untitled

ORIGINAL ARTICLE pissn: 2384-3799 eissn: 2466-1899 Int J Thyroidol 2017 November 10(2): 89-95 https://doi.org/10.11106/ijt.2017.10.2.89 경부림프절전이를동반한갑상선유두암환자에서혈중호중구림프구비율의임상적의의 고신대학교의과대학의학과 1, 이비인후과학교실 2 김화빈 1 *, 이형신 2 *, 김성원 2, 전석원 2, 송지아 2, 이강대 2 Clinical Value of Blood Neutrophil to Lymphocyte Ratio in Patients with Papillary Thyroid Carcinoma with Neck Lymph Node Metastasis Hwa Bin Kim 1 *, Hyoung Shin Lee 2 *, Sung Won Kim 2, Seok Won Jeon 2, Ji Ah Song 2 and Kang Dae Lee 2 Departments of Medicine 1 and Otolaryngology-Head and Neck Surgery 2, Kosin University College of Medicine, Busan, Korea Background and Objectives: Blood neutrophil-to-lymphocyte ratio (NLR) has been reported to have poor prognostic impact in variable malignancies. However, studies evaluating the clinical significance of blood NLR in patient with papillary thyroid carcinoma (PTC) has been relatively rare, and the outcomes were inconsistent. In this study, we sought to analyze the clinical value of NLR in patients with PTC who had cervical lymph node metastasis. Materials and Methods: Retrospective chart review was conducted with 174 patients with confirmed neck metastasis of PTC after initial thyroidectomy. Blood NLR was estimated by dividing the absolute number of blood neutrophil with that of lymphocyte. Statistical analysis was conducted to evaluate correlation between NLR and clinicopathologic factors, patterns of metastatic lymph nodes, and recurrence. Results: Higher NLR (>1.74) was correlated to younger age of patients (<45 years, p=0.045) and smaller size of tumor (<1 cm, p=0.017). Blood NLR had no impact on patterns of lymph node metastasis or recurrence. Conclusion: Blood NLR may not be considered as a predictive factor for clinical aggressiveness or prognosis in patients with PTC with lymph node metastasis. Key Words: Papillary thyroid carcinoma, Neck metastasis, Neutrophil, Lymphocyte 서론 갑상선암은내분비암중에가장흔한암으로서유두암이전체갑상선암중 90% 이상을차지한다. 1) 대부분의환자들은좋은예후를보여질병특이사망률은매우낮지만국소재발이 35% 까지비교적흔하게발생할수있다. 2) 갑상선암의재발은반복되는수술등으로환 자의삶의질을저하시킬뿐만아니라질병특이사망률을높일수있다. 2) 갑상선유두암환자의재발및생존율과연관된인자로는나이, 성별, 종양의크기, 갑상선의피막외침범, TNM stage, 림프절전이등이알려져있다. 1,3) 갑상선유두암환자에서경부림프절전이는 40-90% 로매우흔하게나타나는데, 4) 최근에는림프절전이유무보다전이된림프절의크기, 피막외침범, 개수등이예후의중요한인자로알려져있다. 5) 전이된 Received June 16, 2017 / Revised August 4, 2017 / Accepted August 10, 2017 Correspondence: Kang Dae Lee, MD, Department of Otolaryngology-Head and Neck Surgery, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea Tel: 82-51-990-6470, Fax: 82-51-245-8539, E-mail: kdlee59@gmail.com Hwa Bin Kim and Hyoung Shin Lee equally contributed to this work. 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. 89

