ORIGINAL ARTICLE ISSN 1598-1703 (Print) ISSN 2287-6782 (Online) Korean J Endocr Surg 2014;14:184-189 http://dx.doi.org/10.16956/kaes.2014.14.4.184 The Korean Journal of Endocrine Surgery 갑상선유두암재발의예측인자로서혈중호중구 - 림프구비율의임상적유용성 전북대학교의학전문대학원외과학교실한세웅ㆍ강상율ㆍ김선광ㆍ윤현조ㆍ정성후 Clinical Significance of Blood Neutrophil-to-Lymphocyte Ratio in Patients with Papillary Thyroid Carcinoma Purpose: The neutrophil-to-lymphocyte ratio (NLR) is a strong predictor of poor prognosis in patients with various types of cancer. To date, the utility of NLR for prediction of prognosis in thyroid cancer patients has not been studied. Therefore, the aim of our study was to determine whether NLR is associated with other prognostic factors of papillary thyroid carcinoma and predictive of recurrence. Methods: We conducted a retrospective review of 367 patients who underwent thyroidectomy for papillary thyroid carcinoma from January 2005 to December 2007. We measured the white blood cell count including neutrophil and lymphocyte within one month preoperatively. The NLR was defined as the absolute neutrophil count divided by absolute lymphocyte count. Logistic regression analysis was applied for comparison of NLR with other prognostic factors, including tumor size, lymph node metastasis, multiplicity, extrathyroidal invasion, and TNM stage. We also determined the cut-off value of NLR with a prediction for recurrence. Results: Median age of patients was 47 years (16 86 years) and the rate of papillary thyroid microcarcinoma was 65.7% (241/367 cases). Median follow-up period was 1,841 days (506 3,135 days). The median value of NLR was 1.68 (0.66 6.36). NLR was not related to any other prognostic factors of papillary thyroid carcinoma. The cut-off value of NLR for prediction of recurrence was 1.73, where the sensitivity was 66.7% and specificity was 69.8%. Conclusion: Patients with NLR equal to or higher than 1.73 showed significantly higher recurrence of papillary thyroid carcinoma. Further validation study should be conducted for clinical use of NLR as a prognostic marker. Key Words: Neutrophil-to-lymphocyte ratio, Thyroid carcinoma, Recurrence 중심단어 : 호중구-림프구비율, 갑상선암, 재발 Se Woong Han, Sang Yull Kang, Seon Kwang Kim, Hyun Jo Youn, Sung Hoo Jung Department of Surgery, Chonbuk National University Medical School, Jeonju, Korea Received July 29, 2014, Revised August 30, 2014, Accepted September 27, 2014 Correspondence: Hyun Jo Youn Division of Breast Thyroid Surgery, Department of Surgery, Chonbuk National University Medical School, 634-18, Guemam-dong, Deukjin-gu, Jeonju 561-712, Korea Tel: +82-63-250-2389 Fax: +82-63-271-6197 E-mail: yhj0903@jbnu.ac.kr 서론 갑상선암의대부분을차지하는고분화갑상선암은치료후좋은예후를보인다. 그러나이중 5 20% 의환자는장기적으로국소및전신재발을경험하게되며,(1-3) 약 8% 의환자는재발 로인한사망에이르게된다.(4) 따라서갑상선암의재발을예측할수있는인자들에대해서그동안많은연구가이루어졌으며종양의크기, 림프절전이, 다발성, 갑상선외침범등이재발인자로알려져있다.(5) 염증 (inflammation) 은암의성장과진행에중요한역할을하 Copyright 2014 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.
