早期肾癌保肾手术安全范围的研究
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摘要
肾癌发病率在泌尿系肿瘤中仅次于膀胱癌位于第二位。目前估计全世界肾癌发病率每年增加2%,全世界每年死于肾癌者近10万例。近半数的肾癌患者首次就诊时已属晚期,约40%的患者术后出现复发、转移,未接受治疗者的3年存活率低于5%,由于肾细胞癌恶性程度较高,对放疗和化疗均不敏感,免疫治疗也难以取得理想效果,目前只有手术是较可靠的治疗手段。随着B超在临床的广泛应用,早期肾癌越来越多。早期肾癌相对与晚期肾癌其发生多中心病灶和转移的可能性较低,是肾癌保留肾单位手术的选择性适应症。
     目前肾部分切除术是治疗早期肾癌较好方法。对于T1a的早期肾癌,肾部分切除术和根治性肾癌切除术的治疗效果和预后无明显区别。一般认为肾部分切除术的适应证为:单一肾癌,双肾癌,孤立肾癌或对侧肾功能低下时。近来认为对于小于4cm的小肾癌及部分T1b也可适用于肾部分切除手术方法。
     肾癌切除的目的是最大限度的切除肿瘤组织以减少肿瘤复发率。然而,肾部分切除术其切除范围的大小还存在争议。小于4cm的肾癌多中心病灶和转移的可能性较低,肾部分切除术的疗效明显好于大于4cm的肾癌患者。本课题通过病理切片确定肿瘤浸润范围及通过免疫组化检测肾癌癌组织及癌旁组织受累情况的研究,为手术更彻底地切除肿瘤,防止局部复发提供依据。
     目的:早期肾癌出现多中心病灶和转移灶的可能性小,特别适合行保留肾单位的肾肿瘤切除术。本研究探讨直径4cm以下肾癌保肾手术的安全切除范围及Ki-67和PCNA在肾癌及癌旁组织中的表达。
     方法:直径≤4cm肾癌根治术标本41例,标本分层切开,观察肾内原发癌及癌旁病变累犯范围;并对41例肾癌切除标本采用免疫组化方法,检测癌和癌旁组织Ki-67和PCNA表达情况,分析肿瘤向周边浸润及周围组织癌变趋向的规律。
     结果:41例肾癌平均直径(3.3±0.8)cm(0.8-4.0cm),17.0%(7/41)存在1种以上假包膜外癌灶。形态学观察显示,癌旁0.2cm、0.5cm处高危病变的比例明显高于处1cm、2cm处,且癌变组织多局限于癌旁1cm范围内。随距原发癌越远,癌旁组织Ki-67和PCNA阳性的比例逐渐降低,且癌旁0.2cm与0.5cm、1cm、2cm的表达有差别。癌变组织阳性组7例中,Ki-67和PCNA高表达4例。
     结论:直径≤4cm肾癌保肾手术安全切缘须包括假包膜外1cm以内的正常肾实质。同时对癌旁组织Ki-67和PCNA阳性表达者应扩大切除范围,达到切缘阴性,降低局部复发率。
Renal cell carcinoma (RCC) is one of the malignant tumors which is secondary to carcinoma of urinary bladder in the urinary carcinoma.It’s estimated that the morbility of RCC is increased 2% annumly and about 100,000 patients died from this kind of carcinomas every year in the world. About half members of those patients are in their late stage when they were firstly diagnosed of this cancer,about 40% will be recurrenced after and metabasised before radical renal resection,the survival rate is lower than 3% within 3 years who had not received any treatment.RCC has more malignant and insensitivity to radiotherapy and chemotherapy,and immunotherapy is also has little effect on it.Radical nephrectomy has been proven to be an effective choice for cure of localized renal cell carcinoma (RCC).Renal cell carcinoma (RCC) of 4 cm or less is with a low incidence of multicentricity and metastasis and is usually considered suitable for nephron sparing surgery (NSS).
     Open partial nephrectomy,or nephron sparing surgery (NSS),is now considered the standard of care for the treatment of small renal tumors.The oncologic efficacy and safety of NSS for the treatment of stage - T1a renal tumors has been repeatedly demonstrated to be equivalent to radical nephrectomy.NSS initially was reserved for patients with solitary kidneys,impaired renal function,hereditary tumor syndromes,bilateral renal tumors, and those with significant comorbidities predisposing to future renal failure.The indications have expanded recently to allow elective partial nephrectomy in the setting of a normal contralateral kidney.Furthermore , recent data demonstrate that partial nephrectomy for larger tumors (T1b),which have been historically treated with radical nephrectomy,is a viable option when surgical margins can safely be achieved.
