摘要
研究背景:
在现代医学技术条件下,肾癌的发病率逐年提高。在美国,肾癌的年发病率从1990年的27200例增长到2005年的36160例,上升了24.8%。欧洲最近的一项大规模临床调查(1987～2004年)显示:肾癌的发病率约占全身恶性肿瘤的3%,占肾脏肿瘤的85%,年均发病率约为7.21/10万,并且以每年平均2.06%的速度递增。
对于肾癌的治疗,标准的手术方式为根治性肾切除术。但随着CT等影像技术的普及推广,偶发性肾癌的检出率大大提高,而偶发性肾癌多数为早期肾癌。对于早期肾癌是否采用根治性肾切除术仍存在很大争议。Leibovich等对4～7cm肾细胞癌(RCC)患者行肾部分切除术(NSS)和根治性肾切除术(RN)后,5年生存率的随访显示,两者的癌症特异生存率为98%和86%,无远处转移生存率为94%和83%。考虑到RCC的分期、分级、组织学分型等重要的病理学特性,两者的癌症特异生存率和无远处转移生存率无明显差异。有鉴于此,越来越多的学者倾向于选择肾部分切除术来治疗早期肾癌。
目的:
行肾部分切除术时,安全切除边距的选择尤为重要,综合国内外的专著和文献报道,传统的观点认为安全的切除范围为1～2cm,进来也有许多学者提出只切除距肿瘤包膜0.5cm以上是安全和可行的。为什么会产生这样的争议呢?一方面:因为肾脏的体积较小,正常成年男性平均长10cm,宽5cm,厚4cm,质量为134～150g;女性肾脏的体积和质量均略小于同龄的男性。如果切除过多,不仅引起有效肾单位的减少,同时还增加了手术难度和并发症出现的几率,如果切除范围过小,手术医生和患者又担心肿瘤的残余,可能会引发肿瘤的破裂和肿瘤的复发。另一方面:随着腹腔镜为代表的微创外科的兴起,传统开放肾部分切除术已经逐渐被腹腔镜肾部分切除术所替代,而以“达芬奇”为代表的机器人外科手术系统的出现更是将外科手术向微创化、精确化方向推进了一大步,因而对于安全切除边距的选择要求更高。
基因芯片和组织芯片技术具有高通量、大规模、平行性的特点,可以平行检测多种癌基因和抑癌基因及其相关蛋白产物的组织间表达差异。因此,通过比较癌组织和癌旁不同距离正常组织间肿瘤相关基因和蛋白的差异可以为明确肾部分切除术的安全切除边距提供依据。
方法:
1)采集第二军医大学附属长征医院和上海市第十人民医院2006年1月～2007年10月间行早期肾癌腹腔镜根治性切除术并经术后病理证实为透明细胞癌的病人共计44例,分别在显微外科放大镜下辨别、测量并采集肿瘤组织(A),距肿瘤边缘0.5cm(B)、1.0cm(C)、2.0cm,(D)厚度为0.2cm的正常肾皮质共计44组。
2)全部44组标本常规福尔马林固定、石蜡包埋备用,另选取1组标本液氮冻存备用。
3)1组液氮冻存标本送检基因芯片,芯片采用的是Affymetrix Human Genome U133A2.0Array。采用实时荧光定量PCR验证芯片结果,分别检测:T-cell differentiationprotein(MAL);decorin;galectin 1(LGALSl);transforming growth factotbeta-1(TGF-β1);caveolin 1;bcl-2;secreted apoptosis related protein 2(SARP2);secreted frizzled related protein 1(SFRPl);S100 calcium-bindingprotein A2(S100A2)。
4)44组石蜡标本构建组织芯片。分别行免疫组化检测组织芯片中CD10,RCC-Ma和EMA的表达差异。
结果:
一、基因芯片结果:
(B)vs(A)上调(对数比≥2)的有1442条基因,下调(对数比≤2)的有593条基因;同样,(C)vs(A)上调的有1336条基因、下调的有631条基因;(D)vs(A)上调的有1259条基因、下调的有737条基因。其中,第一大类基因(凋亡、原癌和抑癌基因)(B)vs(A)上调(对数比≥2)的有125条基因、下调(对数比≤2)的有67条基因;同样,(C)vs(A)上调的有111条基因、下调的有74条基因;(D)vs(A)上调的有103条基因、下调的有87条基因。(A)＼(B),(A)＼(C),(A)＼(D)两两之间无论上调基因还是下调基因均存在总体差异(P＜0.05),经聚类分析后这种差异则更为明显。而(B)＼(C)＼(D)三者之间则无明显差异(P＞0.05)。基因芯片试验结果支持:早期肾癌的安全切除边距为0.5cm。
二、荧光定量PCR验证的结果:
(A)＼(B)＼(C)＼(D)四份样本的基因芯片结果ABCD和荧光定量PCR验证结果ApBpCpDp高度吻合,基因芯片结果真实可信。
三、组织芯片结果:
CD10,RCC-Ma和EMA免疫组化染色强阳性率分别为:CD10:A(22.72%),B(72.73%),C(75.00%),D(70.45%)。EMA:A(15.91%),B(84.09%),C(86.36%),D(79.55%)。RCC-Ma:A(18.18%),B(79.55%),C(77.27%),D(75.00%)。(A)＼(B),(A)＼(C),(A)＼(D)两两比较,CD10、EMA和RCC-Ma染色强阳性率均有明显差异(P＜0.05),而(B)＼(C)＼(D)三者间强阳性率无明显差异(P＞0.05)。组织芯片试验结果支持:早期肾癌的安全切除边距为0.5cm。
结论:
肾部分切除术是早期肾癌治疗的重要术式,行肾部分切除术时切除边距达到0.5cm即为安全可行。
Background
With the development of modern medical technology, the detected rate of renal cell carcinoma is increasing year by year. In the United States, the annual incidence of renal cell carcinoma increased by 24.8% from 27,200 cases in 1990 to 36,160 cases in 2005. A recent large-scale European clinical investigation from 1987 to 2004 showed that the incidence of renal cell carcinoma accounted for about 3% of all systemic cancers and 85% of kidney tumors, where the mean annual incidence was about 7.21/100,000, and averagely increased by 2.06% yearly.