Hwa Bin Kim, et al 림프절의침습성을대표하는이와같은특징들은갑상선암의크기, 피막침범등원발암의공격성과도관련이있는것으로보고되고있다. 6,7) 갑상선암의림프절전이또는그임상양상과연관된요인들을밝히고자하는연구들은수술전에림프절전이여부또는그공격성을예측하여적절한수술방법또는범위를결정하는데그목적이있다. 그동안 BRAF, TERT, NRAS 등이갑상선유두암의림프절전이와연관된것으로보고된바있다. 8) 최근이러한분자생물학적인검사없이혈중호중구-림프구비율 (neutrophil-to-lymphocyte ratio, NLR) 을이용하여간편하게암환자의임상양상또는예후를예측할수있다는보고들이다수보고되고있다. 혈중 NLR은폐암, 9) 유방암, 10) 전립샘암, 11) 췌장암, 12) 대장암 13) 등에서불량한예후인자로알려져있는데, 검사의비용적인부담이적고통상적인검사이므로환자에게추가되는위해나부담이없다는것이가장큰장점이다. 다양한암에서혈중 NLR의유용성이검증되고있지만, 갑상선암환자에서는임상적의의가명확하게입증된바가없다. 보고된연구들간에도상충되는결과들이있다. 14) 특히국내환자에대한연구는부족한실정이며림프절전이의양상과혈중 NLR 간의관계를분석한연구는아직국내외에보고된바없다. 15,16) 본연구에서는혈중 NLR이갑상선암의임상병리학적요인들과의연관성여부를분석하고, 특히전이된림프절의침습성및종양재발에영향을미치는지확인해보고자하였다. 대상및방법 본연구는후향적으로이루어졌으며, 본원에서 2011 부터 2012년사이에갑상선절제술을받은갑상선유두암환자 716명중수술후병리조직검사에서림프절전이가확인된환자는 225명이었다. 본연구에서는남성을제외한 174명의여성환자들을대상으로분석을실시하였다. 호중구, 림프구개수를포함한모든혈액검사결과는술전 2주내외에시행되었다. 혈중 NLR 은호중구개수를림프구개수로나누어서계산하였으며동일하게, 혈소판-림프구비율 (platelet-to-lymphocyte ratio, PLR) 은혈소판개수를림프구개수로나누어계산했다. 환자의백혈구수치에영향을줄수있는혈액학적질환, 다른암종진단의과거력, 6개월이내의심혈관질환진단력, 급성염증이있거나 3개월내에스테로이드를복용한환자들은연구에서제외하였다. 술 전갑상선종양의크기는초음파상가장큰지름을기준으로측정했고, 병리학적크기는술후조직검사상가장큰지름으로측정했다. 임상적인경부림프절전이 (clinical lymph node metastasis) 는술전촉진되거나초음파영상에서확인된전이가있었던경우로정의하였다. 환자들은 NLR의중간값을기준으로두그룹으로나누고진단당시나이, 종양의크기, 피막침범여부, 림프-혈관침범등잘알려진갑상선유두암의예후인자에대해교차분석을실시하였다. 또한, 술후시행한림프절조직병리검사결과를바탕으로 NLR과림프절전이병변의크기, 림프절외침범여부, 전이된림프절의개수와의상관관계도분석하였다. PLR 역시중간값을기준으로두그룹으로나누어각요인과의상관관계를분석하였다. 본연구는본기관의연구윤리위원회 (Institutional Review Board) 의승인을받고시행되었다. 통계학적분석은 SPSS v22.0을이용하였다. 연속변수들은평균 ± 표준편차로표기되었으며, 명목변수는 n 수와 % 로나타내었다. 명목변수간의연관성은 Chisquare test를사용하여분석하였으며, p-value가 0.05 미만인경우통계학적으로유의성이있다고판단하였다. 결과 Table 1에서연구에포함된환자들의수술전후확인된임상병리학적특징을정리하였다. 평균연령은 47.6세이며, 45세미만이 71명 (40.8%), 45세이상은 103 명 (59.2%) 이었다. 술전초음파검사상종양의평균크기는 12.36 mm, 술후조직검사결과상에서는평균 11.60 mm였다. 술후병리검사에서술전초음파검사상종양크기보다크게보고된경우는 18례였으며모두축영상 (axial view) 으로측정된술전종양의크기보다병리검사에서의세로 (longitudinal) 길이가크게측정된경우로크기의평균차이는 3.12 mm였다. 본연구에서분석한 174명의환자중 110명은술전검사에서경부림프절전이가확인되지않았으나예방적중심경부림프절절제술후림프절전이가확인되었으며수술전림프절전이가확인되었던환자 64명중 28명은중심경부, 36명은측경부에림프절전이가있어치료적경부림프절절제술을시행받았다. 림프절전이병변의평균크기는 4.15 mm, 전이병변의림프절외침윤은 47례 (27%), 전이된림프절의개수는평균 3.85개로확인되었다. 평균경과관찰기간은 58개월 (24-72개월) 이며, 이기간중에 5명 (2.8%) 에서재발하였 Vol. 10, No. 2, 2017 90