한세웅외 : NLR for Predicting Recurrence of Papillary Thyroid Carcinoma 185 며, 염증의전신반응 (systemic reaction) 이암의재발및예후와관련이있다는보고가있는데,(6) 특히호중구 (neutrophils) 와림프구 (lymphocytes) 가종양의염증과면역에중요한역할을하는것으로알려져있다.(7) 또한수술전혈중호중구-림프구비율 (neutrophil-lymphocyte ratio; NLR) 이간암,(8) 담도암,(9) 대장직장암,(10) 신장암,(11) 유방암,(12) 위암,(13) 췌장암 (14) 과폐암 (15) 등여러암의재발및예후와깊은관련이있다고보고되었으며, 최근에는갑상선암환자의종양크기가 NLR과관련이있다는보고가있었다.(16) 전신염증반응을나타내는표지자로서 NLR은신뢰도가높으며검사비용이저렴하고대부분의기관에서수술전기본검사로측정하여쉽게이용할수있지만현재까지갑상선암의재발인자로서 NLR에대한역할을규명한연구는극히드물다. 이에본연구는유두상갑상선암환자에서 NLR이종양의크기, 림프절전이, 다발성, 갑상선외침범등기존에알려진예후인자와관련이있는지그리고또한유두상갑상선암의재발을예측할수있는지에관해알아보고자하였다. 방법 2005년 1월 1일부터 2007년 12월 31일까지유두상갑상선암으로진단받고수술적치료를시행받은후지속적인추적관찰이가능했던환자들을대상으로의무기록을조사하여후향적연구를시행하였다. 추적관찰기간이 500일미만이거나, 진단당시전신전이가있었던경우, 수술전 6개월이내에염증성질환이나타장기의악성종양으로치료받은과거력이있는경우는대상군에서제외하였으며, NLR에영향을미칠수있는관상동맥질환, 만성신장질환, 뇌혈관질환, 간경화등의질환으로치료받은환자들도대상군에서제외하여총 367명의환자가연구에포함되었다. 대상환자들의성별, 나이, 수술전말초혈액백혈구백분율수치 ( 호중구, 림프구수치 ), 수술후병리학적소견 ( 종양의크기, 림프절전이, TNM 병기, 다발성, 갑상선외침범 ), 갑상선염과재발여부를조사, 분석하였다. 모든대상환자는수술전 1개월이내에혈액검사를받았으며 NLR은절대호중구를림프구로나눈수로계산하였다. 수술후 6개월주기로두차례갑상선초음파와갑상선호르몬검사를시행하였고, 이후에는매년추적검사를시행하였다. 갑상선결절및암진료권고안 에따라방사성요오드치료의대상군에해당되는경우방사성요오드치료를시행하였다.(17) 추적검사상전신전이가발견된예는없었으며, 반대측갑상선또는중앙및측경부림프절에재발로보이는병변이발견되는경우세침흡인 세포검사후수술적치료를통해재발을확진하였다. NLR과다른임상병리학적인자들의관계와갑상선암재발과의관계를평가하기위해 NLR을 NLR 분포에의거하여 4그룹으로나누었다통계학적분석은 SPSS v13.0을이용하여환자의성별, 나이, 림프절전이, 종양크기, 수술전말초혈액의백혈구, 호중구, 림프구, 호중구-림프구비율을분석하였다. Chi-square test와 Fisher s exact test를사용하여명목변수들의상관관계를분석하였고 Cox proportional hazards model을사용하여여러임상병리학적인자들과갑상선암의재발을단변량분석한뒤의미있게나온결과들을다변량분석하였다. 다변량분석에서의미있게나온변수들은수신자판단특성곡선 (receiver operating characteristics curve, ROC curve) 을이용하여재발과관련된 NLR의 cut-off값을정하였다. 유의수준은 P<0.05인경우를의미있는것으로판단하였다. Table 1. Clinopathological features of patients with papillary thyroid carcinoma Characteristics Number of patients (n=367) Gender Male 44 (12%) Female 323 (88%) Age (years) 47.2±11.9 (16 86) 30 27 (7.3%) 31 40 85 (23.1%) 41 50 126 (34.3%) 51 60 71 (19.3%) 61 58 (15.8%) Tumor size (mm) 11.2±7.2 (1 50) 10.0 241 (65.7%) >10.0 126 (34.3%) Lymph node metastasis (-) 277 (75.5%) (+) 90 (24.5%) Multiplicity (-) 254 (69.2%) (+) 113 (30.8%) Extrathyroidal invasion (-) 328 (89.4%) (+) 39 (10.6%) Hashimoto s thyroiditis (-) 298 (81.2%) (+) 69 (18.8%) TNM stage I 298 (81.2%) II 8 (2.2%) III 61 (16.6%) White blood cell 6,257±1,565 (3,010 14,590) Neutrophil 3,494±1,244 (1,170 10,530) Lymphocyte 2,217±657 (640 6,300) Neutrophil-lymphocyte ratio 1.68±0.76 (0.66 6.36) Follow-up (days) 1,841±459 (506 3,135) Recurrence 39 (10.6%)
