ORIGINAL ARTICLE pissn: 2384-3799 eissn: 2466-1899 Int J Thyroidol 2017 November 10(2): 82-88 https://doi.org/10.11106/ijt.2017.10.2.82 설문지조사를이용한시대별갑상선암의진단동기및환경적위험인자의변화 서울대학교의과대학내과 1, 국립암센터갑상선암센터 2, 서울특별시보라매병원내과 3, 국립보건연구원 4 김하나 1 *, 황보율 2 *, 공성혜 1, 송영신 1, 김민주 1, 조선욱 1, 이유진 2, 이가희 3, 박도준 1,4, 이은경 2, 박영주 1 Secular Trends for Diagnostic Motives and Environmental Risk Factors in Thyroid Cancer Using Questionnaire Survey Hana Kim 1 *, Yul Hwangbo 2 *, Sung Hye Kong 1, Young Shin Song 1, Min Joo Kim 1, Sun Wook Cho 1, You Jin Lee 2, Ka Hee Yi 3, Do Joon Park 1,4, Eun Kyung Lee 2 and Young Joo Park 1 Department of Internal Medicine, Seoul National University College of Medicine 1, Seoul, Center for Thyroid Cancer, National Cancer Center 2, Goyang, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center 3, Seoul, Korea National Institute of Health 4, Cheongju, Korea Background and Objectives: We analyzed the clinicopathologic differences of thyroid cancer by diagnosis periods, diagnostic motives, residence history and clinical risk factors in thyroid cancer patients. Materials and Methods: Total 1599 thyroid cancer patients who answered the questionnaires about family history of thyroid cancer, residence history including duration of residence and location were enrolled from two hospitals, Seoul National University Hospital and National Cancer Center in Korea. Demographics and environmental information were collected via questionnaires and clinical data were reviewed via electronic medical records. Results: More thyroid cancer has been diagnosed in 2011 to 2013 by screening test without specific symptom than before 1990. The size of cancer at diagnosis was significantly smaller and multifocal tumor was more frequently found in 2011 to 2013 than before 1990 as well. The tumors of obese or overweight patients tended to harbor extrathyroidal extension and lymph node metastasis than normal weight subjects with statistical significance. However, there were no differences in clinicopathologic characteristics according to residence and smoking history. Conclusion: In this study, there were some different clinicopathologic characteristics according to the diagnosis era, diagnostic motives, family history of thyroid cancer and body mass index. Key Words: Thyroid cancer, Thyroid cancer screening, Environmental factor, Questionnaire 서론 갑상선암은내분비계의악성종양중가장흔하고, 주로유두암및여포암이대부분을차지하며여성에서남성에비해약 3-4배호발한다. 2014년국가암발생 통계자료에따르면여성및전인구대상암발생률및유병률에서 1위를차지하는암으로 1) 전세계적으로도갑상선암의발생률은꾸준히증가하고있다. 