Radical nephrectomy is the standard surgical treatment of renal cell carcinoma. With the popularization and spread of imaging technology such as CT, more cases of sporadic renal cell carcinoma have been detected, and most of them are primary renal cell carcinoma. In their five-year-survival follow up study of patients with 4 to 7cm renal cell carcinoma (RCC) who underwent partial nephrectomy (NSS) and radical nephrectomy (RN), Leibovich et al found that the cancer-specific survival rate was 98% and 86%, with a non-distant metastasis survival rate of 94% and 83% respectively. The stage, grade, histological type and other important pathological characteristics of RCC considered, there was no significant difference in both cancer-specific survival rate and survival rate without distant metastasis between the two groups. In the light of these findings, more and more researchers tend to use partial nephrectomy to treat primary renal cell carcinoma.
Objective
Safe selection of the resection margin is particularly important in partial nephrectomy. An overview of the literature shows that a 1-2cm resection range is traditionally accepted as the safe margin, but many researchers come to agree that a 0.5cm resection range from the tumor capsule is safe and feasible. Why is there such a controversy? On the one hand, the mean size and volume of the kidney is relatively small in male adults measuring about 10cm long, 5cm wide and 4cm thick and weighing 134-150g, and those in female adults of the same age are even a bit smaller. Excessive resection would not only decrease effective renal units but also increase surgical difficulty and risks of complications, while inadequate resection may worry both surgeons and patients for possible tumor residuals, tumor rupture and recurrence. On the other hand, with the advent of laparoscopy as the representative of minimally invasive surgery, traditional open partial nephrectomy has been gradually replaced by laparoscopic partial nephrectomy, and the emergence of the robot surgical system with representative "Da Vinci" promotes the rapid development of surgery in terms of minimal invasion and precise direction, which calls for a higher requirement on the selection of a safe resection margin.
DNA microarray and Tissue microarray have three features: high-flux, large scale, and parallelism. DNA microarray and Tissue microarray can be used for the researching of many oncogenes, anti-oncogenes, and gene-associated protein. Accordingly, to compare the differences of tumor-related genes and proteins of tumor and para-tumor normal renal tissue of different margins, can be helpful for the selecting of safe margin about partial nephrectomy of primary renal cell carcinoma.
Methods
1) Included in the present study were 44 patients with primary clear cell carcinoma of kidney confirmed by postoperative pathology who underwent laparoscopic radical nephrectomy in Changzheng Hospital and Shanghai 10th people's hospital between Jan 2006 and Oct 2007. Tumor tissue (A), and 0.5 cm (B), 1.0cm (C) and 2.0cm (D) para-tumor normal renal cortex were identified, measured and collected with the help of the microsurgery magnifying glass. A total of 44 groups of specimen sections with a 0.2 cm thickness were obtained.
2) A total of 44 groups of specimen were fixed routinely with formalin, and paraffin-embedded for use. One group of specimen was frozen in liquid nitrogen for use.
3) One group of specimen was frozen in liquid nitrogen for DNA microarray, the chip is Affymetrix Human Genome U133A 2.0 Array DNA microarray. Real time quantitive PCR was used for the proving of the results of gene chip, Including: T-cell differentiation protein (MAL) ; decorin; galectin 1 (LGALS1); transforming growth factor beta-1(TGF-β1); caveolin 1; bcl-2; secreted apoptosis related protein 2 (SARP2); secreted frizzled related protein 1 (SFRP1); S100 calcium-binding protein A2 (S100A2).
4) Tissue microarrays of A/B/C/D paraffin-embedded specimens of the 44 groups were constructed in a tissue microarray instrument for use. The express difference of CD10, RCC-Ma and EMA were researched through immunohistochemistry.
Results
1) DNA microarray results:
(B) vs (A) up (log-ratio>2) is 1442, down(log-ratio<2) is 593; as the same, (C) vs (A) up is 1336, down is 631; (D) vs (A) up is 1259, down is 737. In the first gene group (apoptosis; oncogenes and anti-oncogenes), (B) vs (A) up (log-ratio>2) is 125, down(log-ratio<2) is 67; as the same, (C) vs (A) up is 111, down is 74; (D) vs (A) up is 103, down is 87. The difference between (A)\(B); (A)\(C) and (A)\(D) is prominent (p<0.05), and the difference is more noticeable through cluster analysis. (B)\(C)\(D) is no difference (p>0.05). The results of DNA microarray support the conclusion: The safe resection margin about partial nephrectomy of primary renal cell carcinoma is 0.5cm
2) Real time quantitive PCR results:
For the group of specimen was frozen in liquid nitrogen, the DNA microarray results A\B\C\D were as same as the results of Real time quantitive PCR Ap\Bp\Cp\Dp. The DNA microarray results were reliable.
