원저 Lab Med Online Vol. 5, No. 3: 143-148, July 2015 임상화학 폐암환자에서 Cyfra 21-1 의진단적유용성평가 Diagnostic Utility of Serum Cytokeratin Fragment 21-1 in Patients with Lung Cancer 송성욱 유은형 조현정 Sungwook Song, M.D., Eun-Hyung Yoo, M.D., Hyun-Jung Cho, M.D. 건양대학교의과대학진단검사의학교실 Department of Laboratory Medicine, Konyang University Hospital, Konyang University College of Medicine, Daejeon, Korea Background: Lung cancer is the most lethal malignant neoplasm in the world. Serum cytokeratin fragment 21-1 (Cyfra 21-1) is a valuable tumor marker for detection of lung cancer, and it has good sensitivity and specificity. The aim of this study was to investigate the diagnostic value of Cyfra 21-1 levels in patients with lung cancer. Methods: We retrospectively reviewed 814 samples from 169 patients with lung cancer, 124 patients with benign pulmonary diseases, and 521 normal controls from health check-up clinic. Serum Cyfra 21-1 levels were determined with Architect CYFRA 21-1 kit (Abbott, USA) using Architect i2000 analyzer. Results: Median levels and interquartile ranges for Cyfra 21-1 in patients with lung cancer (non-small cell lung cancer: 3.16 [ 1.98, 9.00] ng/ml, small cell lung cancer: 3.32 [ 2.07, 5.20] ng/ml) were higher than those in patients with benign pulmonary diseases (1.50 [ 1.17, 2.17] ng/ml; P < 0.01) and in normal controls (1.26 [ 0.93, 1.75] ng/ml; P <0.01). Sensitivity, specificity, positive predictive value, and negative predictive value for Cyfra 21-1 were 70.4%, 81.2%, 49.6%, and 91.3%, respectively. The area under the curve for Cyfra 21-1 was 0.839 (95% confidence interval, 0.802-0.877). Conclusions: We concluded that Cyfra 21-1 may be useful in the diagnosis of lung cancer. Key Words: Cyfra 21-1, Lung cancer, Tumor marker 서론 폐암은전세계적으로발생률이가장높은암중의하나이며, 암 과연관된사망의주요원인으로알려져있다 [1, 2]. 국내에서도폐 암은 2011 년 10 만명당 43.4 명의발생률을보이며전체암중네번 째로흔하게발생하였으며, 인구 10 만명당 33.1 명의사망률을보 여암으로인한사망의가장흔한원인으로보고되었다 (2013 년통 계청발표 ). 폐암은비소세포성폐암과소세포성폐암으로크게구 분되는데, 비소세포성폐암은전체폐암의 85% 를차지하며편평세 Corresponding author: Hyun-Jung Cho Department of Laboratory Medicine, Konyang University Hospital, 158 Gwangeodong-ro, Seo-gu, Daejeon 371-713, Korea Tel: +82-42-600-9273, Fax: +82-42-600-9272, E-mail: hjchomd@kyuh.ac.kr Received: August 13, 2014 Revision received: March 6, 2015 Accepted: March 6, 2015 This article is available from http://www.labmedonline.org 2015, Laboratory Medicine Online 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. 