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1 Korean J Urol Oncol 2016;14(2):69-75 Original Article 비근육침습성방광요로상피세포암에서 p53, c-erb-b2, Ki-67 의발현이예후에영향을미치는가? 대구가톨릭대학교의과대학 1 비뇨기과학교실, 2 병리학교실, 3 경북대학교의학전문대학원생리학교실 강석현 1 ㆍ정현진 1 ㆍ양은경 2 ㆍ박재신 1 ㆍ오훈규 3 ㆍ김덕윤 1 Is the Expression of p53, c-erb-b2 and Ki-67 Influence the Prognosis of the Non-muscle Invasive Urothelial Bladder Cancer? Seok Hyun Kang 1, Hyun Jin Jung 1, Eun Kyoung Yang 2, Jae Shin Park 1, Hoon Kyu Oh 3, Duk Yoon Kim 1 1 Department of Urology, School of Medicine, Catholic University of Daegu, 2 Department of Physiology, School of Medicine, Kyungpook National University, 3 Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu, Korea Purpose: The immunohistochemial markers can be used to predict prognosis more accurately for several cancers. In non-muscle invasive urothelial carcinoma, p53, c-erb-b2 and Ki-67 are applicable. We investigated a retrospective analysis of the relation between the markers and clinical prognostic factors of urothelial bladder cancer. Materials and Methods: Data from 268 non-muscle invasive urothelial bladder cancer (Ta, T1) patients from one single center were collected. Immunohistochemical evaluation was carried out on 268 (p53, c-erb-b2, Ki-67) cases. Clinical prognostic factors are as follows; number of tumor, tumor invasiveness, tumor grade and recurrence. The sum of all positivity of 3 markers was made as a new factor and evaluation of correlation between this factor and prognostic factors was also done. Statistical analysis was done by chi-squares test and Pearson s correlation test. Results: Through chi-square test, there were significant relations between all markers and tumor invasiveness (p), tumor grade (p). Number of tumor is significantly related with Ki-67 (p=0.043). Recurrence is related with c-erb-b2 (p=0.010) and Ki-67 (p=0.043). There was also significant correlations between the sum of the markers and prognostic factors-tumor invasiveness (p<0,001), tumor grade (p) and recurrence (p=0.007). Conclusions: In this study, evaluated markers were closely related with clinical prognostic factors and may contribute to decision making on risk-assessment and management strategy for non-muscle invasive urothelial bladder cancer. (Korean J Urol Oncol 2016;14:69-75) Key Words: Urinary bladder neoplasms, Immunohistochemistry, Risk assessment Received May 17, 2016, Revised June 29, 2016, Accepted July 25, 2016 Corresponding Author: Duk Yoon Kim, Department of Urology, School of Medicine, Catholic University of Daegu, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Korea. Tel: , Fax: , dykim@cu.ac.kr 서론방광암은가장흔한요로계악성종양중하나로, 전세계적으로남성의경우 10만명중 10명, 여성은 10만명중 3명 69