Neutrophil to Lymphocyte Ratio in PTC Table 1. Summary of clinicopathologic factors Characteristics Patients, n % (n=174) Age (years) 47.6±11.4 (20-72) <45 years 71 (40.8%) 45 years 103 (59.2%) Pre-operative tumor size (mm) 12.36±6.82 (3-41) <1 cm 69 (39.7%) 1 cm size<2 cm 84 (48.3%) 2 cm 21 (12.1%) Pathologic tumor size (mm) 11.60±7.18 (2-36) <1 cm 61 (35.1%) 1 cm size<2 cm 84 (48.3%) 2 cm 29 (16.7%) ETE No 58 (33.3%) Yes 116 (66.7%) Gross ETE (except strap muscles) No 159 (91.4%) Yes 15 (8.6%) Multifocality No 97 (55.7%) Yes 77 (44.3%) Number of dissected LNs 12.82±12.23 (1-76) Number of metastatic LNs 3.85±4.28 (1-29) Central LN mets No 3 (1.7%) Yes 171 (98.2%) Lateral LN mets No 138 (79.3%) Yes 36 (20.6%) LN mets size (mm) 4.15±4.06 (1-24) <2 mm 64 (36.8%) 2 mm 110 (63.2%) LN mets ENE No 127 (73.0%) Yes 47 (27.0%) Extent of thyroidectomy Lobectomy 23 (13.2%) Total thyroidectomy 151 (86.7%) RAI therapy No 31 (17.8%) Yes 143 (82.2%) Recurrence 5 (2.8%) Follow-up (months) 58.02 (24-72) ENE: extranodal extension, ETE: extrathyroidal extension, LN: lymph node, mets: metastasis, RAI: radioactive iodine 다. 평균백혈구개수는 6.33 10 3 /μl, 호중구는 3.73 10 3 /μl, 림프구는 2.05 10 3 /μl이었다. 평균 NLR은 2.02 10 3 (±1.51 10 3 )/μl, 평균 PLR은 134.05 10 3 (±52.47 10 3 )/μl이었다(table 2). NLR은나이와종양의병리학적크기에따라유의미한차이를보였다 (Table 3). 환자의나이가 45세미만인 Table 2. Summary of complete blood counts and hormonal level in enrolled patients Factors Value (mean±sd, range) Hb (g/dl) 12.9±1.2 (8.8-15.6) Hct (%) 38.2±3.2 (27.8-46.2) WBC ( 10 3 /μl) 6.33±1.71 (2.60-13.00) Neutrophil 3.73±1.46 (0.81-11.14) Lymphocyte 2.05±0.59 (0.63-3.72) Monocyte 0.40±0.17 (0.04-1.42) Eosinophil 0.13±0.15 (0.00-1.47) Basophil 0.03±0.02 (0.00-0.08) Platelet ( 10 3 /μl) 253.37±52.643 (103.00-401.00) NLR 2.02±1.51 (0.61-17.41) PLR 134.05±52.47 (56.59-468.75) TSH (μiu/ml) 1.82±1.17 (0.005-6.449) Free T4 (ng/dl) 1.21±0.40 (0.75-5.58) Thyroglobulin (ng/ml) 44.05±79.18 (0.10-636.40) Hb: hemoglobin, Hct: hematocrit, NLR: neutrophil-to-lymphocyte ratio, PLR: platelet-to-lymphocyte ration, SD: standard deviation, TSH: thyroid stimulating hormone, WBC: white blood cell 그룹에서더높은경향을보였으며 (p=0.045), 종양의병리학적크기가 1 cm보다작은그룹에서높은경향이있었다 (p=0.017). 종양의크기를 2 cm 기준으로분석하였을때는유의미한차이가없었으며, 술전초음파검사상측정된종양의크기에대해서는유의미한결과가확인되지않았다. 그외암의재발여부및다른임상병리학적요인에대해서도유의성은관찰되지않았다. PLR 또한환자들의임상병리학적요인들과연관성이없었다 (Table 4). 고찰 갑상선암의임상양상또는재발가능성을예측할수있는지표로서여러종양표지자나유전자에대한연구들이보고되어왔다. 8,17) 이러한유전자검사에비해비용적효율성이라는장점을전제로최근갑상선암환자의혈중 NLR에관한논의도활발하게이루어지고있다. 하지만현재까지보고된논문들의수는아직제한적이며, 15,18-20) 이들에대한메타분석에서도결과들에일관성이없어아직하나의결론을짓기는부족한상태이다. 14) 본연구에서는종양의크기가 1 cm보다작은경우와환자의나이가 45세미만인경우더높은 NLR 을보였으며환자의재발과 NLR의크기는상관관계를보이지않았다. NLR이공격적인임상양상과관계되거나예후에나쁜영향을미친다는것이다른암에서는 91 Int J Thyroidol