     Renal cell carcinoma (RCC) of 4 cm or less is with a low incidence of multicentricity and metastasis and is usually considered suitable for nephron sparing surgery (NSS).It is widely accepted that tumor excision with a surrounding margin of normal parenchyma is the safest approach to ensure no residual tumor in the renal remnant. However agreement on the optimal margin in nephron sparing surgery has never been reached.RCC of 4 cm or less was with a lower incidence of multicentricity and NSS in these tumors has showed an excellent long term results compared with those of larger than 4 cm.This pilot study was designed to investigate the distance between extra-pseudocapsule lesions and primary tumors,and to suggest the optimal margin in NSS for RCC 4 cm or less.
     Objective Renal cell carcinoma (RCC) of 4 cm or less is with a low incidence of multicentricity and metastasis and is usually considered suitable for nephron - sparing surgery (NSS).To explore the excision extension in nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) 4 cm or less in diameter and study Ki-67 and PCNA expression.
     Methods Forty-one kidneys with RCC 4 cm or less in diameter resected by radical nephrectomy were prospectively studied. The kidney samples were sectioned and examined using immunohistochemistry to observe pathological changes and expressions of Ki - 67 and PCNA in primary tumor and paracarcinoma tissues.
     Results The diameter of 41 primary tumors was 3.3±0.8cm(range 0.8–4.0cm). Of these,17.0%(7/41) with positive cancer lesions beyond pseudocapsule. Along with the further distance from primary tumor , the proportions of positive expressions of Ki-67 and PCNA in paracarcinoma tissue were decreased gradually. The ratio of strong expression was 57.4% (4/7)in the group with extra-pseudocapsule cancer lesions.
     Conclusions These data suggest that when NSS is performed in RCC 4 cm or less in diameter,a margin of more than 1 cm of adjacent parenchyma should be excised with the tumor. It is necessary to choice individual treatment for RCC with strong expression of Ki-67 and PCNA.
引文
1.Van Poppel H,Bamelis B,Oyen R,et al. Partial nephrectomy for renal cell carcinoma can achieve long-term tumor control. J Urol,1998,160 (3 Pt 1):674-678
    2.Lerner SE,Hawkins CA,Blute ML,et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol,2003,167 (2 Pt 2):884-889
    3.Uzzo RG,Novick AC. Nephron sparing surgery for renal tumors:indications,techniques and outcome. J Urol,2001,166(1):6-18
    4.Hafez KS,Novick AC,Campbell SC. Patterns of tumor recurrence and guidelines for follow-up after nephron sparing surgery for sporadic renal cell carcinoma. J Urol,1997,157(6):2067-2070
    5.Moll V,Becht E,Ziegler M,et al. Kidney preserving surgery in renal cell tumors: indications,techniques and results in 152 patients. J Urol,1993,150(2 Pt 1):319-323
    6.Delakas D,Karyotis I,Daskalopoulos G,et al . Nephron-sparing surgery for localized renal cell carcinoma with a normal contralateral kidney:a European three center experience. Urology,2002,60(6):998-1002
    7.Lee CT,Katz J,Shi W,et al. Surgical magagement of renal tumors 4 cm or less in a contemporary cohort. J Urol,2000,163(3):730-736
    8.Tsui KH,Shvarts O,Smith RB,et al. Renal cell carcinoma:prognostic significance of incidentally detectedt umors. J Urol,2000,163(2):426-430
    9.Fergany AF,Hafez KS,Novick AC. Long-term result s of nephronsparing surgery for localized renal cell carcinoma:10-year follow-up. J Urol,2000,163(2):442-445
    10.Bulter BP,Novick AC,Miller DP,et al. Management of small unilateral renal cell carcinomas:radical versus nephronsparing surgery. Urology,1995,45(1):34-40