186 Korean J Endocr Surg 2014;14:184-189 journal.kates.or.kr Table 2. Relationship between NLR group and clinicopathologic factors of papillary thyroid carcinoma 1 st quartile (NLR<1.22) (n=91) 2 nd quartile (1.22 NLR<1.53) (n=95) 3 rd quartile (1.53 NLR<1.89) (n=87) 4 th quartile (NLR 1.89) (n=94) P value Gender 0.558 Male 83 (91.2%) 81 (85.2%) 78 (89.7%) 81 (86.2%) Female 8 (8.8%) 14 (14.8%) 9 (10.3%) 13 (13.8%) Age (years) 0.054 30 7 (7.7%) 5 (5.3%) 6 (6.9%) 9 (9.6%) 31 40 16 (17.5%) 25 (26.2%) 16 (18.4%) 28 (29.8%) 41 50 28 (30.8%) 39 (41.1%) 29 (33.3%) 30 (31.9%) 51 60 24 (26.4%) 13 (13.7%) 20 (23.0%) 14 (14.9%) 61 16 (17.6%) 13 (13.7%) 16 (18.4%) 13 (13.8%) Tumor size (cm) 0.553 1.0 58 (63.7%) 57 (60.0%) 45 (51.7%) 53 (56.4%) >1.0 33 (36.3%) 38 (40.0%) 42 (49.3%) 41 (43.6%) Lymph node metastasis 0.182 (-) 69 (75.8%) 79 (83.2%) 63 (72.4%) 66 (70.2%) (+) 22 (24.2%) 16 (16.7%) 24 (27.5%) 28 (29.8%) Multiplicity 0.563 (-) 58 (63.7%) 69 (72.6%) 59 (67.8%) 67 (71.3%) (+) 33 (36.3%) 26 (27.4%) 28 (32.2%) 27 (28.7%) Extrathyroidal invasion 0.337 (-) 81 (89.0%) 90 (94.7%) 76 (87.4%) 86 (91.5%) (+) 10 (11.0%) 5 (5.3%) 11 (12.6%) 8 (8.5%) Hashimoto s thyroiditis 0.980 (-) 74 (81.3%) 78 (82.1%) 71 (81.6%) 75 (79.8%) (+) 17 (18.7%) 17 (19.9%) 16 (18.4%) 19 (20.2%) TNM stage 0.109 I 70 (76.9%) 83 (87.4%) 75 (86.2%) 76 (80.9%) II 2 (2.2%) 2 (2.1%) 1 (1.2%) 2 (2.1%) III 19 (20.9%) 10 (10.5%) 11 (12.6%) 16 (17.0%) 결과 총 367명의환자중여자가 323명 (88%), 남자가 44명 (12%) 이었으며, 평균연령은 47.2세 (±11.9세), 평균추적기간은 1,841일 (±459.5일) 이었다. 종양의평균크기는 11.2 mm (±7.2 mm) 였으며, 65.7% (241/367예) 가 1 cm 이하의미세유두상갑상선암이었다. 90예인 24.5% 의환자에서림프절전이가있었으며, 다발성이 30.8% (113/367예), 그리고갑상선외침범이 10.6% (39/367예) 에서관찰되었다. 대상환자들의평균 NLR은 1.68 (±0.76) 이었으며, 총 39명 (10.6%) 의환자에서재발하였다 (Table 1). 대상환자군을 NLR값의분포에따라 4등분한결과 Table 2 와같이분류되었으며유두상갑상선암의여러임상병리학적인자들과 NLR의관련성을살펴보았을때통계학적으로의미있는상관관계를보이지않았다 (Table 2). 재발과 NLR을포함한다른예후인자들과의상관관계를단변량분석했을때 4번째 NLR 그룹에서 1번째그룹에비해통계적으로유의하게재발위험도가높았으며 (OR=5.844, 95% CI=2.02-16.90, P=0.001), 기존에알려진예후인자인성별, 종 Table 3. Univariate cox proportional regression analysis of relationship between recurrence and clinicopathologic factors papillary thyroid carcinoma Characteristics ODDS ratio 95% CI P value Age 0.681 0.36 1.28 0.681 Gender 0.409 0.19 0.86 0.019 Tumor size 1.071 1.04 1.11 0.000 LN metastasis 3.452 1.84 6.48 0.000 WBC count 1.000 1.00 1.00 0.584 Neutrophil count 1.000 1.00 1.00 0.044 Lymphocyte count 0.999 1.00 1.00 0.003 Multiplicity 0.858 0.43 1.72 0.667 Thyroiditis 0.472 0.17 1.33 0.155 NLR 1 st quartile 1 - - 2 nd quartile 1.220 0.33 4.54 0.767 3 rd quartile 2.001 0.59 6.84 0.269 4 th quartile 5.844 2.02 16.90 0.001 LN = lymph node; WBC = white blood cell; NLR = neutrophillymphocyte ratio. 양크기, 림프절전이여부역시통계학적으로의미있는상관관계를보였다 (P=0.019, P=0.000, P=0.000). 한편백혈구수치는재발과통계학적으로유의한상관관계를보이지않았으나