Hwa Bin Kim, et al Table 3. Comparison of clinicopathologic factors according to blood neutrophil-to-lymphocyte ratio Factors NLR <1.74 (n=87) NLR 1.74 (n=87) p value Age <45 years 29 (33.3%) 42 (48.3%) 0.045* 45 years 58 (66.7%) 45 (51.7%) Pre-operative tumor size (mm) <1 cm 37 (42.5%) 32 (36.8%) 0.438 1 cm 50 (57.5%) 55 (63.2%) <2 cm 77 (88.5%) 76 (87.4%) 0.816 2 cm 10 (11.5%) 11 (12.6%) Pathologic tumor size (mm) <1 cm 23 (26.4%) 38 (43.7%) 0.017* 1 cm 64 (73.6%) 49 (56.3%) <2 cm 73 (83.9%) 72 (82.8%) 0.839 2 cm 14 (16.1%) 15 (17.2%) ETE No 27 (31.0%) 31 (35.6%) 0.520 Yes 60 (69.0%) 56 (64.4%) Gross ETE No 76 (87.4%) 83 (95.4%) 0.103 Yes 11 (12.6%) 4 (4.6%) Multifocality No 51 (58.6%) 46 (52.9%) 0.445 Yes 36 (41.4%) 41 (47.1%) Clinical LN mets Negative 53 (60.9%) 57 (65.5%) 0.529 Positive 34 (39.1%) 30 (34.5%) Central LN mets No 2 (2.3%) 1 (1.1%) 0.560 Yes 85 (97.7%) 86 (98.9%) Lateral LN mets No 72 (82.8%) 66 (75.9%) 0.261 Yes 15 (17.2%) 21 (24.1%) Number of LN mets <5 65 (74.7%) 60 (69.0%) 0.399 5 22 (25.3%) 27 (31.0%) LN mets size (mm) <2 mm 32 (36.8%) 32 (36.8%) 1.000 2 mm 55 (63.2%) 55 (63.2%) LN mets ENE No 63 (72.4%) 64 (73.6%) 0.864 Yes 24 (27.6%) 23 (26.4%) LVI No 34 (39.1%) 28 (32.2%) 0.342 Yes 53 (60.9%) 59 (67.8%) Recurrence No 86 (98.9%) 83 (95.4%) 0.173 Yes 1 (1.1%) 4 (4.6%) ENE: extranodal extension, ETE: extrathyroidal extension, LN: lymph node, LVI: lymphovascular invasion, mets: metastasis, NLR: neutrophil-to-lymphocyte ratio, OP: operative *p<0.05 밝혀졌으나, 9-13) 갑상선암에대한연구결과는현재까지일관성이없다. 일반적으로암의성장과임상양상에염증반응이긴밀하게관여한다는사실은잘알려 져있는데, 염증은암의발달, 진행, 침윤, 전이등에있어서중요한역할을한다. 21) 높은 NLR 수치가암의공격성이나불량한예후에미치는영향및그기전에 Vol. 10, No. 2, 2017 92

Neutrophil to Lymphocyte Ratio in PTC Table 4. Comparison of clinicopathologic factors according to blood platelet-to-lymphocyte ratio Factors PLR <126.47 (n=87) PLR 126.47 (n=87) p value Age <45 years 31 (35.6%) 40 (46.0%) 0.165 45 years 56 (64.4%) 47 (54.0%) Pre op tumor size (mm) <1 cm 34 (39.1%) 35 (40.2%) 0.877 1 cm 53 (60.9%) 52 (59.8%) <2 cm 77 (88.5%) 76 (87.4%) 0.816 2 cm 10 (11.5%) 11 (12.6%) Pathologic tumor size (mm) <1 cm 27 (31.0%) 34 (39.1%) 0.266 1 cm 60 (69.0%) 53 (60.9%) <2 cm 73 (83.9%) 72 (82.8%) 0.839 2 cm 14 (16.1%) 15 (17.2%) ETE No 28 (32.2%) 30 (34.5%) 0.748 Yes 59 (67.8%) 57 (65.5%) Gross ETE No 76 (87.4%) 83 (95.4%) 0.103 Yes 11 (12.6%) 4 (4.6%) Multifocality No 47 (54.0%) 50 (57.5%) 0.647 Yes 40 (46.0%) 37 (42.5%) Clinical LN mets Negative 57 (65.5%) 53 (60.9%) 0.529 Positive 30 (34.5%) 34 (39.1%) Central