    11.Junker K,Thrum K,Schlichter A,et al. Clonal origin of multifocal renal cell carcinoma as determined by microsatellite analysis. J Urol,2002,168(6):2632-2636
    12.Castilla EA,Liou LS,Abrahams NA,et al. Prognostic importance of resection margin width after nephron - sparing surgery for renal cell carcinoma. Urology,2002,60(6):993-997
    13.Junker K,Schlichter A,Hindermann W,et al. Genetic characterization of multifocal tumor growth in renal cell carcinoma. Kidney Int,1999,56(4):1291-1294
    14.Gohji K,Hara I,Gotoh A,et al. Multifocal renal cell carcinoma in Japanese patients with maximal diameters of 50 mm or less. J Urol,1998(4),159:1144-1147
    15.Eschwege P,Saussine C,Steichen G,et al.Radical nephrectomy for renal cell carcinoma 30 mm or less:long-term follow results. J Urol,1996,155(4):1196–1199
    16.Van Poppel H,Claes H,Willemen P,et al. Is there a place for conservative surgery in the treatment of renal carcinoma? Br J Urol,1991,67(2):129-133
    17.Herr HW. Partial nephrectomy for unilateral renal carcinoma and a normal contralateral kidney:10-year follow-up. J Urol,1999,161(1):33-35
    18.Moll V,Becht E,Ziegler M. Kidney preserving surgery in renal cell tumors: indications,techniques and results in 152 patients. J Urol,1993,150 (2 Pt 1):319-323
    19.Piper NY,Bishoff JT,Magee C,et al. Is a 1-CM margin necessary during nephron-sparing surgery for renal cell carcinoma? Urology,2001,58(6):849-852
    20.Sutherland SE,Resnick MI,Maclennan GT,et al. Does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol,2002,167(1):61-64
    21.Fujimoto N,Sugita A,Terasawa Y,et al. Observation on the growth rate of renal cell carcinoma. Int J Urol,1995,2(2):71-76
    22.Rizzo MG,Ottavio L,Travali S,et al. The promoter of the human proliferating cell nuclear antigen (PCNA) gene is bidirectional. Exp Cell Res,1990:188(2):286-293
    23.Kogure T,Takasaki Y,Takeuchi K,et al. Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes involved in cell proliferation are strongly associated with their structure and biologic function in patients with systemic lupus erythematosus. Arthritis Rheum,2002:46(11):2946-2956
    24.Maga G,Hubscher U. Proliferation cell nuclear antigen (PCNA):A dancer with many partners. Journal of Cell Science,2003,116(15):3051-3060
    25.Krishna TS, Kong XP, Gary S,et al. Crystal structure of the eukaryoticDNA polymerase processivity factor PCNA. Cell,1994,79(7):1233-1243
    26.Moarefi I,Jeruzalmi D,Turner J,et al. Crystal structure of the eukaryotic DNA polymerase processivity factor of T4 bacteriophage. J Mol Biol,2000,296(5):1215-1223
    27.Loor G,Zhang SJ,Zhang P,et al. Identification of DNA replication and cell cycle proteins that interact with PCNA. Nucleic Acids Research,1997,25(24):5041-5046
    28.Frouin I,Montecucco A,Spadari S,et al. DNA replication: A complex matter. EMBO Reports,2003,7(4),666-670
    29.Tom S,Henricksen LA,Bambara RA. Mechanism whereby proliferating cell nuclear antigen stimulates flap endonuclease 1. Journal of Biological Chemistry,2000,275(14):10498-10505
    30.Levin DS, Mckenna AE, Motycka TA, et al. Interactions between PCNA and DNA ligase Ⅰ is critical for joining of Okazaki fragments and long-patch base-excision repair. Current Biology,2000,10(15):919-922
    31.Fisher PA, Moutsiakis DL, Mcconnell M, et al. A single amino acid change (E85K) in human PCNA that leads,relative to wild type,to enhanced DNA synthesis by DNA polymerase δ past nucleotide base lesions (TLS) as well as on unmodified templates. Biochemistry, 2004,43(50):15915-15921
    32.Mcconnell M,Miller H,Mozzherin DJ,et al. The mammalian DNApolymerase delta - proliferating cell nuclear antigen template primer complex:Molecular characterization by direct blinding. Biochemistry,1996,35(25):8268-8274