포암, 선암, 대세포암등이이에해당한다 [3]. 폐암환자는특이증상을보이는경우가드물며, 특히초기단계에는더욱그러하다. 그러므로폐암환자는처음진단시이미병기가진행되어효과적인치료시기를놓치는경우가많으므로생존율향상을위해조기진단및수술이필수적이다. 현재고식적진단법인단순흉부방사선사진, 흉부컴퓨터단층촬영, 굴곡기관지경술등은폐암을조기진단하기에는민감도및특이도가좋지못하다. 반면생검조직을필요로하는병리학적, 세포학적검출방법도침습적이며, 반복측정하기어렵다는단점이있다 [1]. 한편혈청종양표지자는악성종양을진단하는비침습적인진단방법이며, 예후를예측하고, 치료의효과를판정하는데에좋은인자로널리이용되고있다. 이중폐암표지자로암배아항원 (CEA, carcinoembryonic antigen), 편평세포암항원 (SCC Ag, squamous cell carcinoma antigen), 뉴런특이에놀라아제 (NSE, neuron-specific enolase), 사이토케라틴분절 21-1 (Cytokeratin fragment 21-1, Cyfra 21-1) 등이알려져있다. 이중 Cyfra 21-1 은 cytokeratin 19의분절로 1993년폐암표지자로제시된이후그유용성에관한연구가계속해서진행되고있으며, 많은연구에서비소세포성폐암의표지자로서가치를인정받고있다 [4, 5]. 특히 Cyfra 21-1 은암병기와관 eissn 2093-6338 www.labmedonline.org 143
련이있으며, 암이진행될수록그리고예후가좋지않을수록양성률및측정값이증가하며, 비소세포성폐암의항암치료에대한반응을예측하는인자로도이용될수있다고보고되었다 [4, 6-9]. 따라서본연구에서는폐암의높은발병률및치사율에따른중요성을감안하여 Cyfra 21-1의진단적유용성을확인하고자폐암환자, 폐암과감별이필요한다양한양성폐질환자및정상인에서 Cyfra 21-1을측정하여민감도및특이도를평가하고, 병기에따른차이및 Receiver operating characteristic (ROC) curve 분석을하였다. 재료및방법 1. 연구대상 본연구는 2012년 12월부터 2014년 2월까지건양대학교병원을방문하여 cyfra 21-1검사를시행한 814명을대상으로후향적으로분석하였다. 기관지내시경또는객담도말세포검사, 경피적조직생검으로확진된원발성폐암환자 169명을폐암군으로하고, 폐암이배제된양성폐질환환자 124명을환자대조군및건강한건강검진환자 521명을정상대조군으로연구를진행하였다. 폐암군은소세포성폐암 16명, 비소세포성폐암 153명 ( 편평상피암 60명, 선암 73명, 기타폐암 20명 ) 이었다. 양성폐질환환자는양성고립성폐결절 20명, 폐결핵 14명, 폐렴 36명, 만성폐쇄성폐질환 11명, 기 타양성폐질환 43명이었다 (Table 1). 2. Cyfra 21-1 및 CEA 측정방법 Cyfra 21-1은혈청에서화학발광미세입자면역분석법 (chemiluminescent micro-particle immunoassay) 을이용하는 Architect CYFRA 21-1 assay kit (Abbott, Malvern, PA, USA) 로측정하였다. CEA는혈청에서화학발광효소면역분석법을이용하는 Access CEA kit (Beckman Coulter Inc., Fullerton, CA, USA) 로측정하였다. Cyfra 21-1 과 CEA의참고치는각각본원에서사용중인 2.08 ng/ml 이하, 5.00 ng/ml 이하로하였다. 3. 통계학적분석통계분석은 Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) 과 SPSS 12.0K (SPSS Inc., Chicago, IL, USA) 를사용하여, 종양표지자의혈중중앙값의비교는 Mann-Whitney U- test를시행하였고, 병기와종양표지자의혈중농도비교는 Kruskall-Wallis test를시행하였다. 현재사용중인결정치를기준으로폐암에대한민감도 (sensitivity), 특이도 (specificity), 양성예측치 (positive predictive value, 및음성예측치 (negative predictive value) 를비교하였다. 