2-5) 갑상선암자체의발생증가위험에대해방사선조사및방사성요오드노출력, 식이요오드섭취의과잉및부족, 가족력등이보고되었으나, 그외환경적, 유 Received November 13, 2017 / Revised November 14, 2017 / Accepted November 15, 2017 Correspondence: Eun Kyung Lee, MD, PhD, Center for Thyroid Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: 82-31-920-1743, Fax: 82-31-920-2798, E-mail: waterfol@ncc.re.kr *These two authors equally contributed to this article. Copyright c 2017, 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 (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 82
Trends for Environmental Risk Factors in Thyroid Cancer 전적위험인자는명확하게밝혀진바가없다. 그간의연구들에따르면환경적요인으로비만, 서구화된식습관및환경호르몬등이갑상선암의발생과관계가있을것으로생각되고있다. 2,6) 최근에갑상선암의급격한증가는주로고해상도초음파검사의보급에의한것으로여겨지나, 시대변화에따라검진으로진단된환자의비율및환경적유전적요인에대한신뢰할수있는자료는부족한상태이다. 이에본연구에서는국내두기관 ( 서울대학교병원과국립암센터 ) 에서갑상선암진단후추적관찰중인환자들을대상으로시대별로임상병리학적소견과진단동기, 유전, 환경적요인을조사하여우리나라의갑상선암의위험요인을규명하고자하였다. 대상및방법 연구대상및방법본연구는 2011년 1월 1일부터 2014년 12월 31일사이에갑상선암으로치료후추적검사를위해서울대학교병원과국립암센터외래에방문한모든환자들을대상으로하였다. 이중갑상선암의유전적, 환경적요인에대한설문조사에동의하여설문지를작성한환자 1599 명을대상으로분석하였다. 설문내용은연구대상자의 갑상선암의진단동기를조사하였고, 갑상선질환과관련된환경적요인을확인하고자현재와과거거주지역, 해안가거주의경험및기간, 갑상선질환 ( 기능이상및결절, 암 ) 의가족력및과거력, 흡연력을설문하였다. 아울러의무기록조사를통해체중, 키를포함한신체계측및진단받은갑상선암의종류및림프절전이여부와피막외침윤및수술방법에대한정보를수집하였다. 본연구는후향적연구로상기정보수집후각각의요인에대해임상병리학적차이를분석하였다. 통계분석연구대상자들에대해진단시기, 진단동기, 거주지에따른갑상선암의임상, 병리학적차이와흡연력및비만도에따른갑상선암의유병률의차이를비교하였다. 집단간차이의분석을위해연속변수에대해서는 Student t-test와 ANOVA, 범주형변수에대해서는 chisquare test를사용하여분석하였다. 통계분석은 SPSS software 19.0 (SPSS Inc., Chicago, IL, USA) 를사용하였으며, 유의수준 0.05 미만을통계적으로유의한것으로판단하였다. 결과 갑상선암환자들의인구사회학적특성을진단시기 Table 1. Characteristics of subjects by diagnosis period Diagnosis period -1990 1991-2000 2001-2005 2006-2010 2011-2013 p n 54 162 160 244 594 Age (mean±sd) 34.7±10.9 40.4±11.1 44.4±12.3 47.0±12.0 48.1±11.1 <0.001 Female, n (%) 52 (96.3%) 145 (89.5%) 139 (86.9%) 203 (83.2%) 470 (79.1%) <0.001 BMI (kg/m 2 ) 21.4±2.8 22.8±3.3 22.5±2.7 22.9±3.2 24.2±4.0 <0.001 Ever smoker, n (%) 1 (1.9%) 15 (9.3%) 16 (10%) 36 (14.8%) 106 (17.8%) <0.001 Coastal residence, n (%) 35 (66%) 54 (34.1%) 47 (29.9%) 67 (30.0%) 120 (21.9%) 0.010 Family history of thyroid 7 (13.0%) 31 (19.1%) 45 (28.1%) 113 (46.3%) 102 (17.2%) 0.479 cancer, n (%) Operation (LT/TT), n (%) 13 (29.5%)/ 31 (70.5%) 23 (15.2%)/ 128 (84.8%) 5 (3.5%)/ 138 (96.5%) 5 (2.2%)/ 224 (97.8%) 89 (15.4%)/ 489 (84.6%) 0.933 Histology (PTC/FTC/others*), n (%) 49 (96.1%)/ 2 (3.4%)/ 0 (0.0%) 155 (96.3%)/ 5 (3.1%)/ 1 (0.6%) 144 (90.0%)/ 12 (7.5%)/ 4 (2.5%) 203 (83.9%)/ 31 (12.8%)/ 8 (3.3%) 567 (97.6%)/ 9 (1.5%)/ 5 (0.9%) Tumor