    33.Mozzherin DJ,Shibutani S,Tan CK,et al. Proliferating cell nuclear antigen promotes DNA synthesis past template lesion by mammalian DNA polymerase delta. Proc Natl Acad Sci USA,1997,94(12):6126-6131
    34.Parrilla-Castellar ER,Arlander SJ,Karnitz L. Dial 9-1-1 for DNA damage:the Rad9-Hus1-Rad1 (9-1-1) clamp complex. DNA Repair,2004,3(8-9):1009-1014
    35.Friedrich-Heineken E,Toueille M,Tannler B,et al. The two DNA clamps Rad9-Rad1-Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1activity. J Mol Biol. 2005,353(5):980-989
    36.Zhang H,Xiong Y,Beach D. Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell. 1993,4(9):897-906
    37.Kranenburg O,Scharnhorst V,Vander Eb AJ,et al. Inhibition of cyclin- dependent kinase activity triggers neuronal differentiation of mouse neuroblastoma cells. J Cell Biol. 1995,131(1):227-234
    38.Kurki P,Vanderlaan M,Dolbere F,et al. Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res. 1986,166(1):209-219
    39.Lee SH,Kwong AD,Ishimi Y,et al. Studies on the DNA elongationinhibitor and its proliferating cell nuclear antigen-dependent control in simian virus 40 DNA replication in vitro. Proc Natl Acad Sci USA. 1989,86(13):4877-4881
    40.Morell-Quadreny L,Clar-Blanch F,Fenollosa-Enterna B,et al. Proliferating cell nuclear antigen (PCNA) as a prognostic factor in renal cell carcinoma. Anticancer Res,1998,18:677-682
    41.Wildemann B,Schmidmaier G,Ordel S,et al. Cell proliferation and differentiation during fracture healing are influenced by locally applied IGF-I and TGF-beta1:Comparison of two proliferation markers,PCNA and BrdU. J Biomed Mater Res. 2003,65(1):150-156
    42.Zheng M,Tian X,Li H,Cheng Y,et al. Expression of PCNA and the count of AgNOR in squamous cell carcinoma of larynx and hypopharynx. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2002,16 (12):653-655
    43.Shen LJ,Zhang HX,Zhang ZJ,et al. Detection of HBV,PCNA and GST-pi in hepatocellular carcinoma and chronic liver diseases. World J Gastroenterol. 2003,9(3):459-462
    44.Kayaselcuk F,Zorludemir S,Gumurduhu D,et al. PCNA and Ki-67 in central nervous system tumors:correlation with the histological type and grade. J Neurooncol. 2002,57(2):115-121
    45.Shang S,Takai N,Nishida M,et al. CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. Int J Mol Med. 2003,11(2):181-186
    46.Belessi CJ,Parasi AS,Manioudaki HS,et al. Prognostic impact of DNA ploidy pattern,S-phase fraction (SPF),and proliferating cell nuclear antigen (PCNA) in patients with primary gastric lymphoma. J Surg Oncol. 2003,82(4):247-255
    47.Wang ZH,Wang CY,Liu XJ,et al. Relationship between recurrence and metastasis of gastric cancer and expression of EGFR,IL-6R,PCNA,and DI. Ai Zheng. 2002,21(7):785-789
    48.Belessi CJ,Parasi AS,Manioudaki HS,et al. Prognostic impact of DNA ploidy pattern,S-phase fraction (SPF),and proliferating cell nuclear antigen (PCNA) in patients with primary gastric lymphoma. J Surg Oncol. 2003,82(4):247-255
    49.Cappello F, Palma A, Martorana A,et al. Biological aggressiveness evaluation in prostate carcinomas: immunohistochemical analysis of PCNA and p53 in a series of Gleason 6 (3+3) adenocarcinomas. Eur J Histochem. 2003,47(2):129-132
    50.Grossi F,Loprevite M,Chiaramondia M,et al. Prognostic significance of K-ras,p53,bcl-2,PCNA,CD34 in radically resected non-small cell lung cancers. Eur J Cancer. 2003,39 (9):1242-1250
    51.Kato T,Kameoka S,Kimura T,et al. C-erbB-2 and PCNA as prognostic indicators of long-term survival in breast cancer. Anticancer Res. 2002,22(2B):1097-1103