또한 ROC 곡선분석을통해현재결정치로이용중인 2.08 ng/ml의타당성을평가하였다. Table 1. Patient characteristics Patient group (N) Gender Lung cancer group (N=169) Benign pulmonary disease group (N=124) Normal group (N=521) Male 123 (24.0%) 94 (18.3%) 296 (57.7%) <0.001 Female 46 (15.3%) 30 (10.0%) 225 (74.8%) Average age (yr) 69.5±9.7 57.6±17.3 39.5±10.7 <0.001 Histology Adenocarcinoma 73 (43.2%) Squamous cell carcinoma 60 (35.5%) Small cell carcinoma 16 (9.5%) Other types of carcinoma 20 (11.8%) Stage I 34 (20.1%) II 15 (8.9%) III 34 (20.1%) IV 85 (50.3%) Unknown 1 (0.6%) Characteristics of benign pulmonary diseases Benign solitary pulmonary nodule 20 (16.1%) Pulmonary tuberculosis 14 (11.3%) Pneumonia 36 (29.0%) Chronic obstructive lung disease 11 (8.9%) Others 43 (34.7%) P value 144 www.labmedonline.org
결과 연구대상자분석에서성별및나이에따른비교군간의차이가존재하여 (P <0.001), 폐암여부에따른다변량분석을위해이분형로지스틱회귀분석을시행하였다. 성별은폐암여부에통계학적으로유의하게영향을미치지않는것으로 (P = 0.893), 나이와 Cyfra 21-1은유의한영향을미치는결과를보였다 (P <0.001) (Table 2). 폐암의조직학적분류에따른 Cyfra 21-1의혈중중앙값및사분범위는비소세포성폐암 3.16 (1.98, 9.00) ng/ml, 소세포성폐암 3.32 (2.07, 5.20) ng/ml로두군모두양성폐질환군 1.50 (1.17, 2.17) ng/ml 및정상대조군 1.26 (0.93, 1.75) ng/ml에비해통계적으로유의하게증가되어있었다 (P <0.01). 이에비해 CEA의혈중평균치는양성폐질환군이 1.81 (1.37, 3.21) ng/ml로비소세포성폐암 3.85 (2.14, 10.53) ng/ml과는통계적으로유의한차이가있었으나 (P <0.01), 소세포성폐암 3.0 (1.44, 4.60) ng/ml과는통계적으로유의한차이를보이지않았다 (P = 0.103). 또한 Cyfra 21-1과 CEA 모두비소세포성폐암과소세포성폐암간에통계적으로유의한차이를보이지않았다 ( 비소세포성폐암 vs. 소세포성폐암 : Cyfra 21-1, P = 0.591; CEA, P = 0.176) (Table 3). 또한비소세포성폐암군중편평상피암과선암간의비교에서는 Cyfra 21-1, CEA 모두통계학적으로유의한차이를보이지않았다 (Cyfra 21-1, P = 0.058; CEA, P = 0.145). 본연구에서는정상대조군의 CEA를측정하지않아 CEA의정상대조군과폐암및양성폐질환군의차이를비교할수없었다. Table 4는 Cyfra 21-1의폐암에대한결정치를 2.08 ng/ml로하 Table 2. Multivariate analysis for lung cancer patients Variable Odds ratio 95% confidence interval P value Sex 0.961 0.542 1.707 0.893 Age 1.780 1.490 2.126 <0.001 Cyfra 21-1 1.110 1.089 1.132 <0.001 였을때, 민감도, 특이도, 양성예측치, 음성예측치를분석하였고, CEA 관해서는결정치 5.0 ng/ml 기준으로민감도를, Cyfra 21-1 과 CEA를동시측정한경우의민감도를분석하였다. 이분석에서도정상대조군의 CEA를측정하지않아특이도등을평가할수없었다. Cyfra 21-1 와 CEA를단독으로측정한경우, 민감도는 70.4%, 36.7% 로 Cyfra 21-1이우수함을알수있었고, 동시측정한경우 75.1% 로 Cyfra 21-1을단독측정했을때보다다소증가하였다. Cyfra 21-1의특이도, 양성예측치및음성예측치는각각 81.2%, 49.6%, 91.3% 였다. 특히 521명의정상대조군중 86명 (16.5%) 에서다소높은위양성률을보였으며, 이들의중앙값및사분범위는 2.63 (2.31, 2.93) ng/ml였다. 위양성을보인 86명중 68명이위염진단을받고나머지 18명은특이소견이관찰되지않았거나위장관계용종또는지방간으로진단되었다. 혈중 Cyfra 21-1 농도를이용한 ROC 곡선분석에서곡선하면적 (AUC, Area under the curve) 이 0.839 (95% confidence interval 0.802-0.877) 였으며, 특히폐암중 Cyfra 21-1에민감한것으로알려진편평상피암환자에대한분석에서곡선하면적이 0.866 (95% CI 0.810-0.922) 으로현재결정치로사용중인 2.08 ng/ml가적절함을확인하였다 (Fig. 1). 본연구에서두표지자를이용한병기간차이의비교에서 CEA 의 P값은 0.078로병기간의혈중농도사이에유의한차이는없었으나, Cyfra 21-1 의 P값은 0.001 미만으로혈중농도차이가있는병기가존재했으며, Mann Whitney U test를이용한사후검정에서유의수준 0.0125 기준으로폐암 4기와폐암 1, 2, 3기각각의비교에서차이를보였다. 