho JK, Kim JY, Jeong CY, Jung EJ, Park ST, Jeong SH, et al. Clinical features and prognostic factors in papillary thyroid microcarcinoma depends on age. J Korean Surg Soc 2012;82:281-7. 26) So YK, Son YI, Hong SD, Seo MY, Baek CH, Jeong HS, et al. Subclinical lymph node metastasis in papillary thyroid microcarcinoma: a study of 551 resections. Surgery 2010;148: 526-31. 27) Xing M. Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 2010;321:86-93. 28) Lee X, Gao M, Ji Y, Yu Y, Feng Y, Li Y, et al. Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann Surg Oncol 2009; 16:240-5. 29) Morita N, Ikeda Y, Takami H. Clinical significance of p53 protein expression in papillary thyroid carcinoma. World J Surg 2008;32:2617-22.