LN mets No 2 (2.3%) 1 (1.1%) 0.560 Yes 85 (97.7%) 86 (98.9%) Lateral LN mets No 73 (83.9%) 65 (74.7%) 0.134 Yes 14 (16.1%) 22 (25.3%) Number of LN mets <5 63 (72.4%) 62 (71.3%) 0.866 5 24 (27.6%) 25 (28.7%) LN mets size (mm) <2 mm 34 (39.1%) 30 (34.5%) 0.529 2 mm 53 (60.9%) 57 (65.5%) LN mets ENE No 64 (73.6%) 63 (72.4%) 0.864 Yes 23 (26.4%) 24 (27.6%) LVI No 33 (37.9%) 29 (33.3%) 0.527 Yes 54 (62.1%) 58 (66.7%) Recurrence No 85 (97.7%) 84 (96.6%) 0.650 Yes 2 (2.3%) 3 (3.4%) ENE: extranodal extension, ETE: extrathyroidal extension, LN: lymph node, LVI: lymphovascular invasion, mets: metastasis, OP: operative, PLR: platelet-to-lymphocyte ratio 93 Int J Thyroidol

Hwa Bin Kim, et al 대해서는아직명확하게알려진바가없다. 현재까지밝혀진바로는호중구에서분비된 granulocyte-macrophage colony-stimulating factor (GM-CSF) 가 matrix metalloproteinase (MMPs) 의발현을증가시켜종양세포의성장과이동을촉진시킨다고알려져있다. 22) 종양의미세환경도중요한데호중구에서분비되는 neutrophil elastase (NE), neutrophil collagenase (MMP8), gelatinase B (MMP9) 등은세포외기질을재구성하여암의진행을돕는다. 또한호중구에서분비되는 oncostatin M, interleukin-6 family는 vascular endothelial growth factor (VEGF) 생성을유도하여혈관신생을증가시킨다. 23) Liu 등 14) 은 NLR이갑상선암의크기와재발의고위험군의위험요인들과유의한관계가있다고보고했다. Gong 등 20) 은 NLR이갑상선유두암환자의림프절전이, 종양의크기, 다발성여부와연관되며 American Joint Cancer Committee의 TNM 병기분류와상관관계가있다고했다. Lang 등 18) 은 NLR이종양의크기와상관관계가있으나갑상선암의재발과는유의한연관성을발견하지못했다고했다. 이러한연구들이 NLR이암의공격적양상과연관성을보인다는타암종의연구결과와일부상통하는반면, 국내연구에서는 NLR 이갑상선암환자의종양의크기등의임상양상및예후와연관성을보이지않는다는보고가있었다. 15) 이연구에서는 45세이상의환자들에서술전 NLR이유의하게낮다고보고하여본연구와같은결과를보였다. 반면해외기관들의연구에서는 NLR과나이는상관관계가없다는보고가있었고, 14,20) 나이가많은환자들에서높은 NLR을보인다는보고들도있다. 18,24) 최근갑상선유두암에서높은 PLR이경부림프절전이와연관이있다는연구결과가있었으나 15) 본연구에서는 PLR과환자들의임상양상및재발률간의의미있는연관성은확인할수없었다. 본연구에서남성환자들을연구대상에서제외시킨것은기존연구에서남성이재발및질병특이사망률이더높고 3) 갑상선암이더공격적인임상양상을보인다는보고가있었기때문이다. 25) 또한여자가남자에비해호중구개수가높은반면림프구수가낮다는보고가있는데, 26) 이는성호르몬의차이때문으로추측된다. 또한, 한국 50대중년남자들의높은흡연율과관련하여남성에서백혈구개수가여성에비해높다는보고도있다. 27) 따라서 NLR 관련연구에서는성별을구분하여분석하는것이매우중요하다. 최근림프절전이병변의크기와림프절외침범이환자의예후와관련이있다는연구결과가있었다. 5,28) 이를근거로기존의 NLR 관련연구들에서다룬적이없었던전이된림프절의수와크기, 림프절피막침범에대해추가적인분석을실시하였으나 NLR이갑상선유두암환자의림프절전이의양상에의미있는영향을주지않는것으로확인되었다. 본연구에는몇가지한계가있다. 이연구는후향적으로이루어졌으며이에따른표본선정편파가있을수있다. 또한연구에포함된환자의수가 174명으로제한적이고, 병리학적으로경부림프절전이가있는환자들만분석하였기때문에이에따른변수가있을수있다. 술후병리조직검사에서종양의크기가술전초음파영상보다크게측정된경우가있었는데이는종양의세로길이를술전에충분히고려하지못했기때문에발생하는문제일수있다. 그러나, 실제종양의크기는병리검사측정결과가더정확하다고볼수있겠다. 향후전향적연구에서는종양의크기측정기준에대한좀더면밀한기준이제시되어야하겠다. 또한, 재발한환자의숫자가적어 NLR이재발에미치는영향에대한평가는사실상어려웠다. 채혈기간이술전 2주내외로수술과의시간차가있었다는점도고려해야한다. 따라서혈중호중구 -림프구비율이갑상선암환자의임상양상이나재발을예측하는인자로서유효한지에대해서는향후대규모환자에서장기간의전향적인연구가필요할것이다. 결론 본연구에서 NLR이갑상선유두암환자의공격적임상적양상, 경부림프절전이의공격성, 재발여부에미치는영향이확인되지않았다. 향후더큰규모의연구가필요하나본연구에서는경부림프절전이가있는국내갑상선유두암환자에서혈중 NLR이임상양상또는예후예측인자로고려되는것은부적절할것으로판단된다. 중심단어 : 갑상선유두암, 경부림프절전이, 호중구, 림프구. References 1) Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26(1):1-133. Vol. 10, No. 2, 2017 94

