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原创 上尿路移行细胞癌恶劣病理结局的预测因素及术后预后因素

陈晓鹏 主治医师 唐都医院 泌尿外科
2018-04-17 228人已读
陈晓鹏 主治医师
唐都医院

作者:陈晓鹏,空军军医大学第二附属医院泌尿外科,陕西西安,710038.

在西方国家,尿路移行细胞癌是继前列腺癌(或乳腺癌)、肺癌和结直肠癌后的第四大常见肿瘤[i]。它包括上尿路(肾盂和输尿管)和下尿路(膀胱和尿道)移行细胞癌。以膀胱癌最为常见,占所有尿路上皮癌的90-95%,是泌尿生殖系统中继前列腺癌后的第二位常见恶性肿瘤。上尿路移行细胞癌(UTUC,upper tract urothelial carcinoma)则十分少见,仅占所有移行细胞癌的5-10%。西方国家的估计年新发病率仅为1-2/100 000人。肾盂肿瘤是输尿管肿瘤的2倍。8-13%UTUC伴随有膀胱癌,术后有30-51%的病例出现膀胱复发,2-6%的病例出现对侧复发。UTUC和膀胱癌病程不同,60%UTUC诊断时60%出现肌层浸润,而膀胱癌只有15%UTUC的好发年龄在7080年龄段,男性发病高于女性,男女比大约为31。基于美国癌症监测、流行病和最后结局规划(SEER)数据库的资料[ii],[iii],分析显示上世纪末20几年间,输尿管肿瘤发病率有轻微的上升,但肾盂肿瘤发病率下降变,原位癌所占比例明显上升,发病年龄升高,男性发病比例下降,白人所占比例下降。并且年龄调整死亡率黑人大于白人,女性多于男性。同样基于SEER数据库资料,Giovanni Lughezzani[iv]分析了上世纪末20年分期和分级的变迁,结果显示非器官局限性肿瘤、远处转移的肿瘤、G3-4分级肿瘤的比例明显上升,肿瘤分期和分级仍然是CSS的重要预后因素。空军军医大学唐都医院泌尿外科陈晓鹏

吸烟和职业因素是膀胱癌和UTUC的共同危险因素。在染料、纺织品、橡胶、化学药品、石油化工、煤炭的行业,工人经常接触包含有二连苯和萘的芳香胺类化学物质。而这些芳香胺是尿路移行细胞癌的致癌物质[v]。非甾体类镇痛药非那西汀是UTUC的危险因素。而对巴尔干地方性肾病Balkan endemic nephropathy)和中草药肾病Chinese herbs nephropathy)的研究发现,口服含马兜铃酸药物所致的马兜铃酸肾病aristolochic acid nephropathy)是这两类疾病共同的发病基础,并且马兜铃酸是UTUC重要的危险因素[vi],[vii]

对于上尿路移行细胞癌,不论是肾盂肿瘤,还是输尿管肿瘤,根治性肾输尿管全长切除术仍然是标准的治疗方式1。然而,对于低组织学分级(G)和低病理分期(T)的上尿路移行细胞癌,包括内镜消融治疗(endoscopic ablation therapy)和输尿管节段性切除的保守治疗方式是一个可取的选择方式[viii],[ix],[x]。既保留了患侧肾脏,也避免了根治性肾输尿管全长切除术相应的围手术期并发症。高组织学分级(G)、高病理分期(T)以及淋巴结转移(N+)是接受手术的上尿路移行细胞癌的不良预后因素10,[xi],[xii]。高组织学分级(G)、高病理分期(T)又与淋巴结转移(N+)明显相关[xiii]。膀胱与肾盂、输尿管相延续,为下尿路结构,三者的上皮组织结构均为尿路上皮。尿路上皮癌均是三者最为常见的恶性肿瘤的病理类型。基于膀胱移行细胞癌的治疗经验充分肯定了术中淋巴结清扫和辅助化疗对于较晚期移行细胞癌的治疗价值。也有一些文献支持在较晚期的UTUCs进行辅助化疗和肌层浸润UTUCs进行术中淋巴结清扫的治疗价值。但肾输尿管全长切除术切除了患侧肾脏,使得一部分病人术后肾功能恶化,无法承受辅助化疗。因此对于较晚期的上尿路移行细胞癌患者,术前新辅助化疗是一个可能的选择方式[xiv],[xv]。因此术前预测上尿路移行细胞癌的晚期病理结局,包括肌层浸润(muscle invasive disease,T2-4)、非器官局限性肿瘤(nonorgan confined,T3-4 and/or N+)、G3级组织学分级能够为泌尿外科医师提供合适的指导,以选择初始治疗的手术方式(根治性或保守手术),决定术中是否行淋巴结清扫,术前是否接受新辅助化疗。

包括台湾人在内的中国汉族人群上尿路移行细胞癌(UTUC)的发病特点与西方发达国家有明显的差异。在欧美国家,UTUC是少发疾病,大约占所有尿路上皮癌的5-10%,占肾部位肿瘤的10%,估计年发病率为1-2例/10万人,并且男性的发病率为女性的2至3倍1。并且有文献报道,欧美人群中女性UTUC患者更倾向于出现高分级、高分期和淋巴结转移[xvi],[xvii]。中国汉族人群,女性发病率略高于男性,男女比例接近于1:1.3[xviii],[xix]。肾盂移行细胞癌约占所有尿路移行细胞癌的20-30%19,[xx],占所有肾部位肿瘤的40%19。另外,据报道中国汉族人群上尿路移行细胞癌临床病理特征的性别差异与欧美人群相反,女性患者高分级、淋巴结转移的比例明显较少,且平均肿瘤体积也明显较小18。中国人群UTUCs的发病率高,人口基数大,至今却少有基于中国人群的UTUCs恶劣病理结局的预测因素及术后预后因素的分析报道。我们回顾已有的文献,对相应内容进行总结归纳。

一术前因素的预测及术后预后作用

1性别94 90 39 46 31 28 36 10 29

Mario I.Fernández[xxi]等分析了UTUC协作组数据库中的1363例UTUCs。男女比为2.1:1,女性患者比男性患者发病年龄较高。分期(T)、分级(G)、生长结构、淋巴血管侵犯(LVI)、原位癌(cis)以及淋巴结转移(LNM)等病理特征不存在明显的性别差异。在无疾病复发生存(RFS)和疾病特异性生存(CSS)上,TGN是独立的预后因素,性别在单因素和多因素分析中均无预后作用。N.Aydin Mungan17分析了荷兰肿瘤登记处的21795例膀胱癌(其中有1254例非移行细胞癌)和1982UTUC的病理特征的差异。膀胱癌男女比为4;1,UTUC的男女比为2.03:1。不论是膀胱移行细胞癌、膀胱非移行细胞癌,还是上尿路移行细胞癌,女性患者高分期、淋巴结转移的比例均较高。Giovanni Lughezzani[xxii]基于SEER数据库,分析了3850T1-T3UTUC的性别差异。女性和高分期、高分级相关,就诊年龄更大。女性、高龄、输尿管是T3的独立预测因素。但性别对疾病特异性生存没有影响。Shahrokh F.Shariat[xxiii]分析了785例多中心的UTUCs的性别差异,男女比为2.17:1,女性发病年龄更高,但高分级比例较低,RFSCSS无性别差异。

台湾的Wen-Wei Huang[xxiv]报道了385UTUC术后膀胱癌复发的危险因素。男女比为1:1.21。术后膀胱复发的独立危险因素包括:男性、高分级、明显的乳头状结构(>90%的乳头状结构)。台湾的Peir-Haur Hung[xxv]报道了404例移行细胞癌临床病理特征和术后肾功能和生存的差异。膀胱移行细胞癌男女比为1.85:1,UTUC的男女比为1:1.26。移行细胞癌(UC)中,女性患者有更高比例的UTUC和高分期、高分级UC,肿瘤体积也更大。男性术后复发的比例更高。然而肿瘤多发性、远处转移、CKD无性别差异。然而男性是术后ERSD的独立预测因素。Ching-Chia Li[xxvi]报道了260UTUC的预后因素,男性和肾功能不全是RNU术后膀胱复发的独立危险因素,而女性是对侧复发的独立危险因素。Lia-Beng Tan[xxvii]分析了141UTUC,位于输尿管和女性、较低分析相关,但性别无预后作用。虞巍等18分析了国内我中心的597UTUC的性别差异,与台湾人群的分析结果类似,男女比1:1.35,女性患者高分期、淋巴结转移的比例较低,肿瘤体积较小。Osamu Kamihira[xxviii]报道了日本1003UTUC,男性是术后膀胱复发的独立危险因素。