3) Tissue microarray results:
The percentage of intensive immunostaining of CD10, RCC-Ma and EMA is as follow:CD10: A(22.72%), B(72.73%), C(75.00%), D(70.45%);EMA: A(15.91%), B(84.09%), C(86.36%), D(79.55%);RCC-Ma: A(18.18%), B(79.55%), C(77.27%), D(75.00%);
The difference between (A)\(B); (A)\(C) and (A)\(D) about CD10; EMA; and RCC-Ma is prominent (p<0.05), (B)\(C)\(D) is no difference (p>0.05). The results of Tissue microarray support the conclusion: The safe resection margin about partial nephrectomy of primary renal cell carcinoma is 0.5cm
Conclusions:
Partial nephrectomy is very important method of the treatment about primary renal cell carcinoma. The safe resection margin about partial nephrectomy of primary renal cell carcinoma is 0.5cm.
引文
[1] Chow W H,Devesa S S,Warren J L.Rising incidence of renal cell cancer in the United States[J]. JAMA, 1999,281:1628-1631.
[2] Kattan M W,Reuter V,Motzer R J,et al.A postoperative prognostic nomogram for renal cell carcinoma[J].J Urol,2001,166:63-67.
[3] Leibovich B C,Blute M L,Cheville J C,et al.Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7cm results in outcome similar to radical nephrectomy[J].J Urol,2004,171:1066-1070.
[4] Permpongkosol S, Bagga HS, Romero FR, et al. Laparoscopic versus open partial nephrectomy for the treatment of pathological T1N0M0 renal cell carcinoma: a 5-year survival rate[J]. J Urol, 2006,176:1984-8;discussion 1988-9.
[5] Zheng Jun-hua, Sun Ying-hao. Some questions about partial laparoscopical nephrectomy in primary renal cell carcinoma [J]. Academic journal of second military medical university, 2007,10:1045-1047.
[6] 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]. J Urol, 2002,167:61-4.
[7] Permpongkosol S, Colombo JR Jr, Gill IS, et al. Positive surgical parenchymal margin after laparoscopic partial nephrectomy for renal cell carcinoma: oncological outcomes[J]. J Urol, 2006,176:24014.
[8] Caruso RP, Phillips CK, Kau E, et al. Robot assisted laparoscopic partial nephrectomy: initial experience[J]. J Urol, 2006,176:36-9.
[9] Zhou M, Roma A, Magi-Galluzzi C. The usefulness of immunohistochemical markers in the differential diagnosis of renal neoplasms[J]. Clin Lab Med JT, 2005,25:247-57.
[10] Guan-Zhen Y, Ying C, Can-Rong N, et al. Reduced protein expression of metastasis-related genes (nm23, KISS1, KAI1 and p53) in lymph node and liver metastases of gastric cancer[J]. Int J Exp Pathol, 2007,88:175-83.
[11] Bensalah K, Zeltser I, Tuncel A, et al. Evaluation of costs and morbidity associated with laparoscopic radiofrequency ablation and laparoscopic partial nephrectomy for treating small renal tumours[J]. BJU Int, 2007.
[12] Srinualnad S, Mahawong P. Conventional laparoscopic partial nephrectomy for a small renal mass[J]. J Med Assoc Thai, 2007,90:1225-30.
[13] Haber GP, Gill IS. Laparoscopic partial nephrectomy: contemporary technique and outcomes[J]. Eur Urol, 2006,49:660-5.
[14] Ortiz-Rey JA, Gomez De Maria C, Pelaez Boismorand E, et al. Expression of CD10 and renal cell carcinoma marker in clear cell renal cell carcinoma: analysis on tissue arrays[J]. Actas Urol Esp, 2006,30:281-6.
[1]Permpongkosol S,Bagga HS,Romero FR,et al.Laparoscopic versus open partial nephrectomy for the treatment of pathological T1NOMO ronal cell carcinoma:a 5-year survival rate[J].J Urol,2006,176:1984-8;discussion 1988-9.
[2]郑军华,孙颖浩.早期肾癌行腹腔镜肾部分切除术的相关问题思考[J].第二军医大学学报,2007,10:1045-1047.
[3]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].J Urol,2002,167:61-4.
[4]Permpongkosol S,Colombo JR Jr,Gill IS,et al.Positive surgical parenchymal margin after laparoscopic partial nephrectomy for renal cell carcinoma:oncological outcomes[J].J Urol,2006,176:2401-4.
[5]Caruso RP,Phillips CK,Kau E,et al.Robot assisted laparoscopic partial nephrectomy:initial experience[J].J Urol,2006,176:36-9.
[6]Zhou M,Roma A,Magi-Galluzzi C.The usefulness of immunohistochemical markers in the differential diagnosis of renal neoplasms[J].Clin Lab Med JT,2005,25:247-57.
[7]Guan-Zhen Y,Ying C,Can-Rong N,et al.Reduced protein expression of metastasis-related genes(nm23,KISS1,KAI1 and p53) in lymph node and liver metastases of gastric cancer[J].Int J Exp Pathol,2007,88:175-83.
[8]Bensalah K,Zeltser I,Tuncel A,et al.Evaluation of costs and morbidity associated with laparoscopic radiofrequency ablation and laparoscopic partial nephrectomy for treating small renal tumours[J].BJU Int,2007.