size (mm) 22.9±11.3 20.7±13.2 20.1±13.3 14.0±12.9 9.4±7.7 <0.001 Multifocality, n (%) 8 (14.3%) 39 (29.8%) 38 (27.0%) 95 (44.2%) 210 (37.1%) 0.006 Extrathyroidal extension, 12 (48.0%) 82 (63.6%) 91 (61.9%) 131 (58.0%) 328 (58.2%) 0.501 n (%) LN metastasis, n (%) 0 (0.0%) 7 (10%) 28 (31.5%) 76 (37.1%) 232 (41.7%) <0.001 BMI: body mass index, FTC: follicular thyroid cancer, LN: lymph node, LT: lobectomy, PTC: papillary thyroid cancer, SD: standard deviation, TT: total thyroidectomy *Others included medullary thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer. 0.183 83 Int J Thyroidol
Hana Kim, et al 에따라비교하였다 (Table 1). 환자들의진단시기는 1960년부터 2013년까지였고 1990년이전, 1991-2000년, 2001-2005년, 2006-2010년, 2011년이후진단받은환자들이각각 54, 162, 160, 244, 594명이었다. 진단당시평균연령이시대별로통계적으로유의한차이를보여서, 1990년이전에는 34.7세, 1991-2000년대는 40.4세, 2001-2005년에는 44.4세, 2011-2013년에는 48.1세로근래까지꾸준히상승하는추세를보였다 (p<0.001). 또한전반적으로는여성환자의비율이높았으나, 시간에따라상대적으로남성의비가유의하게상승하여 1990년이전에는 3.7% 이었던것이 2011-2013년에는 20.9% (224명) 에달하였다 (p<0.001). 비만도및흡연자의비율은과거에비해꾸준히상승하여통계적으로유의하였고, 1990년이전에진단된환자들이상대적으로해안지역에사는비율이많은것으로조사되었다. 반면갑상선암의가족력은 2010년이전까지는꾸준히증가하다가그이후에는더이상증가하지는않았다. 병리학적소견을진단시기에따라비교하면, 진단시기에관계없이갑상선유두암이가장많은비율을차지하였고 (83.9-97.6%) 근래로올수록진단당시갑상선암의크기가유의하게작았다 (1990년이전 : 평균 22.9 mm, 2011-2013년 : 평균 9.4 mm). 그러나병리기록으로확인된다발성종양의비율은증가하였고림프절전이의비율도 2001년이후로증가하였다. 진단동기를살펴보면근래로올수록남성과여성모두갑상선암의선별검사로진단되는비율이급격히상승하였으며, 과거에많던만져지는결절로인한진단은반대로감소하고있었다 (Fig. 1). 진단동기별임상, 병리학적차이를보면선별검사 (screening) 로진단되는경우가가장많았다 (Table 2). 그다음진단동기로 Fig. 1. Difference in diagnosis motivation according to periods. Table 2. Clinicopathological characteristics according to diagnosis motive Palpable nodule Screening Incidentaloma Concern for cancer Nonspecific symptoms p n 377 614 78 49 42 Age (mean±sd) 40.9±12.7 47.4±10.6 50.2±12.0 47.1±9.0 45.0±13.4 <0.001 Female, n (%) 323 (84.6%) 506 (82.4%) 56 (71.8%) 44 (89.8%) 89 (90.5%) 0.835 PTC, n (%) 326 (88.8%) 585 (96.5%) 73 (93.6%) 47 (95.9%) 39 (92.9%) 0.146 Tumor size (mm) 21.7±15.2 9.8±7.6 12.2±8.9 11.7±6.8 10.0±7.0 <0.001 Multifocality, n (%) 101 (33.9%) 211 (36.8%) 25 (35.7%) 22 (47.8%) 8 (21.1%) 0.993 Extrathyroidal extension, n (%) 186 (61.0%) 342 (58.7%) 39 (53.4%) 27 (61.4%) 24 (64.9%) 0.922 LN metastasis, n (%) 72 (32.3%) 196 (36.7%) 25 (41.0%) 20 (50%) 15 (40.5%) 0.042 LN: lymph node, PTC: papillary thyroid cancer, SD: standard deviation Vol. 10, No. 2, 2017 84