한세웅외 : NLR for Predicting Recurrence of Papillary Thyroid Carcinoma 187 Table 4. Multivariate cox proportional regression analysis of relationship between recurrence and clinicopathologic factors of papillary thyroid carcinoma Characteristics ODDS Ratio 95% CI P value NLR 1 st quartile 1 - - 2 nd quartile 1.067 0.27 4.27 0.927 3 rd quartile 1.792 0.51 6.36 0.367 4 th quartile 5.419 1.87 15.71 0.002 LN metastasis 2.37 1.23 4.56 0.002 Tumor size 1.06 1.02 1.09 0.002 NLR = neutrophil-lymphocyte ratio; LN = lymph node. (P=0.584), 호중구 (P=0.044) 와림프구 (P=0.003) 는통계적으로의미있는상관관계를보였다 (P=0.044, P=0.003) (Table 3). 다변량분석에서도 NLR은 4번째그룹에서 1번째그룹에비해통계적으로유의하게재발위험도가높았다 (P=0.002). 림프절전이여부와종양크기역시통계적으로의미있는상관관계를보였으나 (P=0.002, P=0.002), 나이와성별은통계적유의성을보이지않았다 (Table 4). ROC curve를이용하여재발과상관관계가있는 NLR의 cut-off 값을확인한결과 69.8% 의특이도와 66.7% 의민감도를가진 1.73의 cut-off 값이측정되었다 (Fig. 1, Table 5). 재발한 39명의환자중 66.7% 인 26명이 NLR 1.73 이상이었고, 33.5% 의환자가 NLR 1.73 미만이었다. NLR이 1.73 이상인 125명의환자중 26명 (20.8%) 의환자가재발하였고, 1.73 미만인 242명중 13명 (5.4%) 이재발하였다. 이에따라수술전 NLR이 1.73 이상인환자군의재발위험도는 4.6배로측정되었다. 고찰 최근에 NLR은암을포함한여러질병에서재발및예후와관련이있는인자로보고되고있는데, 감염성심내막염,(18) 급성충수돌기염 (19) 과같은염증질환에서예후와관련이있다고알려졌으며, 심장관상동맥질환 (20) 에서도연관이있다고보고되었다. 1996년 Lopez Hänninen이 (21) 전이성신장암에서호중구가불량한예후와관계가있음을발표한이후, 여러암에서유사한결과가보고되었으나현재까지 NLR과갑상선암의예후와의관련성에관한보고는거의없었다. 염증과암과의관계는그기전이명확히밝혀지지않았지만몇몇연구에서종양과관련된호중구증 (neutrophilia) 은효소작용을통해세포외기질을재구성 (remodeling) 하여결과적으로섬유아세포성장인자 (fibroblast growth factor) 를분비하고, 내피세포 (endothelial cell) 를이동시켜종양세포들을분리한다고하였다.(22) 또한호중구에서유래한활성산소 (reactive Fig. 1. ROC curve of NLR to predict recurrence in patients with papillary thyroid carcinoma. Table 5. Accuracy of NLR values NLR Sensitivity 1-Specificity Youden method 1.71818.692.314.378 1.72477.692.310.381 1.72614.692.308.384 1.72973.692.302.391 1.73707.667.299.368 1.73707.667.302.365 1.73864.692.305.368 1.75.641.299.387 1.75625.641.293.345 oxygen species) 는종양세포의세포자멸사 (apoptosis) 를억제하는 nuclear factor(nf)-kb를활성화시켜세포외기질의결합을파괴하는데이런작용들은결국혈관생성, 종양성장, 종양의전이등으로나타나게된다.(23) 또한림프구에관한연구에서는세포독성 T 림프구 (cytotoxic T lymphocyte) 가종양세포의세포자멸사 (apoptosis) 을유도한다고알려졌으며,(24) 췌장암에서는림프구감소증 (lymphopenia) 이좋지않은예후와관련이있다고보고되었다.(25) 이와같이여러연구들에서호중구증가와림프구감소가암의나쁜예후와관련있다고보고되었지만호중구와림프구는하루에도검사시기에따라그수치가달라진다고알려져있다. 즉, 낮에는호중구가증가하지만밤에는림프구가증가하며,(26) 따라서혈액채취시기에따른오류가있을수있어호중구와림프구수치자체보다는 NLR이종양에대한염증반응을더정확하게나타낸다고할수있다. 본연구에서 NLR은유두상갑상선암환자의종양크기와통계적유의성을보이지않아 Liu 등 (16) 이발표하였던기존의연구와는다른결과를보였다. 또한 NLR이연령이높아질수록올라가며,(27-29) 암의진행정도와 NLR값이상관관계가있다고