폐암의조기인 I, II기 (n=49) 와진행된 III, IV 기 (n=119) 의두군으로살펴보았을때, Cyfra 21-1 의중앙값및사분범위가각각 2.00 (1.40, 3.29) ng/ml, 5.09 (2.57, 10.10) ng/ml, CEA의중앙값및사분범위는각각 3.16 (1.59, 4.47) ng/ml, 4.26 (2.18, 12.79) ng/ml로두종양표지자모두조기암군및진행된암군간에통계학적으로유의한차이를나타내었다 (Cyfra 21-1, P <0.001; CEA, P = 0.021). 특히결정치를기준으로 Cyfra 21-1은 Table 3. Cyfra 21-1 and CEA levels (median [interquartile range]) Normal group (N=521) Benign pulmonary disease group (N=124) Lung cancer group (N=169) NSCLC (N=153) SCLC (N=16) Cyfra 21-1 ng/ml 1.26 1.5 3.16 3.32 (0.93, 1.75) (1.17, 2.17) (1.98, 9.00)* (2.07, 5.20)* CEA ng/ml NT 1.81 3.85 3 (1.37, 3.21) (2.14, 10.53)* (1.44, 4.60) *P<0.01 compared with the normal group or benign pulmonary disease group; P=0.591 compared with SCLC; P=0.176 compared with SCLC; P=0.103 compared with the benign pulmonary disease group. Abbreviations: NSCLC, non-small cell lung carcinoma; SCLC, small cell lung carcinoma; NT, not tested. Table 4. Sensitivity, specificity, positive predictive value, and negative predictive value for Cyfra 21-1 and CEA in lung cancer diagnosis Tumor marker (ng/ml) Sensitivity (95% CI) Specificity (95% CI) PPV (95%CI) NPV (95% CI) Cyfra 21-1>2.08 70.4 81.2 49.6 91.3 (0.635 0.773) (0.782 0.842) (0.433 0.559) (0.890 0.936) CEA>5 36.7 NT NT NT Cyfra 21-1 >2.08 or CEA>5 (0.294 0.440) 75.1 (0.686 0.816) NT NT NT Abbreviations: PPV, positive predictive value; NPV, negative predictive value; NT, not tested; CI, confidence interval. www.labmedonline.org 145
1.0 1.0 0.8 0.8 Sensitivity 0.6 0.4 Sensitivity 0.6 0.4 0.2 0.2 0 0 0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 1-Specificity A 1-Specificity Fig. 1. Receiver operating characteristic (ROC) curve using serum Cyfra 21-1 level to discriminate between the lung cancer and control groups (A) (AUC = 0.839 [95% CI, 0.802-0.877]) and the squamous cell cancer and control groups (B) (AUC = 0.866 [95% CI, 0.810-0.922]). B % 100 90 80 70 60 50 40 30 20 10 0 n=49 n=119 n=49 n=119 Stage I, II Stage III, IV Stage I, II Stage III, IV Fig. 2. Positive rates of CEA and Cyfra 21-1 for lung cancer based on the stages of lung cancer. 조기암과진행된암군에서각각 46.9%, 81.5% 의양성률을보였으 며, CEA 도두암군에서각각 69.4%, 80.7% 의양성률로폐암의병 기가진행될수록두종양표지자모두증가하는경향을보였다 (Fig. 2). 또한암의전이여부와관련하여 Cyfra 21-1 은전이가있는 환자군에서증가하는경향을보였으나 (P <0.01), CEA 는두군간 차이를보이지않았다 (P = 0.079). CEA Cyfra 21-1 고찰 Negative Positive Cyfra 21-1 과 CEA 는폐암의조기진단, 예후및치료모니터링에 민감하고유용한표지자로알려져있다 [10]. 