2年龄和ECOG-PS评分31 33 77

关于高龄对恶劣病理结局的预测作用报道较少,但文献基本一致的认为高龄是UTUC的不良预后因素。Giovanni Lughezzani22基于SEER数据库,分析了3850T1-T3UTUC的性别差异,分析显示女性、高龄、肾盂是T3的独立预测因素,且高龄是CSS的独立的不良预后因素。Stanley A.Yap[xxix]基于SEER数据库20年的12639例数据,分析显示随着年龄的增加,女性患者比例、白人、高分期、高分级的比例明显增加,且高龄是OSSCSS独立的不良预后因素。Shahrokh F.Shariat[xxx]分析了1453UTUCs,结论认为高龄是CSS\OSS的独立不良预后因素,但和RFS无关。但Thomas F.Chromecki[xxxi]提出高龄不是UTUCs的独立预后因素。该文章了分析了1169UTUCs,高龄和女性、较高的ECOG PS评分(美国东部肿瘤协作组活动状态评分)ASA评分相关。不包括ECOG PS评分的多因素分析显示,高龄是RFSCSSOSS的独立不良预后因素,但包括ECOG PS评分的多因素分析显示年龄不是RFSCSS的独立预后因素,高ECOG PS评分和高龄是OSS的不良预后因素。Debasish Sundi[xxxii]分析了240UTUCs,结果也支持高ECOG PS评分是CSS的不良预后因素,而高龄不论在单因素还是多因素分析中都不具有预后作用。然而Umberto Capitanio[xxxiii]1249UTUCs,包含年龄、ECOG PS评分、TGN等多因素分析显示,高龄是CSS的不良预后因素。Marco Roscigno[xxxiv]分析了1130UTUCs,多因素分析显示高龄、较高ECOG PS评分均是CSS的不良预后因素。Nicholas J.Hellenthal[xxxv]分析了高危UTUC(即NOC-UTUC)的预后,高龄、较高ECOG PS评分均是CSSOSS的不良预后因素。Juan Ignacio Martinez-Salamanca[xxxvi]分析了427例,平均随访32个月。高龄和ECOG PS评分均均不是RFS\CSS的独立预后因素,但是两者是OSS的独立预后因素。

3种族20

John J.Munoz2Jay D.Raman3基于美国SEER数据库的资料分析显示,白人和西班牙裔的UTUC患者总体生存不存在明显差异,但黑人和其他种族UTUC患者OSS比白人要差,在多因素分析中,种族是独立的预后因素。Kazumasa Matsumoto[xxxvii]比较了日本人和高加索人的种族差异,日本人群UTUC女性比例、发病年龄、LVI、浸润性结构、肿瘤坏死、CIS的比例较低,高分期、高分级的比例以及接受辅助化疗的比例较高,但种族之间RFSCSS不存在差异。

4肥胖82 84

关于肥胖的预测及预后作用的文献较少,且结论相反,这与不同的分界标准有关。Behfar Ehdaie[xxxviii]分析了美国520UTUCs,分析显示高BMI指数(以25 kg/m2为界)与浸润性生长结构和LVI相关,并且高BMI指数是RFSCSSOSS的不良预后因素。Teruo Inamoto[xxxix]分析了日本103UTUCs,高BMI指数(以22 kg/m2为界)与男性相关,和其他临床病理特征没有相关性,且OSSCSS预后较好。

5同侧肾积水

由于上尿路较为狭小的管腔结构,上尿路移行细胞癌伴随肾积水的比例明显较高。但对伴随肾积水和UTUC的病理特征及预后的相关分析仍比较少,仅有近期的数篇文献见诸报道,且包含的病例数较少。这些报道一致认为伴随肾积水和恶劣的病理结局相关,但不是独立的预后因素。Casey K.Ng[xl]报道的106UTUCs中,伴随肾积水的比例为37%。伴随肾积水和输尿管位置、高分期明显相关,且单因素分析显示伴随肾积水的UTUCs术后生存较差。但根据术后病理TGN特征进行多因素校正分析,肾积水不是独立的预后因素。Jamie C.Messer[xli]报道的408UTUCs55%伴随肾积水,且伴随肾积水和肌层浸润期别、非器官局限性分期、高组织学分期相关。James C.Brien[xlii]报道的172UTUCs54%伴随肾积水,且包含尿脱落细胞学检查、活检分级的校正分析显示,肾积水和肌层浸润、非器官局限性分期明显相关。Yujiro Ito[xliii]等报道的91例病例,73.6%伴随肾积水,伴随肾积水的病例更多的位于输尿管,且术前的多因素分析显示伴随肾积水是T3/4期、淋巴血管侵犯(LVI)、G3分级的独立预测因素。但肾积水和疾病特异性生存和无转移生存没有相关性。另外Katsura Hoshino[xliv]报道高龄和术前患侧伴随肾积水是根治术后患者肾功能恶化的独立预测因素。不伴肾积水的病例接受肾输尿管全长切除术后,有较高的比例出现肾功能恶化,丧失接受辅助化疗的机会。因此对于术前伴随肾积水的UTUC接受保守治疗方式应慎重,而不伴肾积水的病例若需术后接受化疗,可考虑在根治术前行新辅助化疗,避免术后肾功能恶化而丧失化疗机会。

6肾功能不全(CKD)17 18 19 22

Chia-Yen Chen[xlv]分析了台湾东部地区的110UTUCs患者,单因素分析显示CKDERSD病人中肿瘤高分级的比例比正常肾功能患者明显较高,并且CSS预后明显较差。台湾的Peir-Haur Hung[xlvi]分析267尿路移行细胞癌,认为尿路上皮癌的恶性度与肾功能不全(CKD)的严重程度相关。高龄、女性、UUTUC、高分期、高分级、较大肿瘤、肿瘤多发和程度较重的CKD相关,但CKD不是OSS的独立的预后因素。Peir-Haur Hung[xlvii]又进一步分析了141例为CKD4/5期或为终末期肾功能衰竭(ERSD)长期接受透析的尿路移行细胞癌患者,CKD4/5期患者高分期比例更高、肿瘤体积也更大,认为CKD4/5期的UTUC肿瘤的恶性度比ERSD期更高。另外在肾功能不全的UTUC患者,男性和高分期是OSS的独立预后因素。台湾的Wei-Ming Li[xlviii]分析了145例输尿管移行细胞癌,术前较差的CKDCSS的独立不良预后因素。虞巍等[xlix]分析了161例国内UTUCs病例,CKD和既往膀胱癌病史是术后膀胱癌复发的独立危险因素。

二手术方式的预后作用

1保守治疗方式101 79 60 62 61

Morgan Rouprêt[l]比较54例开放手术和43例内镜手术的疗效比较。平均随访54个月,手术并发症以及术后膀胱癌复发、对侧上尿路肿瘤复发率无明显差异,但内镜组有11.6%的病例出现同侧的局部复发,而开放组没有局部复发。内镜组25.6%的病例在随访过程中因肿瘤复发接受开放RNU术。术后CSS生存不同的手术组间无明显差异。特别是对于表浅膀胱癌或低级别的UTUCs内镜手术后的CSS与开放RNU术无明显差异。Cenk Gurbuz[li]进一步比较了既往接受输尿管镜肿瘤消融术对后续RNU术疗效的影响。文章纳入175例(13%)既往接受输尿管镜肿瘤消融术病例和1093例(87%)没有内镜治疗史的病例。平均随访52.8个月,两组病例RFSCCS无明显差异。Adam J.Gadzinski[lii]报道了内镜治疗的长期随访结果。96个侧别(93例)中,62侧接受LNU术,34侧接受内镜手术。平均随访57.7个月,生存患者平均随访75.4个月。开放手术组并发症明显较高,但手术方式不是MFSCSSOSS的预后因素。但内镜治疗组术后复发比例较高,34例内镜组病例,8例高分级患者在术后13个月内均出现局部复发,26例低分级患者13个月的无复发率生存率(RFS)为36%5RFS19%11例(32.4%)随访过程中接受部分或根治性切除,5年的保肾率为61%Adam J.Gadzinski[liii]进一步比较11例因先行内镜手术而延迟10个月接受RNU术的病例的长期随访结果,平均随访58个月。和62例即时手术组相比,围手术指标无明显差异,两组的OSS\MFS\CSS均无明显差异,支持内镜消融术作为低分期和低分级病例首选治疗方式的安全性。Jean-Nicolas Cornu[liv]报道了35例接受软输尿管镜肿瘤消融术的表浅UTUCs的中期随访结果。平均随访30个月,21例(60%)出现复发,4例随访过程接受根治手术。没有病人因疾病进展死亡。Pierre Colin[lv]报道了节段性切除与RNU术的短期疗效比较。包括52例接受节段性切除的输尿管肿瘤和416例接受RNU术的UTUCs,平均随访26个月。两组病例在RFS\MFS\CSS均无明显差异。作者进一步分析了≤T2期的100例远端输尿管肿瘤,其中54例接受RNU术,而46例接受远端输尿管切除吻合术。两组RFS\MFS\CSS均无明显差异。Jonathan L.Silberstein[lvi]分析了120例输尿管肿瘤术后肾功能变化及预后,87例行RNU,33例行输尿管节段性切除,平均随访4.2年。RNU手术组具有较高比例的肾积水、高分期,术前eGFR较,术后eGFR有较明显的下降。但两种术式CSS\OSS\RFS无明显差异。台湾的Wei-Ming Li48分析了145UTUCs,其中22例接受节段性切除,较RNU术有较高比例的局部复发,但5CSS生存率无明显差异。

2腔镜肾输尿管全长切除术

RNU肾输尿管全长切除术,ONU开放RNU术,LNU腔镜肾输尿管全长切除术,RLNU腹膜后LNU术,TLNU经腹LNU术)