    52.Dabrowski A,Szumilo J,Brajerski G,et al. Proliferating nuclear antigen (PCNA) as a prognostic factor of squamous cell carcinoma of the oesophagus. Ann Univ Mariae Curie Sklodowska,2001,56:59-67
    53.Tejido Sanchez A,Sanchez Chapado M,Rosino Sanchez A,et al. PCNA and Ki-67 expression in locally confined renal adenocarcinoma.Relationship with various histopathologic variables and prognostic significance. Arch Esp Urol. 2002,55(3):257-26554.Ding X,Yang J,Hu S,et al. Evaluation of p53,p21waf1,and PCNA in the diagnosis on lung cancer. Zhonghua Liu Xing Bing Xue Za Zhi. 2001,22(1):54-57
    55.Scholzen T,Gerdes J. The Ki-67 protein:From the known and unknoun. J cell Physiol,2000,182(3):311-322
    56.Duchrow M,Schluter C,Wohlenberg C,et al. Molecular Characterization of the gene locus of the human cell proliferation-associated nuclear protein defined by monoclonal antibody Ki-67. Cell Prolif,1996,29(1):1-12
    57.Schmidt MH,Broll R,Bruch HP,et al. The proliferation marker Pki–67 becomes masked to MIB-1 Staining after expression of its tandem repeats. Histochem cell Biol,2002,118(5):415-422
    58.Scholzen T,Endl E,Wohlengerg C,et al. The Ki-67 Protein interacts with members of the heterochromatin Protein 1 (HP1) family:a Potential role in the regulation of higher-order chromatin structure. J Pathol,2002,196(2):135-144
    59.Schmidt MH,Broll R,Bruch HP,et al. The proliferation marker PKi–67 organizes the nucleolus during the cell cycle depending on Ran and cyclin B. J Pathol,2003,199(1):18-27
    60.Brown DC,Gatter KC. Ki-67 Protein:the immaculate deception? Histopathology,2002,40(1):2-11
    61.Endl E,Gerdes J. Posttranslational Modifications of the Ki-67 protein Coincide with two major checkpoints during mitosis. J cell physiol,2000,182(3):371-380
    62.Traut W,Endl E,Garagna S,et al. The temporal and spatial distribution of the proliferation associated Ki-67 protein during female and male meiosis.Chromosoma. 2002,111(3):156-164
    63.Endl E,Hollmann C,Gerdes J. Antibodies against the Ki-67 protein:assessment of the growth fraction and tools for cell cycle analysis. Methods Cell Biol. 2001,63:399-418
    64.Kakeji Y,Korenaga D,Tsujitani S,et al. Predictive value of Ki-67 and argyrophilic nucleolar organizer region staining for lymphnode metastasis in gastric cancer. Cancer Res. 1991,51(13):3503-3506
    65.Henzen-Logmans SC,Fieret EJ,Berns EM,et al. Ki-67 staining in benign,borderline,malignant primary and metastatic ovarian tumors:correlation with steroid receptors,epidermal-growth-factor receptor and cathepsin D. Int J Cancer. 57(4):468-472
    66.Huuhtanen RL,Blomqvist CP,Wiklund TA,et al. Comparison of the Ki-67 score and S-phase fraction as prognostic variables in soft-tissue sarcoma. Br J Cancer. 1999,79(5-6):945-951
    67.Okamura K,Miyake K,Koshikawa T,et al. Growth fractions of transitional cell carcinomas of the bladder defined by the monoclonal antibody Ki-67. J Urol,1990,144(4):875-878
    68.Asakura T,Takano Y,Iki M,et al. Prognostic value of Ki-67 for recurrence and progression of superficial Bladder cancer. J Urol,1997,158(2):385-388
    69.Wu TT,Chen JH,Lee YH,et al. The Role of bcl-2,P53,and Ki–67 index in predicting tumor recurrence for low grade superficial transitional cell bladder carcinoma. J Urol,2000,163(3):758-760
    70.Blanchet P,Droupy S,Eschwege P,et al. Prospective evaluation of Ki-67 labeling in predicting the recurrence and progression of superficialbladder transitional cell carcinoma. Eur Urol,2001,40(2):169-175
    71.Dybowski B,Kupryjanczyk J,Rembiszewska A,et al. P27(Kip1) and Ki-67 expression analysis in transitional cell carcinoma of the bladder. Urol Res,2003,31(6):397-401
