DNA copy number aberrations associated with lymphovascular invasion in upper urinary tract urothelial carcinoma

Recent studies have reported that lymphovascular invasion (LVI) is a predictor of patient prognosis in upper urinary tract urothelial carcinoma (UUTUC). DNA copy number aberrations (DCNAs) identified by array-based comparative genomic hybridization (aCGH) had not previously been examined in UUTUC. We therefore examined DCNAs in UUTUC and compared them with DCNAs in LVI. We applied aCGH technology using DNA chips spotted with 4,030 BAC clones to 32 UUTUC patients. Frequent copy number gains were detected on chromosomal regions 8p23.1 and 20q13.12, whereas frequent copy number losses were detected on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2. DCNAs occurred more frequently in tumors with LVI than in those without it (P = 0.0002), and this parameter was more closely associated with LVI than with the tumor grade or pT stage. Disease-specific survival rate was higher in tumors without LVI than in those with it (P = 0.0120); however, tumor grade and stage were not significant prognostic factors of patient outcome. These data support our hypothesis that tumors with LVI have more genetic alterations in terms of total numbers of DCNAs than those without, and provide proof that aggressive adjuvant therapy should be considered for UUTUC patients with LVI.     

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

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The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.     

腔内激光手术治疗肾盂输尿管肿瘤

目的:通过对无法行根治性手术的上尿路上皮肿瘤患者进行腔内红激光治疗情况进行总结,评价该术式的有效性与安全性.方法:对于我院2013年1月到2016年6月期间收治的肾盂、输尿管肿瘤,其中13例行腔内激光手术治疗,分别就术中情况、术后并发症及疗效进行总结.结果:13例患者中,肾盂肿瘤行经皮肾镜激光手术9例,输尿管肿瘤行输尿管镜激光手术4例,平均手术时间分别为(47.22±6.25)min、(25.0±4.84)min;平均出血量分别约为(133.33±24.94)ml、(40.0±7.07)ml;血尿及肾积水情况得到控制,5/13例呈现局部进展,1/13例术后10个月死亡;未出现严重并发症.结论:对于特殊情况下的肾盂、输尿管肿瘤患者,腔内激光手术具有创伤小,止血效果好,可以姑息性切除肿瘤,降低肿瘤负荷,保护肾脏功能,也能减缓肿瘤进展,可以作为这一类患者的首选治疗方案.     

Highly predictive survival nomogram after upper urinary tract urothelial carcinoma

BACKGROUND:

Nephroureterectomy is the surgical standard of care for patients with upper urinary‐tract urothelial carcinoma. The objectives of the current study were to identify the most informative predictors of cancer‐specific mortality after nephroureterectomy, to devise an algorithm capable of predicting the individual probability of cancer‐specific mortality, and to compare its prognostic accuracy to that of the International Union Against Cancer (UICC) staging system.

METHODS:

Within the Surveillance, Epidemiology, and End Results database, the authors identified 5918 patients who had been treated with nephroureterectomy. Within the development cohort (n = 2959), multivariate Cox regression models predicting cancer‐specific mortality were fitted by using age, stage, nodal status, sex, grade, race, type of surgery (nephroureterectomy with or without bladder‐cuff removal), and tumor location (renal pelvis vs ureter). Backward variable elimination according to the Akaike information criterion identified the most accurate and parsimonious model. Model validation and calibration were performed within the external validation cohort (n = 2959). External validation was also applied to the UICC staging system.

RESULTS:

The 5‐year freedom from cancer‐specific mortality rates in both the development and external validation cohorts was 77.3%. The most informative and parsimonious nomogram for cancer‐specific‐mortality–free survival relied on age, pT and pN stages, and tumor grade. In external validation, nomogram prediction of 5‐year cancer‐specific‐mortality–free rate was 75.4% accurate and was significantly better (P < .001) than the UICC staging system (64.8%).

CONCLUSIONS:

The current nomogram is capable of predicting the prognosis in patients with upper urinary‐tract urothelial carcinoma treated by nephroureterectomy with better accuracy than the UICC staging system. The authors recommend the application of this nomogram to routine clinical practice when counseling or making clinical decisions. Cancer 2010. © 2010 American Cancer Society.     