自从1991年报道了第一例腔镜肾输尿管全长切除术后,腔镜手术治疗UTUC逐渐在各个国家得到推广。各个诊疗中心也相继报道了各自的诊疗经验。Masao Tsujihata[lvii]报道了日本25例腹膜后LNU的初始治疗经验。和24ONU术相比,腔镜手术出血更少、进食和拔除尿管更早、住院时间更短、镇痛药使用更少,但在平均22月的随访时间里,两组DFS无明显差异。Ryohei Hattori[lviii]报道了日本名古屋的随访结果。研究包含了53例完全腹膜后腔镜(RLNU)术、36例腹膜后腔镜(RLNU)术和60例开放性(ONU)手术,腔镜手术出血少、手术时间短、术后恢复快,但腔镜手术清扫的淋巴结数目较少。腔镜组合开放组在CSSRFS、术后膀胱肿瘤复发上无明显差异。Michael Muntener[lix]报道了39例腹腔镜(TLNU)术的长期疗效,平均随访74个月,11例出现死亡,分期是唯一的预后因素,27例(69%)出现膀胱复发,位于输尿管与膀胱复发相关。Morgan Rouprêt[lx]报道了法国的单中心经验,包括26例开放手术和20例经腹腔LNU术,平均随访68.5月。腔镜组非肌层浸润、低分级比例较高,住院时间明显较短。在手术并发症、RFSCSS上两者无明显差异。Andre Berger[lxi]报道了美国100LNU7年随访经验,91例腹膜后LNU术,9例经腹LNU术。中转开腹3例,有并发症12例。2年、5年、7年的OSSCSSRFS分别为81%59%50%91%77%72%66%49%36%。长期疗效和已报道的开放手术疗效相当。Matthias Waldert[lxii]报道了澳大利亚的中期随访经验,包括43例腔镜手术和59开放手术,平均随访41个月。腔镜手术组术中出血量和术后住院天数明显较少,但两组在RFS\PFS\CSS上午明显差异。Osamu Kamihira28报道了日本多中心1003例接受LNUUTUCs,平均随访20个月,术中并发症9.3%,术后并发症10.7%3年、5年的OSSRFS生存率分别为80%70%48%42%Morgan Rouprêt[lxiii]报道了法国的多中心的短期随访结果。包括150例经腹LNU术和459ONU术,平均随访2年。腔镜手术组女性手术时间较长,但住院时间较短,并发症无明显差异。CSS\RFS\MFS也无明显差异。特别是对于局部晚期(pT3/4)肿瘤,腔镜和开放手术组CSSRFS也无明显差异,支持了腔镜手术在UTUC肿瘤的运用。Umberto Capitanio33报道了多中心的中期随访结果,包括270LNU术和979ONU术,平均随访49月。LNU组分期更早、N+比例和LVI比例较低、较少位于输尿管。手术方式和CSSRFS无相关性。而且在不同T分期的单独比较分析,手术方式和预后无明显相关,即使是对于T3/4期肿瘤,肯定了LNU具有和ONU相同的肿瘤控制疗效。Francesco Greco[lxiv]报道了德国的长期随访结果,包括70例经腹LNU术和70ONU术,平均随访60个月。腔镜组手术时间更长,但RFS无明显差异。Thomas J.Walton[lxv]报道了国际多中心的703ONU术和70LNU术的比较,平均随访34月。腔镜组高分级比例较高、辅助化疗较高、淋巴结转移较低,但RFS\CSS和开放组无明显差异。基于高分期和淋巴结转移的病例的多因素分析,手术方式也不影响RFS\CSS,支持腔镜手术在UTUCs的运用。Grant D.Stewart[lxvi]报道了至今随访时间最长的英国23例经腹LNU的治疗经验。和39ONU相比,两组病例在分期、分级分布无明显差异,在平均163月(13.6年)的随访时间里,两组在OSSCSSRFS及膀胱复发时间上均无明显差异,肯定了LNU手术疗效。意大利的Giuseppe Simone[lxvii]报道了至今唯一的前瞻性对照试验结果,队列研究纳入了40LNU术和40ONU术。两组病理特征无明显差异,但腔镜组术中出血、住院时间明显减少。平均随访41个月,两组BTFS,CSSMFS无明显差异。但在T3期别和高分级G组,开放手术在CSSMFS优于LNU术组。因此作者认为对于高分期和高分级肿瘤,腔镜手术应慎重使用。另外台湾的Wen-Wei Huang24分析了139LNU术和234ONU术,平均随访69个月,发现LNU术后有较高比例的膀胱复发。国内陈明等[lxviii]进行了71UTUCs的多因素分析,其中31例腹膜后LNU术,40ONU术,平均随访23个月。多因素分析显示手术方式对CSS无明显影响。

3术中淋巴结清扫

淋巴结清扫的治疗意义现在仍存在争论,术中进行淋巴结清扫的指征和淋巴结清扫的范围尚无明确标准。Maurizio A.Brausi[lxix]分析了82例肌层浸润(MIDUTUCs,单因素和包含TGN的多因素分析均显示腹膜后淋巴结清扫组具有更好的DFSOSS生存率。Marco Roscigno[lxx]分析了132例肌层浸润性UTUCs,结果显示对于肌层浸润性UTUCLNDCSS\DFS的重要预后因素。Marco Roscigno12又分析1130UTUCs,Nx病例CSS\DFS预后比N0明显较差。在Shahrokh F.Shariat30的结果中NxN0病例CSS\OSS明显要差,支持LND的治疗价值。Giovanni Lughezzani[lxxi]分析了SEER数据库中的2824UTUCs,包括1835例(64.9%)淋巴结清扫pN0病例,242例(8.6%pN1-3病例以及747例未接受LNDNx病例。N+组有较高比例的高分期和高分级。N+组预后比N0NxCSS明显较差,但NxN0组之间CSS没有明显差异,因此作者认为LND不具有治疗价值。但本文的最大缺陷是包含了30.7%T1期肿瘤,而且选取的病例前后跨越16年,没有统一的LND标准,因此结果并不可信。Ross J.Mason[lxxii]报道了加拿大的1029UTUCs的经验,包含199N0病例,77N+病例,753Nx病例。得到了类似的结果,N+组高分期、高分级、LVI、切缘阳性的比例较高。N+组预后比N0NxCSS明显较差,但NxN0组之间CSS没有明显差异,因此结果不支持LND的治疗价值。但本文存在同样的缺陷,包含了45%T1期肿瘤,而且选取的病例前后跨越20年,也没有统一的LND标准,因此结果也不可信。Maximilian Burger[lxxiii]也得到了类似的结论,同样也存在类似的缺陷。Marco Roscigno34分析了1130UTUCs,包含412例(36.5%pN0病例,578例(51.1%Nx病例,140例(12.4%N+病例,LND清扫有较为统一的范围。N+组病理高分期、高分级、LVICIS、浸润性结构、肿瘤坏死和接受辅助化疗的比例明显较高。多因素分析显示为接受LND病例组(Nx组)DFS\CSS均比LND证实N0的病例差,而且在肌层浸润UTUC的多因素分析也得到相同的结论,充分支持了LND的治疗价值。Marco Roscigno[lxxiv]进一步对LND的意义进行了综述,认为对于特定的N+病例,扩大的淋巴结清扫有助于明确分期,且具有治疗价值。Tsunenori Kondo[lxxv],[lxxvi]提出了不同位置的UTUC淋巴结应清扫的范围,并对109cN0UTUC患者进行比较,76例接受完全淋巴结清扫(CompLND),33例接受不完全淋巴结清扫(IncompLND)。单因素分析显示淋巴结的清扫数目没有预后差异,但完全的模板化淋巴结清扫预后较好。

4新辅助化疗和辅助化疗95 37 73

膀胱移行细胞癌的治疗经验显示以顺铂为基础的化疗方案对移行细胞癌有较好的疗效。但对UTUCs的报道仍比较稀少。Nicholas J.Hellenthal35报道了UTUC协作组辅助化疗治疗高危UTUC的经验。在1390UTUCs中,542例(39%)是高危UTUC(即NOC-UTUCs),高危UTUCs121例(22%)接受辅助化疗(MVAC方案占59%)。结果显示不论是对所有高危UTUC病例,还是对于高危UTUCs的各个分期,是否接受辅助化疗对OSSCSS均没有影响。然而化疗方案、以及疗程差异极大,59%MVAC方案,20%GC方案,结果的可信度较低。Ramy F.Youssef[lxxvii]报道了对区域淋巴结转移的UTUCs进行新辅助化疗的经验。文章比价了3组病例预后差异,组1为术前活检证实区域LNM而接受新辅助化疗的18UTUCs,组2为术后证实N+120UTUCs,组3为术后病理证实为T2-3/N0175UTUCs。结果显示组1和组3有相似的复发和生存率。组2RFSCSS均最低。支持新辅助化疗在局部区域淋巴结转移病例的价值。但组1只有18例,结论的可信度较低。

另外,M.Zak Rajput[lxxviii]的报道支持新辅助化疗后进行经腹腹腔镜肾输尿管全长切除术并区域淋巴结清扫的可行性。

5延迟手术对预后影响63 64 65

近期有3篇文献关注于延迟手术对预后的影响。Matthias Waldert[lxxix]分析了187例,结果显示延迟手术(3个月)和高分级、高分期、肿瘤坏死、浸润性、LVI相关,但和CSS\RFS无关。但在MI-UTUC组病例中,和较差的CSSRFS生存率相关。但这些病例均为接受新辅助化疗,无法验证因接受新辅助化疗而延迟手术是否导致病理分期的上调。Debasish Sundi32分析了240例,结果显示延迟手术(3个月)对CSSOSS并无影响。而基于未接受新辅助化疗的病例的分析也不存在差异。Adam J.Gadzinski53进一步比较11例因先行内镜手术而延迟10个月接受RNU术的病例的长期随访结果,平均随访58个月。和62例即时手术组相比,围手术指标无明显差异,两组的OSS\MFS\CSS均无明显差异。

三病理因素对UTUC恶劣病理的预测及预后作用

1病理分期(pT)