[9]Srinualnad S,Mahawong P.Conventional laparoscopic partial nephrectomy for a small renal mass[J].J Med Assoc Thai,2007,90:1225-30.
[10]Haber GP,Gill IS.Laparoscopic partial nephrectomy:contemporary technique and outcomes[J]. Eur Urol, 2006,49:660-5.
[11] Ortiz-Rey JA, Gomez De Maria C, Pelaez Boismorand E, et al. Expression of CD10 and renal cell carcinoma marker in clear cell renal cell carcinoma: analysis on tissue arrays [J]. Actas Urol Esp, 2006,30:281-6.
[12] Langner C, Ratschek M, Rehak P, et al. Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases[J]. Mod Pathol JT, 2004,17:180-8.
1 Li G,Feng G,Gentil-Perret A,et al.CA9 gene expression in conventional renal cell carcinoma:a potential marker for prediction of early metastasis after nephrectomy[J].Clin Exp Metastasis,2007,24(3):149-55.
2 Jiang Z,Chu PG,Woda BA,et al.Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell carcinoma:a retrospective study[J].Lancet Oncol,2006,7(7):556-64.
3 Merseburger AS,Hennenlotter J,Simon P,et al.Cathepsin D expression in renal cell cancer-clinical implications[J].Eur Urol,2005,48(3):519-26.
4 Araki K,Igarashi T,Tobe T,et al.Serum immunosuppressive acidic protein doubling time as a prognostic factor for recurrent renal cell carcinoma after nephrectomy[J].Urology,2006,68(6):1178-82.
5 Dudderidge TJ,Stoeber K,Loddo M,et al.Mcm2,Geminin,and KI67 define proliferative state and are prognostic markers in renal cell carcinoma[J].Clin Cancer Res,2005,11(7):2510-7.
6 Shioi K,Komiya A,Hattori K,et al.Vascular cell adhesion molecule 1 predicts cancer-free survival in clear cell renal carcinoma patients[J].Clin Cancer Res,2006,12(24):7339-46.
7 Yao M,Tabuchi H,Nagashima Y,et al.Gene expression analysis of renal carcinoma:adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma[J].J Pathol,2005,205(3):377-87.
8 Lidgren A,Hedberg Y,Grankvist K,et al.Hypoxia-inducible factor lalpha expression in renal cell carcinoma analyzed by tissue microarray[J].Eur Urol,2006,50(6):1272-7.
9 Parker AS, Lohse CM, Wu K, et al. Lower expression levels of the transforming growth factor beta receptor type II protein are associated with a less aggressive tumor phenotype and improved survival among patients with clear cell renal cell carcinoma[J]. Hum Pathol, 2007,38(3):453-61.
10 Mignogna C, Staibano S, Altieri V, et. al. Prognostic significance of multidrug-resistance protein (MDR-1) in renal clear cell carcinomas: a five year follow-up analysis[J]. BMC Cancer, 2006,6:293.
1 Faronato M,Muzzonigro G,Milanese G,et al.Increased expression of 5-1ipoxygenase is common in clear cell renal cell carcinoma.Histol Histopathol JT-Histology and histopathology,2007,22(10):1109-18.
2 Sartini D,Muzzonigro G,Milanese G,et al.Identification of nicotinamide N-methyltransferase as a novel tumor marker for renal clear cell carcinoma.J Urol JT-The Journal of urology,2006,176(5):2248-54.
3 Li G,Cuilleron M,Cottier M,et al.The use of MN/CA9 gene expression in identifying malignant solid renal tumors.Eur Urol JT-European urology,2006,49(2):401-5.
4 Togashi A,Katagiri T,Ashida S,et al.Hypoxia-inducible protein 2(HIG2),a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy.Cancer Res JT-Cancer research,2005,65(11):4817-26.
5 Chuang ST,Chu P,Sugimura J,et al.Overexpression of glutathione s-transferase alpha in clear cell renal cell carcinoma.Am J Cin Pathol JT-American journal of clinical pathology,2005,123(3):421-9.
6 Domoto T,Miyama Y,Suzuki H,et al.Evaluation of SIOOAIO,annexin Ⅱ and B-FABP expression as markers for renal cell carcinoma.Cancer Sci JT - Cancer science,2007,98(1):77-82.
7 Diegmann J,Junker K,Gerstmayer B,et al.Identification of CDTO as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling,real-time RT-PCR and immunohistochemistry.Eur J Cancer JT - European journal of cancer(Oxford,England:1990),2005,41(12):1794-801.
8 Ortiz-Rey JA, Gomez De Maria C, Pelaez Boismorand E, et al. [Expression of CD10 and renal cell carcinoma marker in clear cell renal cell carcinoma: analysis on tissue arrays]. Actas Urol Esp JT - Actas urologicas espanolas, 2006, 30(3):281-6.
9 Simsir A, Chhieng D, Wei XJ, et al. Utility of CD10 and RCCma in the diagnosis of metastatic conventional renal-cell adenocarcinoma by fine-needle aspiration biopsy. Diagn Cytopathol JT -Diagnostic cytopathology, 2005, 33(1) :3-7.
10 Junker K, Hindermann W, von Eggeling F, et al. CD70: a new tumor specific biomarker for renal cell carcinoma. J Urol JT - The Journal of urology, 2005, 173(6):2150-3.