Trends for Environmental Risk Factors in Thyroid Cancer 는만져지는결절 (palpable nodule), 다른질병의진단과정에서우연히발견 (incidentaloma), 암에대한염려 (concern for cancer) 로시행한검사에서발견, 비특이적증상 ( 만성피로, 체중감소등 ) 으로검사중발견되는순이었다. 선별검사로진단된환자들의경우진단시종양의크기는 9.8 mm로작았으며 (p<0.001), 림프절전이가발견된환자들이 36.7% (196명) 로, 다른동기로진단된환자군보다적었다 (p=0.042). 이는갑상선유두암환자들만을대상으로시행한하위그룹분석에서도유사한결과를확인하였으며갑상선여포암은대상자가 54명으로진단수가적어유의한결과를확인할수없었다 (data not shown). 갑상선질환과관련된환경적요인 ( 거주지, 가족력, 흡연, 비만 ) 에따른임상병리학적소견을분석하였다. 해안지역이요오드섭취량이높은것으로알려져있어해안지역과내륙지역을비교하였는데, 해안지역에서 10년미만거주한환자들의경우유의하게진단시연령이낮았던것을제외하고는 ( 평균 40세, p=0.004) 거주지별갑상선암의임상병리학적양상의차이를확인할수없었다 (Table 3). 갑상선암의가족력에따라서는, 가족력이있는환자들이유의하게갑상선유두암의비 율이많았고 (96.6% vs. 92.5%, p=0.006), 종양의크기가작았으며 (11.8 mm vs. 14.1 mm, p=0.014), 다발성종양의비율이높았다 (46.0% vs. 32.6%, p<0.001) (Table 4). 흡연의영향을비교하고자남성과여성을나누어분석하였으나흡연자와비흡연자간에갑상선암의임상, 병리학적차이는보이지않았다 (Table 5). 비만도에따라정상, 과체중, 비만군으로나누어분석한결과비만도의상승에따라갑상선암의피막외침윤및림프절전이의비율이유의하게상승하는결과를볼수있었다 (Table 6). 고찰 우리나라의갑상선암진단의시대별차이및환경적위험인자를조사한이번연구에서갑상선암이과거에비해선별검사를통해진단되는경우가많음을알수있었고, 그에따라진단당시의갑상선암의종양크기가통계적으로유의하게작아졌다. 이것은고해상도초음파의발달로인한미세갑상선암의진단율이높아진것의결과로생각된다. 7) 그러나림프절전이의비율은높아졌는데이는보다적극적인림프절절제술의 Table 3. Clinicopathological characteristics according to residence Inland Less than 10 years Costal 10 and more years p n 835 46 260 Age (mean±sd) 45.5±12.2 40.0±11.6 46.3±11.1 0.004 Female, n (%) 687 (82.3%) 35 (76.1%) 228 (87.7%) 0.062 PTC, n (%) 773 (94.4%) 39 (84.8%) 239 (92.6%) 0.379 Size (mm) 13.6±12.0 17.5±13.0 13.5±11.3 0.094 Multifocality, n (%) 263 (35.2%) 18 (43.9%) 79 (36.2%) 0.673 ETE, n (%) 485 (60.6%) 20 (47.6%) 130 (57.8%) 0.342 LN metastasis, n (%) 250 (77.6%) 17 (47.2%) 55 (32.4%) 0.317 ETE: extrathyroidal extension, LN: lymph node, PTC: papillary thyroid cancer, SD: standard deviation Table 4. Clinicopathological characteristics according to family history of thyroid cancer Family history ( ) Family history (+) p n 916 298 Age (mean±sd) 45.7±12.01 45.9±11.6 0.869 Female, n (%) 752 (82.1%) 257 (86.2%) 0.109 PTC, n (%) 832 (92.5%) 286 (96.6%) 0.006 Size (mm) 14.1±12.2 11.8±9.9 0.014 Multifocality, n (%) 265 (32.6%) 120 (46.0%) <0.001 ETE, n (%) 491 (76.2%) 153 (23.8%) 0.354 LN metastasis, n (%) 262 (37.1%) 81 (35.2%) 0.637 ETE: extrathyroidal extension, LN: lymph node, PTC: papillary thyroid cancer, SD: standard deviation 85 Int J Thyroidol