2 70 대한비뇨기종양학술지 : 제 14 권제 2 호 2016 의유병률을가지고있으며그비율은점차증가하는양상을보이고있다. 1 대부분은근육을침범하지않은초기종양으로진단되나잦은재발과근육침윤성으로진행하는위험성으로인해진단후경과및위험도판정, 즉예후에대한판단이치료계획설정에중요한요인이된다. 2 방광암은수술후 1년내재발할확률 15-70%, 5년내진행확률은 7-40% 로상당히넓은분포를보인다. 3,4 따라서, 같은방광암이라하더라도진행및재발에있어서로다른위험도를가짐을예상할수있다. 5 많은연구들이종양의진행과예후에연관된인자를찾기위해진행되었으며, 병기, 악성도, 크기등의인자들이방광암의진행과연관이있음이밝혀졌고, 세계보건기구 (WHO) 에서이를토대로한분류체계를정립하였다. 그러나, 이인자들만으로는임상적경과및예후를정확히판단하는것이불가능하며, 6,7 조직학적기준만을근거로요로상피의병인을이해하기또한매우어렵다는것이밝혀지게되었다. 8 따라서예후와더밀접한연관성을가진다른인자들에대한연구가진행되어왔으며, 면역조직학적표지자 (immunohistochemical markers) 들이여러종류의악성종양에있어발생, 진행, 전이등에관여하는것으로밝혀지고있다. 종양억제유전자 (tumor supressor gene) 또는발암유전자 (oncogene), 원암유전자 (proto-oncogene) 의형태로존재하는이들표지자중에는, 염색체 17p13.1에위치하는종양억제유전자인 p53, 염색체 17q에위치한 tyrosine kinase수용체그룹에작용하는성장인자인 c-erb-b2 (Her-2/ner), 세포증식과관련된표지자인 Ki-67 등이방광암의진행과연관이되어있다고알려져있다. 비근육침습성방광암에서이들표지자는추후근육침습성으로진행할가능성을알려주는지표로이용될수있으며, 이를통해진행이전에조기치료를시행할수있을것이다. 2 본연구에서는이러한표지자들중재발과관련된비근육침습성방광암의예후인자들을중점으로하여, 다발성, 고유층침습성, 등급과같은그외의예후인자들과의연관성이있는지를확인하고자하였다. 대상및방법 2006년 1월부터 2013년 3월사이본원에서경요도적방광종양절제술을시행한환자들중연구기간중새로진단된환자를대상으로하였으며 268명이연구에포함되었다. 요로상피암이외의다른종양으로진단된환자및재발환자 ( 과거첫진단이후연구기간내재발한경우 ) 는제외하였다. 모든검체는절제이후포르말린처리후병리과에서 haematoxylin-eosin 염색과면역조직화학염색을시행하였다. 본연구는본원연구윤리심의위원회에심의면제신 청을하여승인받았다. 연구대상이된모든검체를대상으로염색은 p53 ((Invitrogen, Carlsbad, California, USA, dilution 1:200); c-erb-b2 (DAKO, Glostrup, Denmark, dilution 1:500); Ki-67 (Cell Marque, Rocklin, California, USA, dilution 1:200) 을사용하여시행하였다 (Fig. 1). 염색결과에대한판독은병리학적근거에따라아래와같이시행하였다. p53, Ki-67은양성으로판정되는세포가없을때 (-), 양성세포가전체의 5% 미만일때 (+), 5%-10% 일때 (++), 10% 이상일때 (+++) 로판독하였으며, c-erb B2 의경우, 종양세포내에서염색된세포가발견되지않으면 (-), 종양세포내에염색된막 (membrane) 이보이나부분적으로만염색되었거나, 완전히염색된비율이 10% 이내일경우 (+), 막전체가염색되나전체를둘러싼특정한형태를띠는부분이 10% 에서 30% 사이일경우 (++), 특정한형태로저명하게염색되는부분이 30% 이상인경우를 (+++) 로판독하였다. 또한각표지자의양성도를숫자로환산후더하여 0-9점까지로계산한값을새로운변수 표지자합 (sum of the markers) 으로설정한후이변수와예후인자들과의연관성도비교하였다. 임상적예후인자로는종양의수 ( 단일성, 다발성 ), 침습도 ( 비침습성, 침습성 ; lamina propria 층침범여부로구분 ), 등급 ( 저등급, 고등급 ), 및재발여부 ( 연구기간내첫진단이된환자에서연구종료시점까지재발여부를의미함 ) 의 4가지인자를사용하였다. 통계분석은 IBM SPSS v.21.0 (IBM, Madison Avenue, New York, USA) 프로그램을사용하였으며, 분석기법은각그룹별차이를확인하기위해 Chi-square test를시행하였고, 표지자합과예후인자들과의상관관계는 Pearson s correlation test를이용해분석하였다. 모든분석에서통계적유의성은 p<0.05를기준으로판단하였다. 결과 1. 환자분포총 268명의환자들중, 남성은 205명 (76.9%), 여성은 62 명 (23.1%) 이었다. 종양의수로분류하면, 단일종양은 151 건 (56.3%), 다발성종양은 117건 (43.7%) 으로나뉘었다. 또한비침습성종양은 79건 (29.5%), 침습성종양은 189건 (70.5%) 이었으며, 저등급종양은 138건 (51.5%), 고등급종양이 130건 (48.5%) 이었다. 그리고 182건 (67.9%) 은초발성, 86건 (32.1%) 는재발성종양이었다 (Table 1).

강석현 외 비근육침습성 방광 요로상피세포암에서 p53, c-erb-b2, Ki-67의 발현이 예후에 영향을 미치는가? 71 Fig. 1.

Nuclear overexpression; was seen; (E, F) c-erb B2 immunohistochemistry.