특히 Cyfra 21-1 은비 소세포성폐암에서, 그중에서도편평세포암에민감한종양표지자 이다. Cytokeratin의역할이정확하게알려져있진않지만정상및비정상세포의골격을이루는것으로알려져있으며, 특히 cytokeratin 19가폐암에서증가되어있다 [3, 11-13]. Cyfra 21-1 검사는 cytokeratin 19의분절만을측정하기때문에 cytokeratin 8, 18, 19 가혼합된 tissue peptide antigen (TPA) 를측정하는것보다특이성이높다 [1, 5]. 최근의많은연구에서폐암의예후예측및치료모니터링에 Cyfra 21-1을이용하고있다. Cyfra 21-1 의수치가낮은경우 Gefitinib 또는 Erlotinib 등의 Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) 에치료효과가좋거나생존율이우수하다는보고가있다 [4, 6, 8, 10]. 본연구에서는폐암의진단에있어서 Cyfra 21-1의유용성을평가하고자하였다. Cyfra 21-1 은정상혹은양성폐질환군에비해비소세포성폐암및소세포성폐암모두에서통계학적으로유의한차이를보이며높게측정되었으나 (P <0.01), CEA는소세포성폐암환자에서양성폐질환군과유의한차이를보이진않았다 (P = 0.103) (Table 3). 특히본연구에서는비소세포성폐암과소세포성폐암사이에 Cyfra 21-1의수치가통계학적으로차이를보이지않아비소세포성폐암에서 Cyfra 21-1이증가하는것으로보고한여러연구와는차이를보였다 [1, 4, 5]. 하지만또다른연구들에서는상당수의소세포성폐암에서일부상피세포가분화가동반된폐암의이질성 (heterogeneity) 이있을수있거나소세포성폐암자체내에서 cytokeratin을발현시킬수있어 Cyfra 21-1이높게측정될수있다고보고하였다 [3, 5, 13]. 결국두폐암군의차이가통계적으로차이를보이지않은것은소세포성폐암환자의수 (16명 ) 가비소세포성폐암환자수 (153명 ) 보다극히적은것, 비소세포성폐암에편평상피암이외의다른폐암환자 (93명) 가많이포함된것, 그리고앞의연구에서보인폐암의이질성때문으로판단되었 146 www.labmedonline.org
다. 또한편평상피암과선암간에 Cyfra 21-1의통계적차이를보이지않은데에는선암환자 73명중암의전이가있는환자가 34명으로편평상피암환자 60명중암전이환자가 22명인것에비해높은비율을차지하였기때문으로판단된다. 이는여러연구에서비소세포성폐암의병기가진행될수록 Cyfra 21-1이증가한다는보고와일치한다 [1, 4, 7]. Cyfra 21-1 은민감도 70.4%, 특이도 81.2%, 양성예측치 49.6%, 음성예측치는 91.3% 를보였고, CEA와동시측정시에민감도가 75.1% 로증가하여폐암의선별검사시다른종양표지자들과함께측정할경우유용성이더욱증가할것으로판단되었다. 이는여러연구에서 Cyfra 21-1과 CEA, NSE, SCC Antigen을함께측정하여폐암진단의효율성을개선하였다는보고와일치한다 [1, 14-16]. Cyfra 21-1 의양성예측치가낮은이유는본연구에서건강검진자를대상으로한정상군이폐암환자군에비해월등히많기때문으로판단된다. 이는최근일본의한연구에서보고한폐암의유병률에따라 Cyfra 21-1의양성예측치가달라진다는것과일치한다. 이보고에의하면, 입원환자의폐암환자유병률 51%, 외래환자폐암유병률 12%, 건강검진자폐암유병률 0.1% 일경우에 Cyfra 21-1의양성예측치는각각 80.3%, 34.8%, 0.39% 로유병률이감소할수록양성예측치가감소하였다 [15]. Cytokeratin 은정상조직의상피세포에도존재하여이의손상이있는경우증가할수있으며, 이는본연구의정상대조군중위염, 위장관계용종, 지방간을보였던대상에서 Cyfra 21-1이 16.5% 라는높은빈도로위양성을보인결과와일치한다 [3, 8]. Cyfra 21-1 을이용한 ROC 곡선분석에서곡선하면적이 0.839 (95% confidence interval 0.802-0.877) 로폐암의선별검사시 Cyfra 21-1을유용하게사용할수있을것으로판단되었으나폐및소화기계양성질환등에서도위양성을보일수있음을항상고려해야할것이다. 몇몇종양표지자의경우종양의병기가증가함에따라수치가증가하는것으로알려져있으며, Cyfra 21-1 과 CEA의경우도진행된폐암에서혈중농도가증가하는것으로보고되었다 [17-19]. 본연구에서는 CEA의병기간의혈중농도사이에유의한차이는없었으나, Cyfra 21-1 의병기간혈중농도의차이가있음을확인하여앞선연구들의결과를뒷받침하였다. 특히수술여부를결정하는데중요한조기폐암 (Ⅰ, Ⅱ) 과진행된폐암 (Ⅲ, Ⅳ) 의두군으로구분하여 Cyfra 21-1과 CEA의혈중농도를비교하였을때, 진행된폐암군에서높은농도를보였다 (P <0.01). 또한암의전이여부에따른 Cyfra 21-1과 CEA의분석에서도 Cyfra 21-1에서만두군간의통계학적의미있는차이를보였다 (P <0.01). 한편다른연구들에서는종양의병기간 Cyfra 21-1의평균혈중농도가통계학적으로유의한차이를보이지않았다 [3, 20]. 