    72.Su JS,Arima K,Hasegawa M,et al. Proliferative status is a risk index for recurrence in Primary superficial (PTa/ T1) low-grade Urothelial bladder Carcinoma. Hinyokika Kiyo,2003,49(11):649-658
    73.Kirkali Z,Yorukoglu K,Ozkara E,et al. Proliferative activity,angiogenesis and nuclear morphometry in renal cell carcinoma. Int J Urol,2001,8(12):697-703
    74.Cheville JC,Zincke H,Lohse CM,et al. PT1 clear cell renal carcinoma:a study of the association between MIB- 1 proliferative activity and pathologic features and cancer Specific Survival. Cancer,2002,94(8):2180-2184
    75.Visapaa H,Bui M,Huang Y,et al. Correlation of Ki-67 and gelsolin expression to clinical outcome in renal clear cell carcinoma. Urology,2003,61(4):845-850
    76.Donskov F,Marcussen N,Hokland M,et al. In vivo assessment of the antiproliferative propertities of interferon-alpha during immunotherapy:Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma. Br J Cancer,2004,90(3):626-631
    77.Halvorsen OJ,Haukaa S,Hoisaeter PA,et al. Maximum Ki-67 staining in prostate cancer provides indepent prognostic information after radical prostatectomy. Anticancer Res,2001,21 (6A):4071-4076
    78.Claudio PP,Zamparelli A,Garcia F,et al. Expression of Cell-cycle-regulated Protein PRb2/P130,P107,P27kip1,P53,mdm-2 and Ki-
    67 (MIB-1) in prostatic gland adenocarcinoma. Clin Cancer Res,2002,8(6):1808-1815
    79.Sulik M,Guzinska-Ustymowicz K. Expression of Ki-67 and PCNA as a proliferating markers in prostate cancer. Rocz Akad Med Bialymst,2002,47:262-269
    80.Munoz E,Gomez F,Paz JI,et al. Ki-67 immunolabeling in pre-malignant lesions and carcinoma of the prostate. Histologic correlation and prognostic evaluation. Eur J Histochem,2003,47(2):123-128
    81.Bantis A,Giannopoulos A,Gonidi M,et al. Expression of P120,Ki–67 and PCNA as proliferation biomarkers in imprint smears of prostate carcinoma and their prognostic smears of prostate carcinoma and their prognostic value. Cytopathology,2004,15(1):25-31
    82.Kausch I,Lingnau A,Endl E,et al. Antisense treatment against Ki–67 mRNA inhibits proliferation and tumor growth in vitro and in vivo. Int J Cancer,2003,105(5):710-716
    83.王家箐,盛新福,bcl-2和PCNA在肾癌中的表达及临床意义. 临床泌尿外科杂志,2001,16(2):89-90
    84.Kamai T,Takagi K,Asami H,et al. Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter . BJU Int,2000,86 (1):14-19
    85.Novick AC,Streem SB. Surgery of the kidney. In: Walsh PC, Retik AB,Vaughan ED,et al, eds. Campbell′s Urology. Vol 3. 7th ed. Philadelphia: Harcourt Publisher Limited, 1998. 2973-3061
    86.Steinbach F,Stockle M,Riedmiller H,et al. Tumor enucleation of renalcell carcinoma: operative technique, DNA cytometry, result, complications. Prog Clin Biol Res,1991,370(1):1-7
    87.Novick AC,Streem SB,Montie JE,et al. Conservative surgery for renal cell carcinoma:a single center experience with 100 patients . J Urol,1989,141(4):835-839
    88.Cheng WS,Farrow GM,Zincke H. The incidence of multicentricity in renal cell carcinoma. J Urol,1991,146(5):1221-1223
    89.Uzzo RG,Novick AC. Nephron sparing surgery for renal tumors: indications,techniques and outcomes. J Urol,2001,166(1):6-18
    90.Novick AC,Streem SB. Surgery of the kidney. In: Walsh PC, Retik AB,Vaughan ED,et al, eds. Campbell′s Urology. Vol 3. 7th ed. Philadelphia: Harcourt Publisher Limited,1998. 2973-3061
    91.李泉林,关宏伟,张丽芝,等,早期肾癌保肾手术切除范围的探讨. 中华外科杂志,2003,41(2):81-83
    92.Bravo R,Flank R,Blundeu PA,et al. Cyclin/PCNA is the auxilary protein of DNA polymeras delta. Nature,1987,326(6112):515-517
    93.Tejido Sanchez A,Sanchez Chapado M,Rosino Sanchez A,et al. PCNA and Ki - 67 expression in locally confined renal adenocarcinoma. Relationship with various histopathologic variables and prognosticsignificance. Arch Esp Urol. 2002,55(3):257-265