(F) Positive finding: Membranous expression of c-erb B2 protein was seen;

3 강석현 외 비근육침습성 방광 요로상피세포암에서 p53, c-erb-b2, Ki-67의 발현이 예후에 영향을 미치는가? 71 Fig. 1. Imminohistochemical stainings in urothelial carcinoma of bladder (A, B) Ki-67 immunohistochemistry. (A) Negative finding: The Ki-67 positive cells only in basal layer; magnification x200. (B) Positive finding: The positive cells in whole layer of tumor cells; magnification x200. (C, D) p53 immunohistochemistry. (C) Negative finding: Basally located positive cells; magnification x200. (D) Positive finding: Nuclear overexpression; was seen; magnification x200. (E, F) c-erb B2 immunohistochemistry. (E) Negative finding: No expression of the c-erb B2; magnification x100. (F) Positive finding: Membranous expression of c-erb B2 protein was seen; magnification x 면역조직화학검사 본 연구에서는 3종의 면역조직화학 표지자 (p53, c-erb B2, Ki-67)가 이용되었다. 세 개 표지자 모두에서 음성 (-) 보다는 양성 ((+)에서 (+++))의 비율이 높았으며 p53에 (-)로 나타난 경우는 13건 (4.9%), (+)는 39건 (14.6%), (++)는 99건

4 72 대한비뇨기종양학술지 : 제 14 권제 2 호 2016 (36.9%), (+++) 는 117건 (43.7%) 로확인되었다. c-erb B2 에서는 (-) 가 26건 (9.7%), (+) 가 64건 (23.9%), (++) 는 81건 (30.2%), (+++) 는 97건 (36.2%) 이었다. 마지막으로 Ki-67은 (-) 가 14건 (5.2%), (+) 는 108건 (40,3%), (++) 는 86건 (32.1%), (+++) 는 60건 (22.4%) 이었다 (Table 2). 3. 예후인자들과의관계 위에서언급한각표지자들과방광암의예후인자들간의연관성을통계적으로비교분석하였다. 각인자들과종 Table 1. Demographic parameters of patients with urothelial bladder carcinoma Parameters Sex Male Female Number of Tumor Solitary Multiple Tumor Invasiveness Non-invasive Invasive Patients (n=268) 205 (76.9) 62(23.1) 151 (56.3) 117 (43.1) 79(29.5) 189 (70.5) Parameters Tumor Grade Low High Recurrence No recurred Recurred Patients (n=268) 138 (51.5) 130 (48.5) 182 (67.9) 86(32.1) Table 2. Numbers and results of immunohistochemical markers p53 c-erb B2 Ki-67 (-) (+) (++) (+++) Total 13 (4.9) 26 (9.7) 14 (5.2) 39(14.6) 64(23.9) 108 (40.3) 99 (36.9) 81 (30.2) 86 (32.1) 117 (43.7) 97 (36.2) 60 (22.4) 양의수와의비교분석결과 Chi-square test에서는 p53 (p=0.954), c-erb B2 (p=0.395) 는특별한연관성을보이지않았으나 Ki-67 (p=0.043) 은의미있는연관성을보였고, 표지자의양성도가높을수록다발성종양이늘어나는경향을보였다. 종양의침습도는 Chi-square test 결과세가지표지자모두에서의미있는연관성이확인되었으며,( 모두 p ) (Table 4) 고등급의경우표지자들이더많이발현되었고, (p53 : p; c-erb B2 : p=0.001; Ki-67 : p ) 재발유무에따른 p53의연관성은유의하지않았으나 (p=0.154), c-erb B2 (p=0.010) 와 Ki-67 (p=0.043) 에서는유의한연관성을보였다 (Table 3). 표지자합과예후인자들사이의분석결과는다음과같다. 종양의수와의비교에서상관관계는유의하지않았으나 ( 상관계수 0.084, =0.168), 종양의침습도 ( 상관계수 0.401, ) 및종양등급 ( 상관계수 0.471, ) 에서는유의한상관관계를보였으며재발과도유의한상관관계를보였다 ( 상관계수 0.165, =0.007) (Table 4). Table 4. Correlation analysis between the sum of the markers and prognostic factors Number of tumor Tumor Invasiveness Tumor Grade Recurrence Correlation Coefficient Table 3. Analysis of relation among immunohistochemical markers and conventional prognostic factors Number of Tumor Tumor