11 Mazal PR, Stichenwirth M, Roller A, et al. Expression of aquaporins and PAX-2 compared to CD10 and cytokeratin 7 in renal neoplasms: a tissue microarray study. Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2005, 18(4) :535-40.
12 Zhou M, Roma A, Magi-Galluzzi C. The usefulness of immunohistochemical markers in the differential diagnosis of renal neoplasms. Clin Lab Med JT - Clinics in laboratory medicine, 2005, 25 (2):247-57.
13 Liu L, Qian J, Singh H, et al. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma: an optimal and practical panel for differential diagnosis. Arch Pathol Lab Med JT - Archives of pathology & laboratory medicine, 2007, 131 (8): 1290-7.
14 Garcia E, Li M. Caveolin-1 immunohistochemical analysis in differentiating chromophobe renal cell carcinoma from renal oncocytoma. Am J Clin Pathol JT - American journal of clinical pathology, 2006, 125 (3): 392-8.
15 Went P, Dirnhofer S, Salvisberg T, et al. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol JT - The American journal of surgical pathology, 2005, 29(1): 83-8.
16 Mazal PR, Exner M, Haitel A, et al. Expression of kidney-specific cadherin distinguishes chromophobe renal cell carcinoma from renal oncocytoma. Hum Pathol JT - Human pathology, 2005, 36(1): 22-8.
17 Kuehn A, Paner GP, Skinnider BF, et al. Expression analysis of kidney-specific cadherin in a wide spectrum of traditional and newly recognized renal epithelial neoplasms: diagnostic and histogenetic implications. Am J Surg Pathol JT - The American journal of surgical pathology, 2007, 31 (10): 1528-33.
18 Shomori K, Nagashima Y, Kuroda N, et al. ARPP protein is selectively expressed in renal oncocytoma, but rarely in renal cell carcinomas. Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2007, 20(2):199-207.
19 Li G, Gentil-Perret A, Lambert C, et al. S100A1 and KIT gene expressions in common subtypes of renal tumours. Eur J Surg Oncol JT - European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2005, 31 (3):299-303.
20 Kaya K,Ayan S,Gokce G,et al.Urinary nuclear matrix protein 22 for diagnosis of renal cell carcinoma.Scand J Urol Nephrol JT - Scandinavian journal of urology and nephrology,2005,39(1):25-9.
[1]顾方六.肾肿瘤.见:吴阶平泌尿外科学.济南:山东科学技术出版社,2004.889-917
[2]全国肿瘤防治研究办公室、卫生部卫生统计信息中心.中国试点市、县恶性肿瘤的发病与死亡(1988～1992).北京:中国医药科技出版社,2001.265-291.
[3]全国肿瘤防治研究办公室、卫生部卫生统计信息中心.中国试点市、县恶性肿瘤的发病与死亡(1993～1997).第2卷.北京:中国医药科技出版社,2002.271-297.
[4]Linehan WM,Walther MM,Zbar B.The genetic basis of cancer of the kidney.J Urol,2003,170:2163-2172.
[5]Walsh PC,Retik AB,Vaugh ED,et al.Classification of renal cell carcinoma.Cancer,1997,80:987-989.
[6]Delahunt B,Eble JN,McCredie MR,et al.Morphologic typing of papillary renal cell carcinoma:comparison of growth kinetics and patient survival in 66 cases.Hum Pathol,2001,32:590-595.
[7]颜克钧,王林辉,孙颖洁,等.偶发性肾癌的诊治体会(附44例报告).中国肿瘤临床与康复,2000,2:54-57.
[8]程文,周四维,高建平,等.289例偶发性肾细胞癌与312例症状性肾细胞癌临床分析.江苏医药杂志,2003,6:454-455.
[9]Palapattu GS,tristo B,Rajfer J.Paraneoplastic syndromes in urologic malignancy:the many faces of renal cell carcinoma.Rev Urol,2002,4:163-170.
[10]Godley PA,Stinchcombe TE.Renal cell carcinoma.Curr Opin Oncol,1999,11:213-217.
[11]潘柏年,徐仁方,郭晓,等.肾癌525例临床分析.中华泌尿外科杂志,2000,3:135-137.
[12]李青,程继义,王振声,等.肾癌369例临床分析.中华泌尿外科杂志,2001,23:496-499.
[13]Paul R,Mordhorst J,Busch R,Leyh H,Hartung R.Adrenal sparing surgery during radical nphrectomy in patients with renal cell cancer:a new algorithm,J Urol,2001,166:59-62.
[14]殷长军,晆元庚,吴宏飞,等.肾癌根治术326例报告.中华泌尿外科杂志,2002,23:392-394.
[15]牛志宏,许纯孝,王家耀,等.肾癌根治术是否应常规切除同侧肾上腺?中华泌尿外科杂志,1998,19:161-163.
[16]Swanson DA,Borges PM.Complications of transabdominal radical nephrectomy for renal cell carcinoma.J Urol,1983,129:704-707.
[17]Wunderlich H,Schlichter A,Reichelt O,et al.Renal indications for adrenalectomy in renal cell carcinoma.J Urol,1999,35:272-276.
[18] Sugao H, Matsuda M, Nakano E, et al. Comparison of lumbar flank approach and transperitoneal approach for radical nephrectomy. Urol Int, 1991, 46: 43-45.
[19] Novick AC, Streem S, Montie JE, et al. Conservative surgery for renal cell carcinoma.- a single-center experience with 100 patients. J Urol, 1989, 141: 835-839.