Hana Kim, et al Table 5. Clinicopathological characteristics according to smoking status Never smoker Ever smoker p A. Men n 72 133 Age (mean±sd) 45.4±14.0 48.3±10.8 0.095 PTC, n (%) 67 (93.1%) 112 (87.5%) 0.128 Size (mm) 15.4±13.0 14.4±14.3 0.610 Multifocality, n (%) 21 (30.9%) 39 (38.2%) 0.871 ETE, n (%) 40 (64.5%) 70 (59.3%) 0.524 LN metastasis, n (%) 29 (51.8%) 57 (52.3%) 1.000 B. Women n 968 41 Age (mean±sd) 45.7±11.9 39.5±9.3 0.001 PTC, n (%) 901 (94.4%) 38 (92.7%) 1.000 Size (mm) 13.4±11.2 10.3±10.6 0.094 Multifocality, n (%) 310 (36.4%) 15 (41.7%) 0.597 ETE, n (%) 515 (59.0%) 19 (50.0%) 0.313 LN metastasis, n (%) 246 (33.3%) 11 (33.3%) 1.000 ETE: extrathyroidal extension, LN: lymph node, PTC: papillary thyroid cancer, SD: standard deviation Table 6. Clinicopathological characteristics according to body mass index BMI (kg/m 2 ) BMI <23 23 BMI <25 BMI 25 p n 551 235 317 Age (mean±sd) 42.4±11.8 48.2±10.6 48.8±11.2 <0.001 Female, n (%) 505 (91.7%) 185 (78.7%) 227 (71.6%) <0.001 PTC, n (%) 507 (93.4%) 218 (94.0%) 290 (93.5%) 0.892 Size (mm) 14.4±12.1 12.4±10.3 13.8±12.6 0.127 Multifocality, n (%) 159 (33.8%) 80 (37.6%) 111 (38.3%) 0.189 ETE, n (%) 277 (56.2%) 129 (60.3%) 183 (64.0%) 0.032 LN metastasis, n (%) 134 (33.6%) 68 (36.0%) 111 (42.9%) 0.019 BMI: body mass index, ETE: extrathyroidal extension, LN: lymph node, PTC: papillary thyroid cancer, SD: standard deviation 빈도가높아진것과병리판독에서림프절전이에대한기술이보다자세해진데에기인한것으로생각된다. 또한 2000년도중반이후로다발성갑상선암의빈도가증가하였고이역시과거보다정밀해진병리판독의영향으로판단된다. 진단연령은점차증가하는추세로과거에는비교적젊은나이에경부에종양이만져져서진단되는경우가많았으나최근에는비교적나이가많은환자들이만져지지않는종양을검진하여진단된경우가많아졌기때문으로여겨진다. 이는최근여성보다건강검진을많이받는남성에서갑상선암의발병률이증가하는것과진단된갑상선암의크기가작아지는것과같은맥락으로이해할수있다. 거주지별분석을통해갑상선암의발생과방사선조사력, 식이요오드섭취등의지역적차이가연관될가능성을고려하였으나, 해안 / 내륙지방거주자사이에 갑상선암의임상상및병리학적차이는확인되지않았다. 최근의메타분석연구와이전의연구들에서요오드섭취량의결핍혹은과잉이갑상선암의위험인자라는결과들은많이제시되어왔었고, 만성적인요오드결핍은갑상선종대와갑상선여포함의발생위험을높이고, 8-11) 또한요오드의과잉이갑상선유두암의발생위험도를높인다는것은이미잘알려진바이다. 12,13) 본연구는현재및과거거주지역및기간만이설문을통해조사되었기때문에, 지역및거주기간에따른방사선조사량을정량화하는것이불가능하였으며, 한국인요오드섭취량이전반적으로권장섭취량을상회하기때문에 14) 지역간차이가갑상선암의발생에미치는영향을분석하기에충분치않았을것으로판단된다. 갑상선암의가족력이있는환자에서가족력이없는환자에비해갑상선유두암의진단율이유의하게높았으며, 다발성종양의비율또한통계적으로유의하게 Vol. 10, No. 2, 2017 86
Trends for Environmental Risk Factors in Thyroid Cancer 높았다. 가족력이있는환자의경우다발성종양이흔하다는다른논문과도상통하는결과이다. 15,16) 추가적으로갑상선기능질환의가족력유무와갑상선암의발생과의관련성에대해타연구에서보고된바가있었으나, 17) 본연구에서는갑상선기능질환의가족력을보고한대상자가적어 (68명) 이들을대상으로한하위분석에서는가족력에따른유의한차이를확인할수없었다. 남녀를나누어비흡연자와현재및과거흡연자의갑상선암의임상, 병리학적차이를보았을때유의한차이를확인하지는못하였다. 흡연력이있는환자에서갑상선암발생의상대위험도가낮아짐을보고하였던 31개의연구를포함한메타분석과 18) 달리본연구에서는유의한차이가관찰되지않은것은, 갑상선암의발생에흡연의영향뿐만이아니라다른환경, 유전적인자의영향이공존하기때문일것으로생각된다. 갑상선암환자의비만도가높을수록피막외침윤과림프절전이가통계적으로유의하게증가하였다. 이는체질량지수 25 kg/m 2 또는 30 kg/m 2 를기준으로갑상선암발생의상대위험도가 1.0-1.3배증가한다는기존보고들과일치하는결과이다. 19-21) 최근발표된국내의연구에따르면갑상선결절의발생에있어비만뿐만아니라동반된대사증후군이갑상선결절의발생에영향을줄가능성이제시되었다. 이는갑상선암의발암기전에인슐린저항성이기여할것으로추정되는소견이며, 따라서비만은갑상선암의발생과예후에영향을미칠가능성이높다고볼수있다. 22-24) 본연구는서울및일산에위치한병원에내원한갑상선암환자들을대상으로설문조사에동의한대상자만을포함하여진행된환자군연구로, 대상자들의선택비뚤림이존재하며설문지조사자체의한계인회상비뚤림을배제할수없다. 