多篇文献基本一致地认为病理分期(pT)是UTUC的最为重要的预后因素。Giovanni Lughezzani等[lxxx]Grégory Verhoest等[lxxxi]以及Thomas F.Chromecki等[lxxxii]最近发表的综述性文章,都认为病理分期(pT)是最重要的预后因素。Shahrokh F.Shariat[lxxxiii]提议将pT3分期进一步分为T3a期(肿瘤镜下浸润肾实质)和T3b期(肿瘤肉眼浸润肾实质或肾盂周围脂肪)更能反应疾病的预后。他们分析了266T3期病例中。T3b和高分级、淋巴结转移、肿瘤坏死相关。单因素分析中,T3bRFS\CSS明显较差,多因素分析中RFSCSS的独立的不良预后因素包括T3b和淋巴结阳性。然而Marco Roscigno[lxxxiv]的验证结果不支持T3bT3a期预后上的差异。他们分析了284T3UTUCsT3b和高分级、浸润性结构相关,且在单因素分析中CSS\RFS较差,但在多因素分析中两组病例CSS\RFS\OSS均无差异。另外现在的影像学检查的临床cT分期准确度很差76,无法完全根据临床分期进行临床治疗。有报道腔内高频超声检查[lxxxv]有助于术前准确评估分期。

2病理分级(pG)56 57 58 100 4

组织学分级G同样是上尿路移行细胞癌的重要预后因素,而且是病理分期T的预测因素。Giovanni Lughezzani等80Grégory Verhoest等81以及Thomas F.Chromecki等82最近发表的综述性文章,都认为组织学分级(G)是重要的预后因素。若术前行输尿管镜活检能获得肿瘤的组织学分级,对临床治疗将具有重要的指导意义,但活检组织学分级的准确度较低。Armine K.Smith[lxxxvi]报道了5665次活检结果。共有24次(37%)分级存在变化,包括9次由低级别变化高级别。25次(38%)的分期出现变化。共有24例患者(43%)由低分级、NMID变为高分级、MID分期。Jeffrey K.Wang[lxxxvii]报道了184例输尿管镜活检结果,认为术后病理分级和活检分级相比有较高比例的上调。184例接受活检,只有136例(74%)得到分级结果。24例活检G1级病例,术后16例(67%)为G2级,7例(29%)为G3级。57例活检G2级病例,术后23例(40%)为G3级。Thomas Clements[lxxxviii]分析了238例活检结构。多因素分析中,镜检分级是术后分级和肌层浸润分期的独立预测因素。但是镜检分级较术后病理有较大比例(22%)的分级低估,镜检分期不是术后分期的独立预测因素。镜检140例(59%LG98(41%)HG,术后分级88例(37%LG150例(63%HG。另外A.Skolarikos[lxxxix]分析了51例活检病例,也得到类似结论。活检分级G是病理分级G和病理分期的极相关因素,活检分期和病理分期不相关。活检分级G3的预测准确度为12/13(92%)1例为G232例活检G2级病例,9例病理调整为G3级,其中的8例尿脱落细胞学阳性。认为尿细胞学检查有助于活检G2级分级的判定。Ricardo L.Favaretto[xc]以及James C.Brien42的结果均认为输尿管镜检高分级是MID-UTUCNOC-UTUC的独立预测因素。

3伴随原位癌(cis)78 76 70 53 51 36 35 97 91

近期的较多认为UTUCs伴随原位癌(cis)和不良预后相关,且是恶劣病例结局的相关因素。Wolfgang Otto[xci]分析了772UTUCs88例(11%)伴随cis。伴随cis和高分期、高分级、白种人、LVI相关。多因素分析显示cisCSS\RFS的不良预后因素。在Maximilian Burger73785UTUCs中,12%伴随原位癌,且cisCSS\RFS的独立不良预后因素。Eugene K.Cha[xcii]分析了2244UTUCs21.6%伴随cis,且伴随cisRFS的独立不良预后因素。在单因素分析中,cisCSS不良预后相关,但在多因素分析中cis不是CSS的独立预后因素。Marco Roscigno70分析了132MID-UTUC34.1%伴随cis,伴随cisDFS\CSS的独立不良预后因素。Faysal A.Yafi[xciii]分析了637例,11%伴随cis,伴随cisDFS\CSS的独立不良预后因素。Shahrokh F.Shariat23分析了785例,12.6%伴随cis,伴随cisDFS\CSS的独立不良预后因素。

Marco Roscigno12分析了1130例,31.1%伴随cis,伴随cisCSS的独立不良预后因素,基于MID-UTUC的分析也得到相同的结果。Vitaly Margulis[xciv]分析了1363例,28.7%伴随cis,但在多因素分析中伴随cis不是DFS\CSS的独立预后因素。Ramy F.Youssef[xcv]分析了1316例,27.5%伴随cis7%既往有膀胱cis病史,膀胱cis病史是DFS\CSS的独立不良预后因素。

4淋巴血管侵犯(LVI104 105 70 12

最近的多篇文献基本一致认为淋巴血管侵犯是UTUC的独立不良预后因素。Eiji Kikuchi[xcvi]分析了1453UTUCs349例(24%)伴随LVI,LVI和高分期、高分级、淋巴结转移、浸润性结构、肿瘤坏死、CISLVIRFS\CSS的独立不良预后因素,基于Nx\N0病例的分析,也显示LVIRFS\CSS的独立不良预后因素。Giacomo Novara[xcvii]分析了762例,148(19.4%).伴随LVILVI和高分期、高分级、淋巴结转移相关。LVIRFS\CSS的独立不良预后因素,基于Nx\N0病例的分析,也显示LVIRFS\CSS的独立不良预后因素。Eugene K.Cha92分析了2244UTUCs462例(20.6%)伴随LVILVIRFS\CSS的独立不良预后因素。Shiu-Dong Chung[xcviii]分析了76例肾盂移行细胞癌,平均随访48个月,LVICSS的唯一的独立不良预后因素。

5生长结构1 3 23

数篇文献基本一致的认为浸润性结构(sessile architecture)本身是恶劣病理特征,与高分期、高分级及不良预后相关。Mesut Remzi[xcix]分析了多中心1363UTUCs380(27.8%)为浸润性生长结构。浸润性结构和高分期T、高分级G、淋巴结转移(N+)、LVI、高龄、伴随原位癌(cis)相关,而且是RFS\CSS的独立不良预后因素。Hans-Martin Fritsche[c]分析了多中心754例,平均随访34个月。150例(19.9%)为浸润性生长结构。浸润性结构和高分期T、高分级G、淋巴结转移(N+)相关,而且是RFS\CSS的独立不良预后因素。Vitaly Margulis[ci]分析659UTUCs,平均随访55.3个月。165(25.0%)为浸润性结构,浸润性结构式NOC-UTUC的独立预测因素,而且是RFS\CSS的独立不良预后因素。Eugene K.Cha92分析了2244UTUCs502(22.4%)为浸润性结构。浸润性结构是RFS\CSS的独立不良预后因素。Shahrokh F.Shariat23分析了785UTUCs,146(19.4%)为浸润性结构,浸润性结构是RFS\CSS的独立不良预后因素。

6肿瘤多发性

Thomas F.Chromecki[cii]分析了多中心2492UTUCs590例(23.7%)肿瘤多发(一般定义为多个肿瘤病灶)。肿瘤多发与肿瘤多发性与既往膀胱癌病史、淋巴结转移、输尿管肿瘤、高分期、LVI、高分级、浸润性结构、术后接受辅助化疗相关。在单因素分析中,多发性与RFSCSS不良预后相关,但在多因素分析中无差异。但在1529例的器官局限肿瘤中(T≤1),多发性是RFSCSS的独立不良预后因素。Adil Ouzzane[ciii]分析了法国的609UTUCs,平均随访39.4个月,共有107例(18%)多发(同时累及肾盂和输尿管)。肿瘤多发与高分期、高分级相关。肿瘤位置是CSS\OSS\RFS\MFS的独立预后因素,且预后上肿瘤多发比输尿管肿瘤差,输尿管肿瘤比肾盂肿瘤差。Faysal A.Yafi[civ]分析了多中心637例,46例(7%)多发(同时累及肾盂和输尿管),平均随访42个月。肿瘤多发与高分期相关,且是CSS\RFS的独立不良预后因素,肿瘤多发比输尿管肿瘤差,输尿管肿瘤比肾盂肿瘤差。Morgan Rouprêt63的分析也得到相似的结论。Giuseppe Simone[cv]分析了162例意大利的UTUCs42例(25.9%)肿瘤多发,但多发性不是MFS\DFS的独立预后因素。Ricardo L.Favaretto[cvi]报导了纪念斯隆-凯特琳癌症中心(Memorial Sloan-Kettering cancer center)的253UTUCs64例(25%)多发。多发性不是RFS\CSS的预后因素。

台湾的Wen-Wei Huang24报道了385UTUC术后膀胱癌复发的危险因素,58例(15.1%)肿瘤多发,肿瘤多发与术后膀胱复发无相关性。Kenji Kuroda[cvii]分析了日本121UTUCs9例(7.4%)肿瘤多发,且多发性与CSS\RFS\LVI无相关性。Mototsugu Muramaki等分析了日本的59UTUCs19例(32.2%)多发,多发与膀胱复发相关,但不是膀胱外复发的相关因素。Osamu Kamihira28分析了1003UTUCs105例(11.9%)多发,但多发性不是RFS的预后因素。Chia-Yen Chen45报道的110UTUCs21例(19.1%)肿瘤多发。虞巍等49报道了国内的161,40例(24.8%)多发,但多发性和术后膀胱复发没有相关性。