[20] Sandock DS, Seftel AD, Resnick MI. A new protocol for the follow up of renal cell carcinoma based on pathological stage. JUrol, 1995, 154: 28-31.
[21] Levy DA, Slaton JW, Swanson DA, et al. Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol, 1998, 159: 1163-1167.
[22] Collins S, Mckiernan J, Landman J. Update on the epidemiology and biology of renal cortical neoplasms. JEndourol, 2006, 20: 145-153.
[23] Bensalah K, Zeltser I, Tuncel A, et al. Evaluation of costs and morbidity associated with laparoscopic radiofrequency ablation and laparoscopic partial nephrectomy for treating small renal tumours. BJU Int, 2007, 33: 165-168.
[24] Srinualnad S, Mahawong P. Conventional laparoscopic partial nephrectomy for a small renal mass. J Med Assoc Thai, 2007, 90: 1225-30.
[25] Haber GP, Gill IS. Laparoscopic partial nephrectomy: contemporary technique and outcomes. Eur Urol, 2006, 49: 660-5.
[26] Leibovich BC, Blute ML, Cheville JC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7cm results in outcome similar to radical nephrectomy. J Urol, 2004, 171: 1066-1070.
[27] Permpongkosol S, Bagga HS, Romero FR, et al. Laparoscopic versus open partial nephrectomy for the treatment of pathological T1N0M0 renal cell carcinoma: a 5-year survival rate. J Urol, 2006, 176: 1984-8; discussion 1988-9.
[28] Higgins JP, Shinghal R, Gill H, et al. Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Am J Pathol, 2003, 162: 925-32.
[29] Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med, 2003, 349: 125-38.
[30] Balkovetz DF, Gerrard ER Jr, Li S, et al. Gene expression alterations during HGF-induced dedifferentiation of a renal tubular epithelial cell line (MDCK) using a novel canine DNA microarray. Am J Physiol Renal Physiol, 2004, 286: F702-10.
[31] Jung M, Ramankulov A, Roigas J, et al. In search of suitable reference genes for gene expression studies of human renal cell carcinoma by real-time PCR. BMC Mol Biol, 2007, 8: 47.
[32] Diegmann J, Junker K, Gerstmayer B, et al. Identification of CD70 as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling , real-time RT-PCR and immunohistochemistry. Eur J Cancer, 2005, 41: 1794-801.
[33] ChuanzhongY, Ming G, Fanglin Z, et al. Real-time quantitative reverse transcription-PCR assay for renal cell carcinoma-associated antigen G250. Clin Chim Acta, 2002, 318: 33-40.
[34] Rigaill G, Hupe P, Almeida A, et al. ITALICS: an algorithm for normalization and DNA copy number calling for Affymetrix SNP arrays. Bioinformatics, 2008, 24: 768-74.
[35] Stec J, Wang J, Coombes K, et al. Comparison of the predictive accuracy of DNA array-based multigene classifiers across cDNA arrays and Affymetrix GeneChips. J Mol Diagn, 2005, 7: 357-67.
[36] Sheffler W, Upfal E, Sedivy J, et al. A learned comparative expression measure for affymetrix genechip DNA microarrays. Proc IEEE Comput Syst Bioinform Conf, 2005: 144-54.
[37] Schraml P, Kononen J, Bubendorf L, et al. Tissue microarrays for gene amplification surveys in many different tumor types. Clin Cancer Res, 1999, 5: 1966.
[38 ] Ka(?)suma S , Tsujimoto G. Genome medicine promised by microarray technology. Expert Rev Mol Diagn, 2001, 1 (4): 377.
[39] Kallioniemi OP. Biochip technologies in cancer research. Ann Med, 2001, 33: 142-147.
[40] Mohr S, Leikauf GD, Keith G, et al. Microarrays as cancer keys: an array of possibilities. J Clin Oncol. 2002 Jul 15, 20 (14): 3165-75.
[41] Kallioniemi OP , Wagner U, Sauter G, et al. Tissue microarray technology for high-throughput molrcular profiling of cancer. Hum Mol Genel, 2001, 10 (7): 657-662.
[42] Aguilar-Mahecha A, Hassan S, Ferrario C, et al. Microarrays as validation strategies in clinical samples: tissue and protein microarrays. OMICS. 2006 Fall; 10 (3): 311-326.
[43] Barlund M, Monni O, Kononen J, et al. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res, 2000, 60: 534.
[44] Mousses S, Kallioniemi A, Kauraniemi P, et al. Clinical and functional target validation using tissue and cell microarrays. Curr Opin Chem Biol. 2002 Feb; 6(1): 97-101.
[45] Moch H, Kononen T, Kallioniemi OP, et al. Tissue microarrays: what will they bring to molecular and anatomic pathology? Adv Anat Pathol, 2001, 8(1): 14-20.
[46] Giltnane JM, Rimm DL. Technology insight: Identification of biomarkers with tissue microarray technology. Nat Clin Pract Oncol. 2004 Dec; 1 (2): 104-111.
[47] Nocito A, Kononen J, Kallioniemi OP, et al. Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer. 2001 Oct 1; 94(1): 1-5.
[48] Higgins JP, Shinghal R, Gill H, et al. Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Am J Pathol, 2003, 162: 925-32.
[49] Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med, 2003, 349: 125-38.
[50] Balkovetz DF, Gerrard ER Jr, Li S, et al. Gene expression alterations during HGF-induced dedifferentiation of a renal tubular epithelial cell line ( MDCK) using a novel canine DNA microarray. Am J Physiol Renal Physiol, 2004, 286: F702-10.