이러한연구들간의결과차이는진행된병기혹은전이여부등의검체성상의차이에인한것으로판단된다. 본연구는단일기관에서 Cyfra 21-1을측정한대상을후향적으로분석하여얻어진결과로선택편향 (selection bias) 이있을수있으며, 특히건강검진자군의 CEA 결과가누락되었다. 이로인해 CEA 단독및 Cyfra 21-1과복합측정시특이도, 양성예측치, 음성예측치를구할수없었던단점이있다. 또한연구대상자분석에서비교군간나이차이가존재하며나이가증가할수록폐암의발병률이증가하는결과를보였다. 따라서이후다기관연구를통해환자군을넓히고, 나이차를보정하여전향적인분석을한다면좀더정확하고의미결과를도출할수있을것이다. 폐암, 특히비소세포성폐암은진단법의발전에도불구하고진단시이미진행된병기로발견되어수술적치료가힘든경우가많다. Cyfra 21-1 은폐암의진단에우수한민감도, 특이도를가진종양표지자이며, 선별검사시기존의종양표지자와동시에사용할경우더욱효과적으로사용될수있을것으로판단되었다. 또한폐암의병기, 전이에대한예측인자로도의미가있을것으로판단되며이에대한연구도지속적으로필요할것이다. 요약 배경 : 폐암은전세계적으로가장치명적인암중의하나이다. 혈청사이토케라틴분절 21-1 (Cytokeratin fragment 21-1, Cyfra 21-1) 측정은폐암의진단에서좋은민감도와특이도를지닌종양표지자로알려져있다. 본연구에서폐암의선별검사로 Cyfra 21-1의유용성을평가하고자한다. 방법 : 연구대상은건양대학교병원을방문한폐암환자 169명, 양성폐질환자 124명, 정상건강검진자 521명으로총 814명을후향적으로분석하였다. 혈청 Cyfra 21-1은 Architect CYFRA 21-1 kit를이용하여 Architect i2000 분석기에서측정하였다. 결과 : 폐암환자에서 Cyfra 21-1의중앙값및사분범위 ( 비소세포성폐암 : 3.16 [1.98, 9.00] ng/ml, 소세포성폐암 : 3.32 [2.07, 5.20] ng/ ml) 는양성폐질환자 (1.50 [1.17, 2.17] ng/ml) 및정상군 (1.26 [0.93, 1.75] ng/ml) 보다통계적으로유의하게높았다 ( 각각 P <0.01). Cyfra 21-1의민감도, 특이도, 양성예측치, 음성예측치는각각 70.4%, 81.2%, 49.6%, 91.3% 였다. 또한 Cyfra 21-1 의곡선하면적은 0.839 (95% confidence interval 0.802-0.877) 였다. 결론 : 본연구결과 Cyfra 21-1은폐암을진단하는데유용한종양표지자임을확인할수있었다. REFERENCES 1. Wang R, Wang G, Zhang N, Li X, Liu Y. Clinical evaluation and cost-effectiveness analysis of serum tumor markers in lung cancer. Biomed www.labmedonline.org 147
Res Int 2013;2013:195692. 2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917. 3. Park HD, Jeong HS, Park JS, Lim SH, Lee EJ, Yun JW, et al. Usefulness of cyfra 21-1 as a tumor marker of lung cancer. Korean J Med 2002;62: 415-21. 4. Park SY, Lee JG, Kim J, Park Y, Lee SK, Bae MK, et al. Preoperative serum CYFRA 21-1 level as a prognostic factor in surgically treated adenocarcinoma of lung. Lung Cancer 2013;79:156-60. 5. Stieber P, Bodenmüller H, Banauch D, Hasholzner U, Dessauer A, Ofenloch-Hähnle B, et al. Cytokeratin 19 fragments: a new marker for non-small cell lung cancer. Clin Biochem 1993;26:301-4. 6. Edelman MJ, Hodgson L, Rosenblatt PY, Christenson RH, Vokes EE, Wang X, et al. CYFRA 21-1 as a prognostic and predictive marker in advanced non-small cell lung cancer in a prospective trial: CALGB 150304. J Thorac Oncol 2012;7:649-54. 7. Lee S, Lee CY, Kim DJ, Hong DJ, Lee JG, Chung KY. Pathologic correlation of serum carcinoembryonic antigen and cytokeratin 19 fragment in resected nonsmall cell lung cancer. Korean J Thorac Cardiovasc Surg 2013;46:192-6. 