7位置102 10 96 93 51 45 32

2004年韩国的Sungchan Park[cviii]分析了86UTUCs,平均随访44个月。41例输尿管肿瘤高分期、高分级、N+比例较高。单因素分析显示TG、位置和RFSCSS相关。但在多因素分析中位置是DFS的唯一预后因素,N、位置是RFS的独立预后因素,输尿管肿瘤预后较肾盂明显较差。因此作者提出肾盂和输尿管UTUCs可能是两类不同预后有明显差异的疾病。但该文86例病理中,只有5例女性,而且输尿管肿瘤高分期、高分级、N+比例较高,与大多数文献的报道相反,提示所选取的病例代表性极差,而且病例数较小。后续的文献报道基本否定了这种看法,仍充分肯定分期T和分级G的重要的预后作用,而且有文献认为肾盂TTCs较输尿管TTC分期更晚。但肿瘤位置是否有预后的差异仍没有定论。Hendrik Isbarn[cix]分析了2824例,平均随访60月。肾盂肿瘤高分级(T3\4)N+的比例明显较高,年龄较低、女性比例更高。单因素分析肾盂CSS比输尿挂更差(p=0.007)。但在多因素分析中,肿瘤位置不是CSS的预后因素。Ricardo L.Favaretto106报导了纪念斯隆-凯特琳癌症中心的单中心经验。分析了253例,平均随访48个月。肾盂TCC术前影像学肾实质或周围脂肪的侵犯的比例、伴随CIS、多发性比例、高分期的比例均较高,血尿较常见、肾积水比例较低。肿瘤位置不是RFSCSS的相关因素。Faysal A.Yafi104报道的多中心637例的结果和Adil Ouzzane103报道的法国的609UTUCs的结果,均认为肿瘤位置是CSS\RFS的独立不良预后因素,同时累积肾盂和输尿管的病例预后比输尿管肿瘤差,输尿管肿瘤比肾盂肿瘤差。Jay D.Raman[cx]分析了多中心1249UTUCs,426(34.1%)为输尿管TCC。肾盂肿瘤有较高比例的NOC-UTUC。位置不是RFS\CSS的独立相关因素。局限器官局限性UTUC的分析也表明位置不是RFS\CSS的独立相关因素。Giovanni Lughezzani[cxi]分析了多中心的2299UTUCs875例(38.1%)位于输尿管。肾盂肿瘤高分期、淋巴转移的比例较高,女性患者较多,发病年龄较低,且单因素分析显示肾盂肿瘤CSS预后较差。但多因素分析中肿瘤位置不是CSS的独立预后因素。Vitaly Margulis101分析了659例,225(34.1%)位于输尿管,位于肾盂是NOC-UTUC的独立预测因素,但位置不是RFS\CSS的预后因素。Michael Rink[cxii]分析了2495UTUCs877例(35.2%)位于输尿管,同样的肾盂肿瘤高分期、伴随cis和女性患者的比例较高。但对于UTUCs,肿瘤位置不是RFS\CSS的预后因素。Osamu Kamihira28的结果认为中下段输尿管TCCRFS生存率较肾盂和上段输尿管TCC的预后要差。Morgan Rouprêt63的分析结果亦认为位置是独立的预后因素,同时累及肾盂和输尿管的肿瘤比输尿管肿瘤差,而输尿管肿瘤比肾盂预后差。台湾的Lia-Beng Tan[cxiii]分析了141UTUCs,输尿管肿瘤女性更多、低分期的比例更高,但不同位置的CSS没有明显差异。女性患者输尿管肿瘤的比例较多与国外报道相反。

8肿瘤坏死86

肿瘤坏死的定义为纤维镜下>10%的肿瘤面积存在坏死。Christian Seitz[cxiv]报道了肿瘤坏死和临床病理特征及预后的相关性。存在肿瘤坏死定义为在显微镜下10%以上的肿瘤区域存在坏死。该文分析了754UTUCs,平均随访40个月。肿瘤坏死和高分级、高分期、N+LVI相关。但肿瘤坏死不是RFS\CSS的独立不良预后因素。Giuseppe Simone105分析了162UTUCs,结果认为肿瘤坏死是RFS\CSS的独立不良预后因素。Richard Zigeuner[cxv]分析了1425UTUCs,肿瘤坏死和高分期、高分级、伴随cisLVI、浸润性结构明显相关,而且肿瘤坏死是RFS\CSS的独立不良预后因素。

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[xxxix](82)Teruo Inamoto,Kazumasa Komura,Toshikazu Watsuji,Haruhito Azuma.Specific body mass index cut-off value in relation to survival of patients with upper urinary tract urothelial carcinomas.Int J Clin Oncol,2011,in press.http://doi:10.1007/s10147-011-0284-5.

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[xlviii](11)Wei-Ming Li,Ching-Chia Li,Hung-Lung Ke,Wen-Jeng Wu,Chun-Nung Huang,Chun-Hsiung Huang.The Prognostic Predictors of Primary Ureteral Transitional Cell Carcinoma After Radical Nephroureterectomy.J Urol,2009,182:451-458,

[xlix](22)Yu Wei,Abudureheman,He Qun,Song Yi,Jin Jie.Chronic kidney disease as arisk factor for synchronous bladder cancer in patients with upper urinary tract urothelial carcinoma.Chin J Urol,2010,31(10):703-706.

[l](101)Morgan Rouprêt,Vincent Hupertan,Olivier Traxer,Guillaume Loison,Emmanuel Chartier-Kastler,Pierre Conort,Marc-Olivier Bitker,Bernard Gattegno,Francois Richard,Olivier Cussenot.Comparison of open nephroureterectomy and ureteroscopic and percutaneous management of upper urinary tract transitional cell carcinoma.UROLOGY,2006,67:1181–1187.

[li](79)Cenk Gurbuz,Ramy F.Youssef,Shahrokh F.Shariat,Yair Lotan,Christopher G.Wood,Arthur I.Sagalowsky,Richard Zigeuner,Eiji Kikuchi,Alon Weizer,Jay D.Raman,Mesut Remzi,Marco Roscigno,Francesco Montorsi,Christian Bolenz,Wassim Kassouf,Vitaly Margulis.The Impact of Previous Ureteroscopic Tumor Ablation on Oncologic Outcomes After Radical Nephrouretectomy for Upper Urinary Tract Urothelial Carcinoma.J Endourol,2011,25.in press.http://doi:10.1089=end.2010.0396.

[lii](60)Adam J.Gadzinski,William W.Roberts,Gary J.Faerber,J.Stuart Wolf Jr.Long-Term Outcomes of Nephroureterectomy Versus Endoscopic Management for Upper Tract Urothelial Carcinoma.J Urol,2010,183:2148-2153.

[liii](65)Adam J.Gadzinski,William W.Roberts,Gary J.Faerber,J.Stuart Wolf.Long-term Outcomes of Immediate Versus Delayed Nephroureterectomy for Upper Tract Urothelial Carcinoma.J Endourol,2011,25.in press.http://doi:10.1089/end.2011.0220.

[liv](61)Jean-Nicolas Cornu,Morgan Rouprêt,Xavier Carpentier,Bogdan Geavlete,Sixtina Gil Diez de Medina,Olivier Cussenot,Olivier Traxer.Oncologic control obtained after exclusive flexible ureteroscopic management of upper urinary tract urothelial cell carcinoma.World J Urol,2010,28:151–156.

[lv](62)Pierre Colin,Adil Ouzzane,Géraldine Pignot,Emmanuel Ravier,Sébastien Crouzet,Mehdi M.Ariane,Marie Audouin,Yann Neuzillet,Baptiste Albouy,Sophie Hurel,Fabien Saint,Julien Guillotreau,Laurent Guy,Pierre Bigot,Alexandre De La Taille,Frédéric Arroua,Charles Marchand,Alexandre Matte,Pierre O.Fais and Morgan Rouprêt,for the French Collaborative National Database on UUT-UC.Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract:results from a large French multicentre study.BJU Int,2012.in press.

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[lvi]Jonathan L.Silberstein,Nicholas E.Power,Caroline Savage,Tatum V.Tarin,Ricardo L.Favaretto,Daniel Su,Matthew G.Kaag,Harry W.Herr,Guido Dalbagni.Renal Function and Oncologic Outcomes of Parenchymal Sparing Ureteral Resection Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.J Urol,2012,187:429-434.

[lvii]Masao Tsujihata,Norio Nonomura,Akira Tsujimura,Kazuhiro Yoshimura,Yasushi Miyagawa,Akihiko Okuyama.Laparoscopic Nephroureterectomy for Upper Tract Transitional Cell Carcinoma:Comparison of Laparoscopic and Open Surgery.Eur Urol,2006,49:332–336.

[lviii]Ryohei Hattori,Yasushi Yoshino,Momokazu Gotoh,Masahi Katoh,Osama Kamihira,Yoshinari Ono.Laparoscopic Nephroureterectomy for Transitional Cell Carcinoma of Rena Pelvis and Ureter:Nagoya Experience.UROLOGY,2006,67:701–705.

[lix]Michael Muntener,Matthew E.Nielsen,Frederico R.Romero,Edward M.Schaeffer,Mohamad E.Allaf,Fabio Augusto R.Brito,Christian P.Pavlovich,Louis R.Kavoussi,Thomas W.Jarrett.Long-Term Oncologic Outcome after Laparoscopic Radical Nephroureterectomy for Upper Tract Transitional Cell Carcinoma.Eur Urol,2007,51:1639–1644.

[lx]Morgan Rouprêt,Vincent Hupertan,Kristin M.Sanderson,Justin D.Harmon,Xavier Cathelineau,Eric Barret,Guy Vallancien,François Rozet.Oncologic Control After Open or

Laparoscopic Nephroureterectomy for Upper Urinary Tract Transitional Cell Carcinoma:A Single Center Experience.UROLOGY,2007,69:656–661.