Invasiveness Tumor Grade Recurrence (n=268) Solitary Multiple Noninvasive Invasive Low Grade High grade No Recurred Recurred p53 c-erb B2 Ki (3.0) 21 (7.8) 57 (21.3) 65 (24.3) 13 (4.9) 41 (15.3) 47 (17.5) 50 (18.7) 9(3.4) 71 (26.5) 40 (14.9) 31 (11.6) 18 (6.7) 42 (15.7) 52 (19.4) 13 (4.9) 23 (8.6) 34 (12.7) 47 (17.5) 46 (17.2) 29 (10.8) (7.5) 17 (6.3) 14 (5.2) 28 (10.4) 21 (7.8) 16 (6.0) 7(2.6) 49 (18.3) 19 (7.1) 4(1.5) 8(3.0) 19 (7.1) 62(23.1) 100 (37.3) 12 (4.5) 36(13.4) 60(22.4) 81(30.2) 7(2.6) 59(22.0) 67(25.0) 56(20.9) 31 (11.6) 65 (24.3) 16 (6.0) 44 (16.4) 41 (15.3) 11 (4.1) 90 (33.6) 32 (11.9) 8 (3.0) 8 (3.0) 34 (12.7) 80 (29.9) 10 (3.7) 20 (7.5) 40 (14.9) 60 (22.4) 3 (1.1) 18 (6.7) 54 (20.1) 55 (20.5) (3.0) 27 (10.1) 75 (28.0) 72 (26.9) 20 (7.5) 50 (18.7) 59 (22.0) 54 (20.2) 9(3.4) 84 (31.3) 52 (19.4) 12 (4.5) 24 (9.0) 45 (16.8) 7(2.6) 14 (5.2) 22 (8.2) 42 (15.6) 24 (9.0) 34 (12.7) 23 (8.6)

5 강석현외 : 비근육침습성방광요로상피세포암에서 p53, c-erb-b2, Ki-67 의발현이예후에영향을미치는가? 73 고찰초기방광암의높은재발과근침윤성종양으로의진행가능성은정확한치료방침및예후예측인자의중요성을더욱절실히요구하는원인이되고있다. 2,9 특히고등급의종양에서조기에방광전절제술을시행함으로인한부담이치료지연에의한사망률의증가보다더이익이있을수있다는의견까지대두되고있다. 10 방광요로상피암의재발또는진행의예측을위해서많은연구단체들이종양분류체계를만들기위해노력해왔고, 그결과로 WHO 분류체계와같은기준이만들어졌다. 그러나, 이기준만으로는환자에따른다양한결과를설명하기어렵고, 11 구체적정보를더얻기위한노력의일환으로개발된것이여러종양표지자들이다. 따라서다른종양의연구과정에서밝혀진표지자들이방광암의연구에도적용되었고, 이중일부가재발및진행과연관성이있음이확인되고있다. p53은염색체 17p13.1. 에위치하는종양억제유전자 (tumor suppressor gene) 이다. 12,13 이유전자는세포의자연사, 유전적안정성및혈관신생의억제에관여하는것으로알려져있으며, 14 변이가발생한 p53 유전자는정상 p53에비해세포핵내에장기간존재하는단백질을생성한다. 이축적된단백질을통해우리는유전자의변이를감지할수있다. p53 유전자의과발현및그에따른생산물의증가는방광요로상피암의진행을알리는표지자로서의역할을하며, 15 나쁜예후와연관되어있는것으로알려져있다. 14,16,17 또한 p53은병기와무관하게암특이사망률 (cancer-specific mortality) 을예측할수있는지표가된다는연구결과도있다. 또한, 핵내에서 p53이발견된경우재발율이상승하고생존율이감소한다는보고도있었다. 18 본연구에서도 p53 은침습성, 고등급과연관성이높음을확인할수있었다. 그러나재발율과의연관성은유의성을보이지않았다. 기존의연구결과에서도총재발위험도 (overall risk of recurrence) 는 1.6이나 27% 의연구에서예후예측에유의한것으로분석되어연구에따라유의성에는차이가있는것으로보고되어있다. 6 c-erb B2 (HER-2/neu로도알려져있다 ) 는원암유전자 (proto-oncogene) 로서, 염색체 17q에위치한타이로신인산화효소 (tyrosine kinase) 수용체그룹에작용하는성장인자이다. 19 이유전자의과발현은세포의종양으로의전환및진행과관련이있으며, 따라서종양등급, 병기, 치료에대한저항성등관련예후인자들과밀접한연관성이있다. 15,19,20 c-erb B2는방광보다는주로유방및간의악성종 양과관련되어주로연구가이루어져왔는데, 18,21 이표지자와방광암사이에도연관성이있을가능성이높다는가설이여러연구자들로부터제시됨에따라, 이연관성을확인하기위한연구도진행되어왔으나, 현재까지일관된결과가도출되지는않았다. c-erb B2의발현과높은종양등급간에는밀접한연관성이있다고기술한연구가있는반면, 22 이표지자와예후간에는연관성이없다고언급한연구도있었다. 23 본연구에서는종양의침습도, 등급, 재발성의 3가지항목에서유의한연관관계가있음을확인할수있었다. Ki-67 항원은세포증식과관련된유용한표지자로, 이항원의검출은 MIB-1 단일클론항체를통해서가능하다. 15 이단백질은세포주기의 G1, S, G2, M기에서발현되는데, Ki-67이발현된세포의비율은방광암의재발, 등급및병기와밀접한연관이있으며, 비근육침습성방광암의예후인자로이용하기위해많은연구가이루어져왔다 다른연구결과를보면, FGFR3의돌연변이와 Ki-67의증식을합쳐서예후예측인자로서사용을시도하였는데, 이결과병리학적병기에상관없이재발성, 진행성및암특이생존율과유의한연관이있었다. 29 최근의연구에서는 Ki-67 강양성을보일경우종양세포의증식도가증가하고, 따라서침습도및진행위험성이높아진다는결과가있다. 24 또한다변량분석을이용한연구에서 Ki-67이단독으로진행성및생존율을예측할수있는인자로이용될수있으나재발과관련하여서는현재단계에서는그근거가부족하다는의견을기술하였다. 2 본연구에서는종양의수, 침습도, 등급, 재발성모두와 Ki-67이깊은연관성이있는것으로확인되었다. 두개의표지자를같이사용해예후인자로이용하는방법도일부연구에서진행되고있었다. CK20과 Ki-67을병합해예후인자로이용할수있다는연구결과가발표된바있는데, 5 본연구에서는이에착안하여연구에이용된 3가지표지자의양성도를합하여새로운기준을작성해보았고, 그결과이기준과예후사이에도밀접한연관성이확인되었다. 결론비근육침습성방광암은재발하는경우가많고, 추후근육침습성으로진행할가능성이항상존재하기에초기에예후를예측하여개별적인치료적접근을할수있다면환자의예후향상에도움이될것이다. 본연구에서시행한모든표지자들은방광암의예후와밀접한연관이있음을확인할수있었다. 그러나현재까지이루어진여러연구들과본연구의결과를종합해볼때, 이들표지자를독립적인예후