8. Ono A, Takahashi T, Mori K, Akamatsu H, Shukuya T, Taira T, et al. Prognostic impact of serum CYFRA 21-1 in patients with advanced lung adenocarcinoma: a retrospective study. BMC Cancer 2013;13:354. 9. Chen Q, Ge F, Cui W, Wang F, Yang Z, Guo Y, et al. Lung cancer circulating tumor cells isolated by the EpCAM-independent enrichment strategy correlate with Cytokeratin 19-derived CYFRA21-1 and pathological staging. Clin Chim Acta 2013;419:57-61. 10. Jung M, Kim SH, Hong S, Kang YA, Kim SK, Chang J, et al. Prognostic and predictive value of carcinoembryonic antigen and cytokeratin-19 fragments levels in advanced non-small cell lung cancer patients treated with gefitinib or erlotinib. Yonsei Med J 2012;53:931-9. 11. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31:11-24. 12. Niklinski J, Furman M, Rapellino M, Chyczewski L, Laudanski J, Oliaro A, et al. CYFRA 21-1 determination in patients with non-small cell lung cancer: clinical utility for the detection of recurrences. J Cardiovasc Surg (Torino) 1995;36:501-4. 13. Pujol JL, Grenier J, Daurès JP, Daver A, Pujol H, Michel FB. Serum fragment of cytokeratin subunit 19 measured by CYFRA 21-1 immunoradiometric assay as a marker of lung cancer. Cancer Res 1993;53: 61-6. 14. Cho KJ, Lee KH, Lee JW, Song KE, Lee WK, Kim JS, et al. CYFRA 21-1, the new marker for lung cancer. Korean J Clin Pathol 1997;17:55-64. 15. Okamura K, Takayama K, Izumi M, Harada T, Furuyama K, Nakanishi Y. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer 2013;80:45-9. 16. Yu H, Huang X, Zhu Z, Hu Y, Ou W, Zhang L, et al. Significance of combined detection of LunX mrna and tumor markers in diagnosis of lung carcinoma. Chin J Cancer Res 2014;26:89-94. 17. Hatzakis KD, Froudarakis ME, Bouros D, Tzanakis N, Karkavitsas N, Siafakas NM. Prognostic value of serum tumor markers in patients with lung cancer. Respiration 2002;69:25-9. 18. Kulpa J, Wójcik E, Reinfuss M, Kolodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem 2002; 48:1931-7. 19. Schneider J. Tumor markers in detection of lung cancer. Adv Clin Chem 2006;42:1-41. 20. Haam SJ, Kim GD, Cho SH, Lee DY. Clinical effectiveness of tumor markers (CEA, NSE, Cyfra 21-1) in completely resected non-small cell lung cancer. J Lung Cancer 2006;5:75-83. 148 www.labmedonline.org