[lxi]Andre Berger,Georges-Pascal Haber,Kazumi Kamoi,Monish Aron,Mihir M.Desai,

Jihad H.Kaouk,Inderbir S.Gill.Laparoscopic Radical Nephroureterectomy for Upper Tract Transitional Cell Carcinoma:Oncological Outcomes at 7 Years.J Urol,2008,180:849-854.

[lxii]Matthias Waldert,Mesut Remzi,Hans Christoph Klingler,Lukas Mueller,Michael Marberger.The oncological results of laparoscopic nephroureterectomy for upper urinary tract transitional cell cancer are equal to those of open nephroureterectomy.BJU Int,2008,103:66-70.

[lxiii]Mehdi Mokhtar Ariane,Pierre Colin,Adil Ouzzane,Geraldine Pignot,Marie Audouin,Jean-Nicolas Cornu,Baptiste Albouy,Julien Guillotreau,Yann Neuzillet,Sébastien Crouzet,Sophie Hurel,Frederic Arroua,Pierre Bigot,Charles Marchand,Pierre Olivier Fais,Alexandre de la Taille,Fabien Saint,Emmanuel Ravier,Alexandre Matte,Laurent Guy,Franck Bruye`re,Morgan Rouprêt.Assessment of Oncologic Control Obtained After Open Versus Laparoscopic Nephroureterectomy for Upper Urinary Tract Urothelial Carcinomas(UUT-UCs):Results from a Large French Multicenter Collaborative Study.Ann Surg Oncol,2012,19:301-308.

[lxiv]Francesco Greco,Sigrid Wagner,Rashid M.Hoda,Amir Hamza,Paolo Fornara.Laparoscopic vs open radical nephroureterectomy for upper urinary tract urothelial cancer:oncological outcomes and 5-year follow-up.BJU Int,2009,104,1274-1278.

[lxv]Thomas J.Walton,Giacomo Novara,Kazumasa Matsumoto,Wassim Kassouf,Hans-Martin Fritsche,Walter Artibani,Patrick J.Bastian,Juan I.Martínez-Salamanca,Christian Seitz,Stephen A.Thomas,Vincenzo Ficarra,Maximilian Burger,Stefan Tritschler,Pierre I.KarakiewiczShahrokh F.Shariat.Oncological outcomes after laparoscopic and open radical nephroureterectomy:results from an international cohort.BJU Int,2010,http://doi:10.1111/j.1464-410X.2010.09826.x.

[lxvi]Grant D.Stewart,Katie J.Humphries,Mark L.Cutress,Antony C.P.Riddick,S.Alan McNeill,David A.Tolley.Long-Term Comparative Outcomes of Open Versus Laparoscopic Nephroureterectomy for Upper Urinary Tract Urothelial-Cell Carcinoma After a Median Follow-Up of 13 Years.J Endourol,2011,25,1329-1335.

[lxvii]Giuseppe Simone,Rocco Papalia,Salvatore Guaglianone,Mariaconsiglia Ferriero,Costantino Leonardo,Ester Forastiere,Michele Gallucci.Laparoscopic versus Open Nephroureterectomy:Perioperative and Oncologic Outcomes from a Randomised Prospective Study.Eur Urol,2009,

56:520-526.

[lxviii]Chen Ming,Xu Danfeng,Cui Xingang,Gao Yi,Ren Jizhong.Multivariate analysis of prognosis of patients with upper urinary tract transitional cell carcinoma.Academic Journal of Second Military Medical University,2008,29(10):1217-1220.

[lxix](52)Maurizio A.Brausi,Mirko Gavioli,Giuseppe De Luca,Giorgio Verrini,GianCarlo Peracchia,GianLuca Simonini,Massimo Viola.Retroperitoneal Lymph Node Dissection(RPLD)in Conjunction with Nephroureterectomy in the Treatment of Infiltrative Transitional Cell Carcinoma(TCC)of the Upper Urinary Tract:Impact on Survival.Eur Urol,2007,52:1414–1420

[lxx](53)Marco Roscigno,Cesare Cozzarini,Roberto Bertini,Vincenzo Scattoni,Massimo Freschi,Luigi Filippo Da Pozzo,Alberto Briganti,Andrea Gallina,Umberto Capitanio,Renzo Colombo,Guazzoni Giorgio,Francesco Montorsi,Patrizio Rigatti.Prognostic Value of Lymph Node Dissection in Patients with Muscle-Invasive Transitional Cell Carcinoma of the Upper Urinary Tract.Eur Urol,2008,53:794–802.

[lxxi]Giovanni Lughezzani,Claudio Jeldres,Hendrik Isbarn,Shahrokh F.Shariat,Maxine Sun,Daniel Pharand,Hugues Widmer,Philippe Arjane,Markus Graefen,Francesco Montorsi,Paul Perrotte,and Pierre I.Karakiewicz.A Critical Appraisal of the Value of Lymph Node Dissection at Nephroureterectomy for Upper Tract Urothelial Carcinoma.UROLOGY,2010,75:118-125.

[lxxii]Ross J.Mason,Wassim Kassouf,David G.Bell,Louis Lacombe,Anil Kapoor,Niels Jacobsen,Adrian Fairey,Jonathan Izawa,Peter Black,Simon Tanguay,Joseph Chin,Alan So,Jean-Baptiste Lattouf,Fred Saad,Edward Matsumoto,Darrel Drachenberg,Ilias Cagiannos,Yves Fradet,and Ricardo A.Rendon.The Contemporary Role of Lymph Node Dissection During Nephroureterectomy in the Management of Upper Urinary Tract Urothelial Carcinoma:The Canadian Experience.UROLOGY,2012.in press.http://doi:10.1016/j.urology.2011.11.058.

[lxxiii](76)Maximilian Burger,Shahrokh F.Shariat,Hans-Martin Fritsche,Juan Ignacio Martinez-Salamanca,Kazumasa Matsumoto,Thomas F.Chromecki,Vincenzo Ficarra,Wassim Kassouf,Christian Seitz,Armin Pycha,Stefan Tritschler,Thomas J.Walton,Giacomo Novara.No overt inXuence of lymphadenectomy on cancer-specific survival in organ-confined versus locally advanced upper urinary tract urothelial carcinoma undergoing radical nephroureterectomy:a retrospective international,multi-institutional study.World J Urol,2011,29:465–472.

[lxxiv]Marco Roscigno,Maurizio Brausi,Axel Heidenreich,Yair Lotan,Vitaly Margulis,Shahrokh F.Shariat,Hendrik Van Poppel,Richard Zigeuner.Lymphadenectomy at the Time of Nephroureterectomy for Upper Tract Urothelial Cancer.Eur Urol,2011,60:776-783.

[lxxv]Tsunenori Kondo,Yasunobu Hashimoto,Hirohito Kobayashi,Junpei Iizuka,Hayakazu Nakazawa,Fumio ItoKazunari Tanabe.Template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract:Impact on patient survival.International Journal of Urology,2010,17:848–854.

[lxxvi]Tsunenori Kondo,Kazunari Tanabe.The role of lymph node dissection in the management of urothelial carcinoma of the upper urinary tract.Int J Clin Oncol,2011.in press.

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[lxxvii]Ramy F.Youssef,Shahrokh F.Shariat,Yair Lotan,Christopher G.Wood,Arthur I.Sagalowsky,Richard Zigeuner,Eiji Kikuchi,Alon Weizer,Jay D.Raman,Mesut Remzi,Wareef Kabbani,Cord Langner,Charles C.Guo,Marco Roscigno,Francesco Montorsi,Christian Bolenz,Wassim Kassouf,Vitaly Margulis.Upper urinary tract urothelial carcinoma with loco-regional nodal metastases:insights from the Upper Tract Urothelial Carcinoma Collaboration.BJU Int,2011.in press.http://doi:10.1111/j.1464-410X.2011.10075.x.

[lxxviii]M.Zak Rajput,Ashish M.Kamat,Jonathan Clavell-Hernandez,Arlene O.Siefker-Radtke,

H.Barton Grossman,Colin P.N.Dinney,and Surena F.Matin.Perioperative Outcomes of Laparoscopic Radical Nephroureterectomy and Regional Lymphadenectomy in Patients With Upper Urinary Tract Urothelial Carcinoma After Neoadjuvant Chemotherapy.UROLOGY,2011,78:61–67.

[lxxix](63)Matthias Waldert,Pierre I.Karakiewicz,Jay D.Raman,Mesut Remzi,Hendrik Isbarn,Yair Lotan,Umberto Capitanio,Karim Bensalah,Michael J.Marberger and Shahrokh F.Shariat.A delay in radical nephroureterectomy can lead to upstaging.BJU Int,2009,105:812–817.

[lxxx]Giovanni Lughezzani,Maximilian Burger,Vitaly Margulis,Surena F.Matin,Giacomo Novara,Morgan Roupret,Shahrokh F.Shariat,Christopher G.Wood,Richard Zigeuner.Prognostic Factors in Upper Urinary Tract Urothelial Carcinomas:A Comprehensive Review of the Current Literature.Eur Urol,2012.in press.http://doi:10.1016/j.eururo.2012.02.030.

[lxxxi]Grégory Verhoest,Shahrokh F.Shariat,Thomas F.Chromecki,Jay D.Raman,Vitaly Margulis,Giacomo Novara,Christian Seitz,Mesut Remzi,Morgan Rouprêt,Douglas S.Scherr,Karim Bensalah.Predictive factors of recurrence and survival of upper tract urothelial carcinomas(review).World J Urol,2011,29:495–501.