또한환자들은수술전에설문작성을한것이아니라장기추적관찰중인환자들을대상으로하였기때문에이환자들이전체갑상선암을대표한다고보기어렵다. 아울러갑상선유두암이 90% 이상을차지하고있어암종별차이를분석해볼수는없었다. 그러나우리나라에서갑상선암환자들을대상으로시대별, 진단동기별, 위험인자의유무에따른갑상선암의임상, 병리학적특성을살펴본연구가기존에없었기때문에본연구의의의가있을것으로생각된다. 향후다양한위험인자의갑상선암의발생과의연관성확인을위해서는코호트연구를포함한많은역학연구결과가필요할것으로보인다. Acknowledgments This work was supported by a grant from Research Grants No. 1410640-3, 1710430-1 to Eun Kyung Lee from the National Cancer Center. 중심단어 : 갑상선암, 선별검사, 환경적요인, 설문조사. References 1) Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat 2017;49(2):292-305. 2) Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013;2013: 965212. 3) Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, et al. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control 2009;20(5):525-31. 4) Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006;295(18):2164-7. 5) Liu S, Semenciw R, Ugnat AM, Mao Y. Increasing thyroid cancer incidence in Canada, 1970-1996: time trends and age-period-cohort effects. Br J Cancer 2001;85(9):1335-9. 6) Nikiforov YE, Fagin JA. Risk factors for thyroid cancer. Trends Endocrinol Metab 1997;8(1):20-5. 7) Ahn HY, Park YJ. Incidence and clinical characteristics of thyroid cancer in Korea. Korean J Med 2009;77(5):537-42. 8) Feldt-Rasmussen U. Iodine and cancer. Thyroid 2001;11(5): 483-6. 9) Nagataki S, Nystrom E. Epidemiology and primary prevention of thyroid cancer. Thyroid 2002;12(10):889-96. 10) Lind P, Langsteger W, Molnar M, Gallowitsch HJ, Mikosch P, Gomez I. Epidemiology of thyroid diseases in iodine sufficiency. Thyroid 1998;8(12):1179-83. 11) Franceschi S. Iodine intake and thyroid carcinoma--a potential risk factor. Exp Clin Endocrinol Diabetes 1998;106 Suppl 3:S38-44. 12) Cao LZ, Peng XD, Xie JP, Yang FH, Wen HL, Li S. The relationship between iodine intake and the risk of thyroid cancer: A meta-analysis. Medicine (Baltimore) 2017;96(20):e6734. 13) Lee JH, Hwang Y, Song RY, Yi JW, Yu HW, Kim SJ, et al. Relationship between iodine levels and papillary thyroid carcinoma: A systematic review and meta-analysis. Head Neck 2017;39(8):1711-8. 14) Lee HS, Min H. Iodine intake and tolerable upper intake level of iodine for Koreans. Korean J Nutr 2011;44(1):82-91. 15) Park YJ, Ahn HY, Choi HS, Kim KW, Park DJ, Cho BY. The long-term outcomes of the second generation of familial nonmedullary thyroid carcinoma are more aggressive than sporadic cases. Thyroid 2012;22(4):356-62. 87 Int J Thyroidol
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