Management of upper urinary tract urothelial carcinoma

Upper urinary tract urothelial carcinoma (UTUC) is relatively uncommon. In this article, we review prognostic factors, criteria and indications for treatment with the available modalities using contemporary data. A systematic search on PubMed was performed using the keywords ‘upper tract urothelial carcinoma’, ’upper tract transitional cell carcinoma’, ’nephroureterectomy’, ‘laparoscopic’, ‘endoscopic’ and ‘prognostic factor’. The literature on UTUC is scarce. No prognostic factors have been formally validated in either the diagnosis or treatment of UTUC. The gold-standard management for invasive UTUC is radical nephroureterectomy with a bladder-cuff excision. Laparoscopic and endoscopic approaches represent alternatives in properly selected individuals. Segmental ureterectomy may also be considered. The extent and role of lymph node dissection remains to be validated. Chemotherapy may also be considered in select patients. Additional multi-institutional studies are needed to identify and validate prognostic factors that can predict the outcomes of patients diagnosed with UTUC. Randomized controlled trials are needed to assess the efficacy of the treatment modalities.     

Postoperative recurrence detection using individualized circulating tumor DNA in upper tract urothelial carcinoma

Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0–202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence.     

上尿路尿路上皮癌淋巴结清扫的研究进展

上尿路尿路上皮癌(UTUC)指发生于肾盂及输尿管的尿路上皮恶性肿瘤,约占全部尿路上皮癌的 5%～10%。目前,UTUC淋巴引流的解剖范围暂不明确,一些研究表明淋巴结清扫范围对患者生存的影响可能大于清扫淋巴结数量的影响,但这一观点尚未得到证实。近年来,由于微创手术的快速发展,虽然在技术操作方面和标准化方面取得了重大进展,但对于淋巴结清扫的意义和范围仍缺乏共识。本文就UTUC淋巴结清扫的意义、范围、适应证、并发症及微创手术地位的研究进展作一综述。     

High visfatin expression predicts poor prognosis of upper tract urothelial carcinoma patients

Visfatin, a newly discovered adipocytokine, is a pro-inflammatory cytokine. This study aimed to evaluate the predictive value of visfatin on prognosis of patients with upper tract urothelial carcinoma. One-hundred and five patients (median age=64, range=24-84 years) were included in this study. Visfatin expression in upper tract urothelial carcinoma tissues was analyzed by immunohistochemistry. Visfatin expression was correlated with clinicopathologic variables using the χ² test. The prognostic value of visfatin for recurrence-free and cancer-specific survival was evaluated by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Cox regression model was also used to evaluate the hazard ratios of visfatin on survival. High visfatin expression in upper tract urothelial carcinoma tissues was significantly correlated with tumor stage (P=0.001), grade (P=0.007) and p53 expression (P=0.07). High visfatin expression was associated with poor recurrence-free and cancer-specific survival. Cox regression analysis also revealed that visfatin is an independent predictor of recurrence-free (HR=3.22, P=0.009) and cancer-specific survival (HR=5.74, P=0.023). Our findings indicated that higher visfatin expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of visfatin in the carcinogenesis of upper tract urothelial carcinoma.     

External validation of an online nomogram in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma

Background:

The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort.

Methods:

The study comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell''s concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan–Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis.

Results:

The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan–Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis.

Conclusion:

The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.     

Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract

To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma (UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-α (ERα), ERβ, glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired non-neoplastic urothelial tissues. AR/ERα/ERβ/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [57% (P < 0.001)/40% (P = 0.001)/85% (P = 0.001)/84% (P = 0.002)/13% (P = 0.489)]. There were no significant associations between each receptor expression pattern and histopathological characteristic of the tumors including tumor grade/stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor expression in these 99 patients. However, patients with UUTUC positive for either ERα or PR had a significantly higher risk of disease-specific mortality (P = 0.025), compared with those with UUTUC negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of disease-specific mortality (P = 0.040). Multivariate analysis further identified the expression of ERα and/or PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio, 2.434; P = 0.037). Thus, in accordance with previous observations in bladder specimens, significant decreases in the expression of AR/ERα/ERβ/GR in UUTUC, compared with that in non-neoplastic urothelium, were observed. Meanwhile, the negativity of both ERα and PR in UUTUC as well as the negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator.     

Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation

Background

Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients.

Methods

In a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3–144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence.

Results

Thirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2–139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.

Conclusions

Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.     

Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell‐free DNA in upper tract urothelial carcinoma

Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non‐invasive test for detecting UTUC, but its sensitivity is low. A novel non‐invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell‐free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger‐scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non‐invasive diagnostic marker and reliable factor for tumor staging.     

上尿路移行细胞癌术后预防性膀胱灌注的临床研究

目的:探讨上尿路移行细胞癌术后预防性膀胱灌注的有效性。方法:61例上尿路移行细胞癌患者行根治性切除术,其中34例患者术后预防性使用吡柔比星膀胱灌注,27例患者单纯随访,比较两组患者2年内膀胱肿瘤的发生率以及发生时间,并观察药物灌注毒副反应发生的情况。结果:吡柔比星灌注组膀胱癌发生率为14.7%,观察随访组膀胱癌的发生率为37.0%,差异有统计学意义(P<0.05),再发时间分别为20个月和14个月,二者比较差异有统计学意义(P<0.05)。患者灌注过程中均耐受,未出现中止灌注的情况。结论:本研究初步显示,吡柔比星预防性膀胱灌注可有效减少膀胱肿瘤的发生,毒副反应少,值得临床推广。     

Copy number gain of ACTN4 is associated with poor prognosis in patients with upper urinary tract urothelial carcinoma

α-Actinin4 (ACTN4), an isoform of non-muscular α-actinin, is involved in enhancing cell motility and promoting cancer infiltration and metastasis in various cancers. However, information remains limited regarding the pathological significance of ACTN4 expression in upper urinary tract urothelial carcinomas (UUTUCs). We obtained tumor samples from 168 consecutive patients with newly diagnosed UUTUCs (92 with renal pelvic cancers and 76 with ureteral cancers), who were treated with nephroureterectomy or partial ureterectomy, and analyzed the expression of the ACTN4 protein and the amplification of ACTN4 using immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. The median follow-up duration was 65 months. Among 168 cases, 49 (29%) showed ACTN4 protein overexpression and 25 (15%) showed copy number gain (≥4 copies per cell) of ACTN4. The copy number gain of ACTN4 detected using FISH significantly correlated with ACTN4 protein overexpression and several adverse clinicopathological factors, including higher pathological T stage, lymphovascular invasion, lymph node metastasis, positive surgical margin, concomitant subtype histology, and non-papillary gross finding. Cox univariate regression analyses revealed that both copy number gain of ACTN4 and ACTN4 protein overexpression were significant risk factors for extraurothelial recurrence and death (each p < 0.0001), but multivariate analysis revealed that only copy number gain of ACTN4 was an independent risk factor for extraurothelial recurrence and death (p = 0.038 and 0.027, hazard ratio = 2.16 and 2.17, respectively). This is the first study demonstrating the aberrant expression status of ACTN4 in UUTUC and indicating its putative usefulness as a prognostic indicator in patients with UUTUC.     

Anatomical templates of lymph node dissection for upper tract urothelial carcinoma: a systematic review of the literature

Introduction: Indications and techniques of lymph node dissection (LND) for upper tract urothelial carcinoma (UTUC) are still controversial.

Areas covered: In this study, a systematic review of the English-language literature was performed up to 1 July 2016 using the Medline, Scopus, Cochrane Library and Web of Sciences databases to provide a detailed overview of the most commonly dissected surgical templates of LND for UTUC according to laterality and location of the tumor. Overall, sixteen studies were analyzed. Based on the shared experiences in the scientific literature, the LND template typically included: for right-sided tumors of the renal pelvis, upper third and middle third of the ureter, the renal hilar, paracaval, precaval and retrocaval nodes, while for left-sided tumors the renal hilar, paraaortic and preaortic nodes. For tumors of the lower ureter, an extended pelvic LND was performed in most cases; however, the paracaval, paraaortic or presacral nodes were dissected in selected series.

Expert commentary: LND is not routinely performed at the time of surgery for UTUC and both indication and extent of LND vary among surgeons and institutions. Future high-quality studies are needed to define the most accurate LND templates and to assess their oncological efficacy and surgical morbidity.