[lxxxii]Thomas F.Chromecki,Karim Bensalah,Mesut Remzi,Grégory Verhoest,Eugene K.Cha,Douglas S.Scherr,Giacomo Novara,Pierre I.Karakiewicz and Shahrokh F.Shariat.Prognostic factors for upper urinary tract urothelial carcinoma(review).Nat Rev Urol,2011,8:440–447.

[lxxxiii](67)Shahrokh F.Shariat,Richard Zigeuner,Michael Rink,Vitaly Margulis,Jens Hansen,Eiji Kikuchi,Wassim Kassouf,Jay D.Raman,Mesut Remzi,Theresa M.Koppie,Karim Bensalah,Charles C.Guo,Shuji Mikami,Kanishka Sircar,Casey K.Ng,Andrea Haitel,Wareef Kabbani,Felix K.Chun,Christopher G.Wood,Douglas S.Scherr,Pierre I.Karakiewicz,Cord Langner.Subclassification of pT3 Urothelial Carcinoma of the Renal Pelvicalyceal System is Associated With Recurrence-Free and Cancer-Specific Survival:Proposal for a Revision of the Current TNM Classification.Eur Urol,2012.in press.http://doi:10.1016/j.eururo.2012.01.019.

[lxxxiv](66)Marco Roscigno,Eugene K.Cha,Michael Rink,Christian Seitz,Giacomo Novara,Thomas F.Chromecki,Hans-Martin Fritsche,Kazumasa Matsumoto,Thomas J.Walton,Joaquin Carballido,Luigi Filippo Da Pozzo,Roberto Bertini,Vincenzo Ficarra,Wolfgang Otto,Pierre I.Karakiewicz,Armin Pycha,Harun Fajkovic,Richard Naspro,Douglas S.Scherr,Francesco Montorsi,Shahrokh F.Shariat.International validation of the prognostic value of subclassifi cation for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis.BJU Int,2012.in press.http://doi:10.1111/j.1464-410X.2012.10930.x.

[lxxxv](59)Surena F.Matin,Ashish M.Kamat,H.Barton Grossman.High-Frequency Endoluminal

Ultrasonography as an Aid to the Staging of Upper Tract Urothelial Carcinoma:Imaging Findings and Pathologic Correlation.J Ultrasound Med,2010,29:1277-1284.

[lxxxvi](56)Armine K.Smith,Andrew J.Stephenson,Brian R.Lane,Benjamin T.Larson,Anil A.Thomas,Michael C.Gong,J.Stephen Jones,Steven C.Campbell,Donna E.Hansel.Inadequacy of Biopsy for Diagnosis of Upper Tract Urothelial Carcinoma:Implications for Conservative Management.UROLOGY,2011,78:82–86.

[lxxxvii](57)Jeffrey K.Wang,Matthew K.Tollefson,Amy E.Krambeck,Landon W.Trost,R.Houston Thompson.High Rate of Pathologic Upgrading at Nephroureterectomy for Upper Tract Urothelial Carcinoma.UROLOGY,2012,79:615–619.

[lxxxviii](58)Thomas Clements,Jamie C.Messer,John D.Terrell,Michael P.Herman,Casey K.Ng,Douglas S.Scherr,Benjamin Scoll,Stephen A.Boorjian,Robert G.Uzzo,Mark Wille,Scott E.Eggener,Steven M.Lucas,Yair Lotan,Shahrokh F.Shariat,and Jay D.Raman.High-Grade Ureteroscopic Biopsy Is Associated with Advanced Pathology of Upper-Tract Urothelial

Carcinoma Tumors at Definitive Surgical Resection.J Endourol,2012,26(4).In press.http://doi:10.1089/end.2011.0426.

[lxxxix](100)A.Skolarikos,T.R.L.Griffiths,P.H.Powell,D.J.Thomas,D.E.Neal,J.D.Kelly.

Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment.UROLOGY,2003,61:1146–1150.

[xc](4)Ricardo L.Favaretto,Shahrokh F.Shariat,Caroline Savage,Guilherme Godoy,Daher C.Chade,Matthew Kaag,Bernard H.Bochner,Jonathan Coleman,Guido Dalbagni.Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma.

BJU Int,2011.in press.http://doi:10.1111/j.1464-410x.2011.10288.x.

[xci](78)Wolfgang Otto,Shahrokh F.Shariat,Hans-Martin Fritsche,Amit Gupta,Kazumasa Matsumoto,Wassim Kassouf,Guido Martignoni,Thomas J.Walton,Stefan Tritschler,Shiro Baba,

Patrick J.Bastian,Juan I.Martínez-Salamanca,Christian Seitz,Armin Pycha,Maximilian Burger,Pierre I.Karakiewicz,Vincenzo Ficarra,Giacomo Novara.Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial

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[xcii](70)Eugene K.Cha,Shahrokh F.Shariat,Matthias Kormaksson,Giacomo Novara,Thomas F.Chromecki,Douglas S.Scherr,Yair Lotan,Jay D.Raman,Wassim Kassouf,Richard Zigeuner,Mesut Remzi,Karim Bensalah,Alon Weizer,Eiji Kikuchi,Christian Bolenz,Marco Roscigno,Theresa M.Koppie,Casey K.Ng,Hans-Martin Fritsche,Kazumasa Matsumoto,Thomas J.Walton,Behfar Ehdaie,Stefan Tritschler,Harun Fajkovic,Juan I.Martínez-Salamanca,Armin Pycha,Cord Langner,Vincenzo Ficarra,Jean-Jacques Patard,Francesco Montorsi,Christopher G.Wood,Pierre I.Karakiewicz,Vitaly Margulis.Predicting Clinical Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.Eur Urol,2012,61:818825.

[xciii]Faysal A.Yafi,Giacomo Novara,Shahrokh F.Shariat,Amit Gupta,Kazumasa Matsumoto,Thomas J.Walton,Hans-Martin Fritsche,Assaad El-Hakim,Stefan Trischler,Juan I.Martínez-Salamanca,Christian Seitz,Vincenzo Ficarra,Filiberto Zattoni,Pierre I.Karakiewicz,Wassim Kassouf.Impact of tumour location versus multifocality in patients with upper tract urothelial carcinoma treated with nephroureterectomy and bladder cuff excision:a homogeneous

series without perioperative chemotherapy.BJU Int,2011.in press.http://doi:10.1111/j.1464-410X.2011.10792.x.

[xciv](97)Vitaly Margulis,Shahrokh F.Shariat,Surena F.Matin,Ashish M.Kamat,Richard Zigeuner,Eiji Kikuchi,Yair Lotan,Alon Weizer,Jay D.Raman,Christopher G.Wood,and the Upper Tract Urothelial Carcinoma Collaboration.Outcomes of Radical Nephroureterectomy:A Series From the Upper Tract Urothelial Carcinoma Collaboration.Cancer,2009,115:1224–1233.

[xcv](91)Ramy F.Youssef,Shahrokh F.Shariat,Yair Lotan,Christopher G.Wood,Arthur I.Sagalowsky,Richard Zigeuner,Cord Langner,Francesco Montorsi,Christian Bolenz,and Vitaly Margulis.Prognostic Effect of Urinary Bladder Carcinoma In Situ on Clinical Outcome of Subsequent Upper Tract Urothelial Carcinoma.UROLOGY,2011,77:861–866.

[xcvi]Eiji Kikuchi,Vitaly Margulis,Pierre I.Karakiewicz,Marco Roscigno,Shuji Mikami,Yair Lotan,Mesut Remzi,Christian Bolenz,Cord Langner,Alon Weizer,Francesco Montorsi,Karim Bensalah,Theresa M.Koppie,Mario I.Ferna′ndez,Jay D.Raman,Wassim Kassouf,Christopher G.Wood,Nazareno Suardi,Mototsugu Oya,and Shahrokh F.Shariat.Lymphovascular Invasion Predicts Clinical Outcomes in Patients With Node-Negative Upper Tract Urothelial Carcinoma.J Clin Oncol,2009,27:612-618.

[xcvii]Giacomo Novara,Kazumasa Matsumoto,Wassim Kassouf,Thomas J.Walton,Hans-Martin Fritsche,Patrick J.Bastian,Juan I.Martínez-Salamanca,Christian Seitz,R.John Lemberger,Maximilian Burger,Assaad El-Hakim,Shiro Baba,Guido Martignoni,Amit Gupta,Pierre I.Karakiewicz,Vincenzo Ficarra,Shahrokh F.Shariat.Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract:An International Validation Study.Eur Urol,2010,57:10641071.

[xcviii]Shiu-Dong Chung,Shuo-Meng Wang,Ming-Kuen Lai,Chao-Yuan Huang,Chun-Hou Liao,Kuo-How Huang,Yeong-Shiau Pu,Shih-Chieh Chueh,Hong-Jeng Yu.Lymphovascular invasion predicts poor outcome of urothelial carcinoma of renal pelvis after nephroureterectomy.BJU Int,2011,103,1047–1051.

[xcix](1)Mesut Remzi,Andrea Haitel,Vitaly Margulis,Pierre Karakiewizc,Francesco Montorsi,Eiji Kikuchi,Richard Zigeuner,Alon Weizer,Christian Bolenz,Karim Bensalah,Nazareno Suardi,Jay D.Raman,Yair Lotan,Matthias Waldert,Casey K.Ng,Mario Fernández,Theresa M.Koppie,Philipp Ströbel,Wareef Kabbani,Masaru Murai,Cord Langner,Marco Roscigno,Jeffrey Wheat,Charles C.Guo,Christopher G.Wood,Shahrokh F.Shariat.Tumour architecture is an independent predictor of outcomes after nephroureterectomy:a multi-institutional analysis of 1363 patients.BJU Int,2008,103,307–311.