6 74 대한비뇨기종양학술지 : 제 14 권제 2 호 2016 인자로서치료에적용하는것은아직어려울것으로생각된다. 이를위해서는좀더대규모의, 다기관연구가추후진행되어야할것으로보인다. REFERENCES 1. Ferlay J, Randi G, Bosetti C, Levi F, Negri E, Boyle P, et al. Declining mortality from bladder cancer in Europe. BJU Int 2008;101: Bertz S, Otto W, Denzinger S, Wieland WF, Burger M, Stöhr R, et al. Combination of CK20 and Ki-67 immunostaining analysis predicts recurrence, progression, and cancer-specific survival in pt1 urothelial bladder cancer. Eur Urol 2014;65: Allard P, Bernard P, Fradet Y, Têtu B. The early clinical course of primary Ta and T1 bladder cancer: a proposed prognostic index. Br J Urol 1998;81: Kurth KH, Denis L, Bouffioux C, Sylvester R, Debruyne FM, Pavone-Macaluso M, et al. Factors affecting recurrence and progression in superficial bladder tumors. Eur J Cancer 1995;31A: Ogata DC, Marcondes CA, Tuon FF, Busato WF Jr, Cavalli G, Czeczko LE. Superficial papillary urothelial neoplasms of the bladder (pta E pt1): correlation of expression of p53, Ki-67 and CK20 with histologic grade, recurrence and tumor progression. Rev Col Bras Cir 2012;39: Malats N, Bustos A, Nascimento CM, Fernandez F, Rivas M, Puente D, et al. P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol 2005;6: Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, Palou J, Vicente-Rodríguez J. Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 2000;163: Milord RA, Lecksell K, Epstein JI. An objective morphologic parameter to aid in the diagnosis of flat urothelial carcinoma in situ. Hum Pathol 2001;32: Kiemeney LA, Witjes JA, Heijbroek RP, Verbeek AL, Debruyne FM. The clinical epidemiology of superficial bladder cancer. Dutch South-East Cooperative Urological Group. Br J Cancer 1993;67: Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. Early versus deferred cystectomy for initial high-risk pt1g3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53: Kiemeney LA, Witjes JA, Heijbroek RP, Verbeek AL, Debruyne FM. Predictability of recurrent and progressive disease in individual patients with primary superficial bladder cancer. J Urol 1993;150: Cina SJ, Lancaster-Weiss KJ, Lecksell K, Epstein JI. Correlation of Ki-67 and p53 with the new world health organization/international society of urological pathology classification system for urothelial neoplasia. Arch Pathol Lab Med 2001;125: Levine AJ, Momand J, Finlay CA. The p53 tumor supressor gene. Nature 1991;351: Mumtaz