Neutrophil to Lymphocyte Ratio in PTC 2) Mazzaferri EL, Kloos RT. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86(4):1447-63. 3) Ito Y, Miyauchi A. Prognostic factors and therapeutic strategies for differentiated carcinomas of the thyroid. Endocr J 2009; 56(2):177-92. 4) Moo TA, McGill J, Allendorf J, Lee J, Fahey T 3rd, Zarnegar R. Impact of prophylactic central neck lymph node dissection on early recurrence in papillary thyroid carcinoma. World J Surg 2010;34(6):1187-91. 5) Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid 2012;22(11): 1144-52. 6) Lee HS, Park C, Kim SW, Noh WJ, Lim SJ, Chun BK, et al. Pathologic features of metastatic lymph nodes identified from prophylactic central neck dissection in patients with papillary thyroid carcinoma. Eur Arch Otorhinolaryngol 2016;273(10): 3277-85. 7) Lee HS, Park C, Kim SW, Park T, Chun BK, Hong JC, et al. Correlation of minimal extrathyroidal extension with pathologic features of lymph node metastasis in patients with papillary thyroid carcinoma. J Surg Oncol 2015;112(6):592-6. 8) Melo M, Gaspar da Rocha A, Batista R, Vinagre J, Martins MJ, Costa G, et al. TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. J Clin Endocrinol Metab 2017;102(6):1898-907. 9) Yin Y, Wang J, Wang X, Gu L, Pei H, Kuai S, et al. Prognostic value of the neutrophil to lymphocyte ratio in lung cancer: a meta-analysis. Clinics (Sao Paulo) 2015;70(7):524-30. 10) Wei B, Yao M, Xing C, Wang W, Yao J, Hong Y, et al. The neutrophil lymphocyte ratio is associated with breast cancer prognosis: an updated systematic review and meta-analysis. Onco Targets Ther 2016;9:5567-75. 11) Gu X, Gao X, Li X, Qi X, Ma M, Qin S, et al. Prognostic significance of neutrophil-to-lymphocyte ratio in prostate cancer: evidence from 16,266 patients. Sci Rep 2016;6:22089. 12) Yang JJ, Hu ZG, Shi WX, Deng T, He SQ, Yuan SG. Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis. World J Gastroenterol 2015; 21(9):2807-15. 13) Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer 2014;134(10):2403-13. 14) Liu JF, Ba L, Lv H, Lv D, Du JT, Jing XM, et al. Association between neutrophil-to-lymphocyte ratio and differentiated thyroid cancer: a meta-analysis. Sci Rep 2016;6:38551. 