[c](3)Hans-Martin Fritsche,Giacomo Novara,Maximilian Burger,Amit Gupta,Kazumasa Matsumoto,Wassim Kassouf,Kanishka Sircar,Filiberto Zattoni,Tom Walton,Stefan Tritschler,Shiro Baba,Patrick J.Bastian,Juan I.Martínez-Salamanca,Christian Seitz,Wolfgang Otto,Wolf Ferdinand Wieland,Pierre I.Karakiewicz,Vincenzo Ficarra,Arndt Hartmann,Shahrokh F.Shariat.Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma.Urol Oncol,2010.in press.http://doi:10.1016/j.urolonc.2010.07.010.

[ci]Vitaly Margulis,Ramy F.Youssef,Pierre I.Karakiewicz,Yair Lotan,Christopher G.Wood,Richard Zigeuner,Eiji Kikuchi,Alon Weizer,Jay D.Raman,Mesut Remzi,Marco Roscigno,Francesco Montorsi,Christian Bolenz,Wassim Kassouf,Shahrokh F.Shariat and the Upper Tract

Urothelial Carcinoma Collaborative Group.Preoperative Multivariable Prognostic Model for Prediction of Nonorgan Confined Urothelial Carcinoma of the Upper Urinary Tract.J Urol,2010,184:453-458.

[cii](34)Thomas F.Chromecki,Eugene K.Cha,Harun Fajkovic,Vitaly Margulis,Giacomo Novara,Douglas S.Scherr,Yair Lotan,Jay D.Raman,Wassim Kassouf,Karim Bensalah,Alon Weizer,Eiji Kikuchi,Marco Roscigno,Mesut Remzi,Kazumasa Matsumoto,Thomas J.Walton,Armin Pycha,Vincenzo Ficarra,Pierre I.Karakiewicz,Richard Zigeuner,Karl Pummer,Shahrokh F.Shariat.The Impact of Tumor Multifocality on Outcomes in Patients Treated With Radical Nephroureterectomy.Eur Urol,2011.in press.http://doi:10.1016/j.eururo.2011.09.017.

[ciii](45)Adil Ouzzane,Pierre Colin,Evanguelos Xylinas,Geraldine Pignot,Mehdi Mokhtar Ariane,Fabien Saint,Nicolas Hoarau,Emilie Adam,Marie Dominique Azemar,Henri Bensadoun,Luc Cormier,Olivier Cussenot,Alain Houlgatte,Gilles Karsenty,Franck Bruyère,Charlotte Maurin,Francois Xavier Nouhaud,Véronique Phe,Thomas Polguer,Mathieu Roumiguiés,Alain Ruffion t,Morgan Rouprêt for the French Collaborative National Database on UUT-UC.Ureteral and Multifocal Tumours Have Worse Prognosis than Renal Pelvic Tumours in Urothelial Carcinoma of the Upper Urinary Tract Treated by Nephroureterectomy.Eur Urol,2011,60:1258-1265.

[civ](51)Faysal A.Yafi,Giacomo Novara,Shahrokh F.Shariat,Amit Gupta,Kazumasa Matsumoto,Thomas J.Walton,Hans-Martin Fritsche,Assaad El-Hakim,Stefan Trischler,Juan I.Martínez-Salamanca,Christian Seitz,Vincenzo Ficarra,Filiberto Zattoni,Pierre I.Karakiewicz,Wassim Kassouf.Impact of tumour location versus multifocality in patients with upper tract urothelial carcinoma treated with nephroureterectomy and bladder cuff excision:a homogeneous

series without perioperative chemotherapy.BJU Int,2011.in press.http://doi:10.1111/j.1464-410X.2011.10792.x.

[cv]Giuseppe Simone,Rocco Papalia,Andrea Loreto,Costantino Leonardo,Steno Sentinelli,Michele Gallucci.Independent prognostic value of tumour diameter and tumour necrosis in upper urinary tract urothelial carcinoma.BJU Int,2008,103,1052–1057.

[cvi](93)Ricardo L.Favaretto,Shahrokh F.Shariat,Daher C.Chade,Guilherme Godoy,Ari Adamy,Matthew Kaag,Bernard H.Bochner,Jonathan Coleman,Guido Dalbagni.The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center.Eur Urol,2010,58:574-580.

[cvii](47)Kenji Kuroda,Junichi Asakuma,Akio Horiguchi,Shinsuke Tasaki,Hidehiko Yoshii,Akinori Sato,Keiichi Ito,Kenji Seguchi,Makoto Sumitomo,Tomohiko Asano.Prognostic Factors for Upper Urinary Tract Urothelial Carcinoma after Nephroureterectomy.Urol Int,2012.in press.

http://doi:10.1159/000335274.

[cviii](102)Sungchan Park,Bumsik Hong,Choung-Soo Kim,Hanjong Ahn.The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary tract.J Urol,2004,171:621-625.

[cix](96)Hendrik Isbarn,Claudio Jeldres,Shahrokh F.Shariat,Daniel Liberman,Maxine Sun,Giovanni Lughezzani,Hugues Widmer,Philippe Arjane,Daniel Pharand,Margit Fisch,Markus Graefen,Francesco Montorsi,Paul Perrotte,Pierre I.Karakiewicz.Location of the Primary Tumor is Not an Independent Predictor of Cancer Specific Mortality in Patients With Upper Urinary Tract Urothelial Carcinoma.J Urol,2009,182:2177-2181.

[cx](32)Jay D.Raman,Casey K.Ng,Douglas S.Scherr,Vitaly Margulis,Yair Lotan,Karim Bensalah,Jean-Jacques Patard,Eiji Kikuchi,Francesco Montorsi,Richard Zigeuner,Alon Weizer,Christian Bolenz,Theresa M.Koppie,Hendrik Isbarn,Claudio Jeldres,Wareef Kabbani,Mesut Remzim,Mathias Waldert,Christopher G.Wood,Marco Roscigno,Mototsuga Oya,Cord Langner,J.Stuart Wolf,Philipp Ströbel,Mario Fernández,Pierre Karakiewcz,Shahrokh F.Shariat.Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy.Eur Urol,2010,5 7:1072-1079.

[cxi]Giovanni Lughezzani,Claudio Jeldres,Hendrik Isbarn,Maxine Sun,Shahrokh F.Shariat,Ahmed Alasker,Daniel Pharand,Hugues Widmer,Philippe Arjane,Markus Graefen,Francesco Montorsi,Paul Perrotte,Pierre I.Karakiewicz.Nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma:A population-based study of 2299 patients.Eur J Cancer,2009,45:3291-3297.

[cxii]Michael Rink,Behfar Ehdaie,Eugene K.Cha,David A.Green,Pierre I.Karakiewicz,Marko Babjuk,Vitaly Margulis,Jay D.Raman,Robert S.Svatek,Harun Fajkovic,Richard K.Lee,Giacomo Novara,Jens Hansen,Siamak Daneshmand,Yair Lotan,Wassim Kassouf,Hans-Martin Fritsche,Armin Pycha,Margit Fisch,Douglas S.Scherr,Shahrokh F.Shariat,for the Bladder Cancer Research Consortium(BCRC)and for the Upper Tract Urothelial Carcinoma Collaboration(UTUCC).Stage-Specific Impact of Tumor Location on Oncologic Outcomes in Patients With Upper and Lower Tract Urothelial Carcinoma Following Radical Surgery.Eur Urol,2012.in press.doi:10.1016/j.eururo.2012.02.018.

[cxiii]Lia-Beng Tan,Lin-Li Chang,Kuang-I.Cheng,Chun-Hsiung Huang,Aij-Lie Kwan.Transitional cell carcinomas of the renal pelvis and the ureter:comparative demographic characteristics,pathological grade and stage and 5-year survival in a Taiwanese population.BJU Int,2009,103(3):312-316.

[cxiv]Christian Seitz,Amit Gupta,Shahrokh F.Shariat,Kazumasa Matsumoto,Wassim Kassouf,Thomas J.Walton,Hans-Martin Fritsche,Wolfgang Otto,Stefan Tritschler,Patrick J.Bastian,Joaquin Carballido,Vincenzo Ficarra,Pierre I.Karakiewicz,Walter Artibani,Guido Mazzoleni,Giacomo Novara.Association of Tumor Necrosis With Pathological Features and Clinical Outcome in 754 Patients Undergoing Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma:An International Validation Study.

[cxv](109)Richard Zigeuner,Shahrokh F.Shariat,Vitaly Margulis,Pierre I.Karakiewicz,Marco Roscigno,Alon Weizer,Eiji Kikuchi,Mesut Remzi,Jay D.Raman,Christian Bolenz,Karim Bensalah,Umberto Capitanio,Theresa M.Koppie,Wassim Kassouf,Kanishka Sircar,Jean-Jacques Patard,Mario I.Fernández,Christopher G.Wood,Francesco Montorsi,Philipp Ströbel,Jeffery C.Wheat,Andrea Haitel,Mototsugu Oya,Charles C.Guo,Casey Ng,Daher C.Chade,Arthur Sagalowsky,Cord Langner.Tumour Necrosis Is an Indicator of Aggressive Biology in Patients with Urothelial Carcinoma of the Upper Urinary Tract.Eur Urol,2010,57:575-581.

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