188 Korean J Endocr Surg 2014;14:184-189 journal.kates.or.kr 보고한기존의다른보고 (27) 와는달리본연구에서는 NLR이환자의성별, 연령, 림프절전이, TNM 병기와통계적유의성을보이지않았다. 이러한차이를보인이유에대해서는좀더심도깊은연구가필요한데, 암의진행정도가 NLR값과상관관계를보인이유가진행된암이더많은염증반응을유도하는지, 그렇지않으면염증그자체가종양을성장하게하고더잘퍼지게하는지규명하는것이선행되어야하겠다.(12) NLR과유두상갑상선암의재발과의상관관계에대해분석한결과 NLR은통계학적으로의미있는상관관계를보였다 (P< 0.0001). 이것은 Liu 등 (16) 이발표한연구에서보인수술전높은 NLR이갑상선암의재발과관련이있다는결과와일치한다. 통계적유의성을보였던 NLR과재발과의관계를 ROC curve를이용하여분석했을때, 1.73 ( 민감도 =0.667, 특이도 =0.698, P=0.001) 의 cut-off 값을구할수있었다. 따라서, 유두상갑상선암환자에서수술전혈액검사상 NLR이 1.73 이상인경우에는경부컴퓨터단층촬영을포함한보다정밀한검사와적극적인수술중경부림프절절제술을고려해볼수있으며수술후세심한추적관찰이필요할것으로보인다. 본연구의제한점은단일기관에서시행된후향적연구로대상군의수가부족하고 NLR과관련이있다고알려진여러인자 ( 흡연, 음주, 고혈압, 당뇨등 ) 들의선택적비뚤림 (selective bias) 이존재할수있으며종양과관련된호중구, 림프구에대한평가가부족하다는점이다. 그러나유두상갑상선암환자에서 NLR과재발과의관련성을밝힌기존의보고는극히드물다는점에의의를둘수있으며향후다기관, 전향적연구를통해유두상갑상선암의재발인자로서 NLR의역할을규명할수있을것으로생각한다. 결론 유두상갑상선암환자에서수술전혈중 NLR은기존에알려진다른예후인자들과상관관계를보이지않았다. 본연구에서갑상선유두암의재발과상관관계를보인 NLR의 cut-off value 는 1.73이었다. 따라서수술전혈중 NLR이 1.73 이상인환자들의수술및추적관찰에좀더세심한주의를요하며, 향후다기관, 전향적연구를통해 NLR을유두상갑상선암의새로운재발인자로고려할수있을지밝히려는노력이필요하다. REFERENCES 1. Mazzaferri EL, Kloos RT. Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86:1447-63. 2. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297-306. 3. Sherman SI. Thyroid carcinoma. Lancet 2003;361:501-11. 4. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418-28. 5. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214. 6. Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol 2013;33 Suppl 1:S79-84. 7. Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A. Molecular pathways in cancer-related inflammation. Biochem Med (Zagreb) 2011;21:264-75. 8. Gomez D, Farid S, Malik HZ, Young AL, Toogood GJ, Lodge JP, et al. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg 2008;32:1757-62. 9. Gomez D, Morris-Stiff G, Toogood GJ, Lodge JP, Prasad KR. Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol 2008;97:513-8. 10.Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91:181-4. 11. Ohno Y, Nakashima J, Ohori M, Hatano T, Tachibana M. Pretreatment neutrophil-to-lymphocyte ratio as an independent predictor of recurrence in patients with nonmetastatic renal cell carcinoma. J Urol 2010;184:873-8. 12. Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer 2013;16:55-9. 13. Hirashima M, Higuchi S, Sakamoto K, Nishiyama T, Okada H. The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer. J Cancer Res Clin Oncol 1998;124:329-34. 14. Bhatti I, Peacock O, Lloyd G, Larvin M, Hall RI. Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil- lymphocyte versus platelet-lymphocyte ratio. Am J Surg 2010; 200:197-203. 15. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 2009;137:425-8. 16. 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;107:493-7. 17. Yi KH, Park YJ, Koong SS, Kim JH, Na DG, Ryu JS, et al. Revised Korean thyroid association management guidelines for patients with thyroid nodules and thyroid cancer. Endocrinol Metab 2010;25:270-97.
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