[51] Jung M, Ramankulov A, Roigas J, et al. In search of suitable reference genes for gene expression studies of human renal cell carcinoma by real-time PCR. BMC Mol Biol, 2007, 8: 47.
[52] Diegmann J, Junker K, Gerstmayer B, et al. Identification of CD70 as a diagnostic biomarker for clear cell renal cell carcinoma by gene expression profiling , real-time RT-PCR and immunohistochemistry. Eur J Cancer, 2005, 41: 1794-801.
[53] Chuanzhong Y, Ming G, Fanglin Z, et al. Real-time quantitative reverse transcription-PCR assay for renal cell carcinoma-associated antigen G250. Clin Chim Acta, 2002, 318: 33-40.
[54] Rigaill G, Hupe P, Almeida A, et al. ITALICS: an algorithm for normalization and DNA copy number calling for Affymetrix SNP arrays. Bioinformatics, 2008, 24: 768-74.
[55] Stec J, Wang J, Coombes K, et al. Comparison of the predictive accuracy of DNA array-based multigene classifiers across cDNA arrays and Affymetrix GeneChips. J Mol Diagn, 2005, 7: 357-67.
[ 56 ] Sheffler W, Upfal E, Sedivy J, et al. A learned comparative expression measure for affymetrix genechip DNA microarrays. Proc IEEE Comput Syst Bioinform Conf, 2005: 144-54.
[57] Sultmann H, von Heydebreck A, Huber W, et al. Gene expression in kidney cancer is associated with cytogenetic abnormalities, metastasis formation, and patient survival. Clin Cancer Res, 2005, 11: 646-55.
[ 58 ] Yao M, Tabuchi H, Nagashima Y, et al. Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol, 2005, 205: 377-87.
[59] Ami Y, Shimazui T, Akaza H, et al. Gene expression profiles correlate with the morphology and metastasis characteristics of renal cell carcinoma cells. Oncol Rep, 2005, 13: 75-80.
[60] Alonso MA, Weissman SM. cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation. Proc Natl Acad Sci U S A, 1987, 84: 1997-2001.
[61] Schonherr E, Sunderkotter C, Iozzo RV, et al. Decorin, a novel player in the insulin-like growth factor system. J Biol Chem, 2005, 280: 15767-72.
[62] Schaefer L, Tsalastra W, Babelova A, et al. Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin. Am J Pathol, 2007, 170: 301-15.
[63] Williams KJ, Qiu G, Usui HK, et al. Decorin deficiency enhances progressive nephropathy in diabetic mice. Am J Pathol, 2007, 171: 1441-50.
[64] Ostalska-Nowicka D, Zachwieja J, Nowicki M, et al. Immunohistochemical detection of galectin-1 in renal biopsy specimens of children and its possible role in proteinuric glomerulopathies. Histopathology, 2007, 51: 468-76.
[65] Valkova N, Yunis R, Mak SK, et al. Nek8 mutation causes overexpression of galectin-1, sorcin, and Vimentin and accumulation of the major urinary protein in renal cysts of jck mice. Mol Cell Proteomics, 2005, 4: 1009-18.
[66] Francois C, van Velthoven R, De Lathouwer O, et al. Galectin-1 and galectin-3 binding pattern expression in renal cell carcinomas. Am J Clin Pathol, 1999, 112: 194-203.
[67] Huang W, Xu C, Kahng KW, et al. Aldosterone and TGF-beta 1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells. Am J Physiol Renal Physiol, 2008.
[68] Fedulov AV, Ses TP, Gavrisheva NA, et al. Serum TGF-beta 1 and TNF-alpha levels and cardiac fibrosis in experimental chronic renal failure. Immunol Invest, 2005, 34: 143-52.
[69] Hugo C. The thrombospondin 1-TGF-beta axis in fibrotic renal disease. Nephrol Dial Transplant, 2003, 18: 1241-5.
[70] Campbell L, Jasani B, Edwards K, et al. Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma. Br J Cancer, 2008, 98: 931-40.
[71] Garcia E, Li M. Caveolin-1 immunohistochemical analysis in differentiating chromophobe renal cell carcinoma from renal oncocytoma. Am J Clin Pathol, 2006, 125: 392-8.
[72] Campbell L, Gumbleton M, Griffiths DF. Caveolin-1 overexpression predicts poor disease-free survival of patients with clinically confined renal cell carcinoma. Br J Cancer, 2003, 89: 1909-13.
[73] Cao G, Yang G, Timme TL, et al. Disruption of the caveolin-1 gene impairs renal calcium reabsorption and leads to hypercalciuria and urolithiasis. Am J Pathol, 2003, 162: 1241 -8.
[74] Maruyama R, YamanaK, ItoiT, et al. Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma. BrJ Cancer, 2006, 95: 1244-9.
[75] Skolarikos A, Alivizatos G, Bamias A, et al. Bcl-2 protein and DNA ploidy in renal cell carcinoma: do they affect patient prognosis? . Int J Urol, 2005, 12: 563-9.
[76] Molto L, Rayman P, Paszkiewicz-Kozik E, et al. The Bcl-2 transgene protects T cells from renal cell carcinoma-mediated apoptosis. Clin Cancer Res, 2003, 9: 4060-8.
[77] Svensson A, Norrby M, Libelius R, et al. Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle. J Mol Histol, 2008.