S, Hashmi AA, Hasan SH, Edhi MM, Khan M. Diagnostic Utility of p53 and CK20 immunohistochemical expression grading urothelial malignancies. Int Arch Med 2014;7: Mallofré C, Castillo M, Morente V, Solé M. Immunohistochemical expression of CK20, p53, and Ki-67 as objective markers of urothelial dysplasia. Mod Pathol 2003;16: van der Kwast TH, Bapat B. Predicting favourable prognosis of urothelial carcinoma: gene expression and genome profiling. Curr Opin Urol 2009;19: López-Knowles E, Hernández S, Kogevinas M, Lloreta J, Amorós A, Tardón A et al. The p53 pathway and outcome among patients with T1G3 bladder tumors. Clin Cancer Res 2006;12: Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994;331: Lönn U, Lönn S, Friberg S, Nilsson B, Silfverswärd C, Stenkvist B. Prognostic value of amplification of c-erb-b2 in bladder carcinoma. Clin Cancer Res 1995;1: Bassullu N, Turkmen I, Dayangac M, Yagiz Korkmaz P, Yasar R, Akyildiz M, et al. Predictive and prognostic significance of c-erb-b2, EGFR, PTEN, mtor, PI3K, p27, and ERCC1 expression in hepatocellular carcinoma. Hepat Mon 2012;12(10 HCC):e Ross JS. Fletcher JA. HER-2/neu(c-erb-B2) gene and protein in breast cancer. Am J Clin Pathol 1999;112(1 Suppl 1):S Tsuji M, Kojima k, Murakami Y, Kanayama H, Kagawa S. Prognostic value of Ki-67 antigen and p53 protein in urinary bladder cancer: immunohistochemical analysis of radical cystectomy specimens. Br J Urol 1997;79: Traṣcặ E, Buzulicặ R, Nicolescu I, Traṣcặ ET. Immunohistochemical determinations in evaluating the prognostic in patient with urinary bladder tumors. Rom J Morphol Embryol 2006;47: Goyal S, Singh UR, Sharma S, Kaur N. Correlation of mitotic indices, AgNor count, Ki-67 and Bcl-2 with Grade and Stage in papillary urothelial bladder cancer. Urol J 2014;11: Nakopoulou L, Vourlakou C, Zervas A, Tzonou A, Gakiopoulou H, Dimopoulos MA. The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder carcinomas and their clinico-pathologic correlates. Hum Pathol 1998;29: van Tilborg AA, Bangma CH, Zwarthoff EC. Bladder cancer biomarkers and their role in surveillance and screening. Int J Urol 2009;16:23-30

7 강석현외 : 비근육침습성방광요로상피세포암에서 p53, c-erb-b2, Ki-67 의발현이예후에영향을미치는가? Quintero A, Alvarez-Kindelan J, Luque RJ, Gonzalez-Campora R, Requena MJ, Montironi R, et al. Ki-67 MIB1 labelling index and the prognosis of primary TaT1 urothelial cell carcinoma of the bladder. J Clin Pathol 2006;59: Tsujihashi H1, Nakanishi A, Matsuda H, Uejima S, Kurita T. Cell proliferation of human bladder tumors determined by BrdU and Ki-67 immunostaining. J Urol 1991;145: van Rhijn BW, Vis AN, van der Kwast TH, Kirkels WJ, Radvanyi F, Ooms EC et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 2003;21:

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