15) Kim SM, Kim EH, Kim BH, Kim JH, Park SB, Nam YJ, et al. Association of the preoperative neutrophil-to-ymphocyte count ratio and platelet-to-lymphocyte count ratio with clinicopathological characteristics in patients with papillary thyroid cancer. Endocrinol Metab (Seoul) 2015;30(4):494-501. 16) Han SW, Kang SY, Kim SK, Youn HJ, Jung SH. Clinical significance of blood neutrophil-to-lymphocyte ratio in patients with papillary thyroid carcinoma. Korean J Endocr Surg 2014;14(4):184-9. 17) Pak K, Suh S, Kim SJ, Kim IJ. Prognostic value of genetic mutations in thyroid cancer: a meta-analysis. Thyroid 2015; 25(1):63-70. 18) Lang BH, Ng CP, Au KB, Wong KP, Wong KK, Wan KY. Does preoperative neutrophil lymphocyte ratio predict risk of recurrence and occult central nodal metastasis in papillary thyroid carcinoma? World J Surg 2014;38(10):2605-12. 19) Liu CL, Lee JJ, Liu TP, Chang YC, Hsu YC, Cheng SP. Blood neutrophil-to-lymphocyte ratio correlates with tumor size in patients with differentiated thyroid cancer. J Surg Oncol 2013;107(5):493-7. 20)Gong W, Yang S, Yang X, Guo F. Blood preoperative neutrophil-to-lymphocyte ratio is correlated with TNM stage in patients with papillary thyroid cancer. Clinics (Sao Paulo) 2016;71(6):311-4. 21) Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140(6):883-99. 22) Hong IS. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. Exp Mol Med 2016;48(7):e242. 23) Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends Immunol 2016;37(1):41-52. 24) Liu J, Du J, Fan J, Liu K, Zhang B, Wang S, et al. The neutrophil-to-lymphocyte ratio correlates with age in patients with papillary thyroid carcinoma. ORL J Otorhinolaryngol Relat Spec 2015;77(2):109-16. 25) Ito Y, Kudo T, Takamura Y, Kobayashi K, Miya A, Miyauchi A. Prognostic factors of papillary thyroid carcinoma vary according to sex and patient age. World J Surg 2011;35(12): 2684-90. 26) Gwak MS, Choi SJ, Kim JA, Ko JS, Kim TH, Lee SM, et al. Effects of gender on white blood cell populations and neutrophil-lymphocyte ratio following gastrectomy in patients with stomach cancer. J Korean Med Sci 2007;22 Suppl:S104-8. 27) Jee SH, Park JY, Kim HS, Lee TY, Samet JM. White blood cell count and risk for all-cause, cardiovascular, and cancer mortality in a cohort of Koreans. Am J Epidemiol 2005;162(11): 1062-9. 28) Ito Y, Miyauchi A, Kihara M, Kobayashi K, Miya A. Prognostic values of clinical lymph node metastasis and macroscopic extrathyroid extension in papillary thyroid carcinoma. Endocr J 2014;61(8):745-50. 95 Int J Thyroidol