[78] Gumz ML, Zou H, Kreinest PA, et al. Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clin Cancer Res, 2007, 13: 4740-9.
[79] Zhong X, Desilva T, Lin L, et al. Regulation of secreted Frizzled-related protein-1 by heparin. J Biol Chem, 2007, 282: 20523-33.
[80] Nagy N, Brenner C, Markadieu N, et al. S100A2, a putative tumor suppressor gene, regulates in vitro squamous cell carcinoma migration. Lab Invest, 2001, 81: 5 99-612.
[81] Wicki R, Franz C, Scholl FA, et al. Repression of the candidate tumor suppressor gene S100A2 in breast cancer is mediated by site-specific hypermethylation. Cell Calcium, 1997, 22: 243-54.
[82] Tsai WC, Tsai ST, Jin YT, et al. Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell carcinoma. Mol Cancer Res, 2006, 4: 539-47.
[83] Schraml P, Kononen J, Bubendorf L, et al. Tissue microarrays for gene amplification surveys in many different tumor types. Clin Cancer Res, 1999, 5: 1966.
[84] Katsuma S, Tsujimoto G. Genome medicine promised by microarray technology. Expert Rev Mol Diagn, 2001, 1 (4) : 377.
[85] Kallioniemi OP. Biochip technologies in cancer research. Ann Med, 2001, 33: 142-147.
[86] Mohr S, Leikauf GD, Keith G, et al. Microarrays as cancer keys: an array of possibilities. J Clin Oncol. 2002 Jul 15; 20(14): 3165-75.
[87] Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-through put molecular profiling of tumor specimens. Nat Med. 1998 Jul; 4 (7): 844-847.
[88] Manley S, Mucci NR, De Marzo AM, et al. Relational database structure to manage high-density tissue microarray data and images for pathology studies focusing on clinical outcome: the prostate specialized program of research excellence model. Am JPathol. 2001, Sep; 159(3): 837-843.
[89] Kallioniemi OP, Wagner U, Sauter G, et al. Tissue microarray technology for high-through put molrcular profiling of cancer. Hum Mol Genel, 2001, 10 (7): 657-662.
[90] Aguilar-Mahecha A, Hassan S, Ferrario C, et al. Microarrays as validation strategies in clinical samples: tissue and protein microarrays. OMICS. 2006 Fall; 10 (3): 311-326.
[91] Barlund M, Monni O, Kononen J, et al. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res, 2000, 60: 534.
[92] Mousses S, Kallioniemi A, Kauraniemi P, et al. Clinical and functional target validation using tissue and cell microarrays. Curr Opin Chem Biol. 2002, Feb; 6 (1): 97-101.
[93]Moch H,Kononen T,Kallioniemi OP,et al.Tissue microarrays:what will they bring to molecular and anatomic pathology?.Adv Anat Pathol,2001,8(1):14-20.
[94]Giltnane JM,Rimm DL.Technology insight:Identification of biomarkers with tissue microarray technology.Nat Clin Pract Oncol.2004 Dec;1(2):104-111.
[95]Nocito A,Kononen J,Kallioniemi OP,et al.Tissue microarrays(TMAs) for high-throughput molecular pathology research.Int J Cancer.2001 Oct 1;94(1):1-5.
[96]Bensalah K,Zeltser I,Tuncel A,et al.Evaluation of costs and morbidity associated with laparoscopic radiofrequency ablation and laparoscopic partial nephrectomy for treating small renal tumours.BJU Int,2007.
[97]Srinualnad S,Mahawong P.Conventional laparoscopic partial nephrectomy for a small renal mass.J Med Assoc Thai,2007,90:1225-30.
[98]Haber GP,Gill IS.Laparoscopic partial nephrectomy:contemporary technique and outcomes.Eur Urol,2006,49:660-5.
[99]郑军华,孙颖洁.早期肾癌行腹腔镜肾部分切除术的相关问题思考.第二军医大学学报,2007,10:1045-1047.
[100]Ortiz-Rey JA,Gomez De Maria C,Pelaez Boismorand E,et al.Expression of CD10 and renal cell carcinoma marker in clear cell renal cell carcinoma:analysis on tissue arrays.Actas Urol Esp,2006,30:281-6.
[101]Ortiz-Rey JA,Gomez De Maria C,Pelaez Boismorand E,et al.Expression of CD10 and renal cell carcinoma marker in clear cell renal cell carcinoma:analysis on tissue arrays.Actas Urol Esp,2006,30:281-6.
[102]Langner C,Ratschek M,Rehak P,et al.Expression of MUC1(EMA) and E-cadherin in renal cell carcinoma:a systematic immunohistochemical analysis of 188 cases.Mod Pathol JT,2004,17:180-8.
[103]倪灿荣,李芳梅,朱明华,于观贞.提高组织芯片切片成功率的方法与体会.中华病理学杂志,2002,31(6):559-560.
[104]Robert L,Camp LA,Charette DL,et al.Validation of tissue microarray technology in breast carcinoma.Lab Invest,2000,80(12):1943-1949.
[105]Bubendorf L,Nocito A,Moch H,et al.Tissue microarray(TMA) technology:miniaturized pathology archives for high-throughput in-situ studies.J Pathol.2001,195(1):72-79.
[106]Hoos A,Stojadinovic A,Mastorides S,et al.High Ki-67 proliferative index predicts disease specific survival in patients with high-risk soft tissue sarcoma.Cancer,2001,92(4):869-874.