Advertisement

Prognostic value of T1 substaging on oncological outcomes in patients with non-muscle-invasive bladder urothelial carcinoma: a systematic literature review and meta-analysis

  • Mehdi Kardoust Parizi
  • Dmitry Enikeev
  • Petr V. Glybochko
  • Veronika Seebacher
  • Florian Janisch
  • Harun Fajkovic
  • Piotr L. Chłosta
  • Shahrokh F. ShariatEmail author
Open Access
Original Article

Abstract

Purpose

To evaluate the prognostic value of substaging on oncological outcomes in patients with T (or pT1) urothelial carcinoma of the bladder.

Methods

A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted on March 2019 to identify relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. The pooled disease recurrence (DR) and disease progression (DP) rate in T1(or pT1) patients were calculated using a fixed or random effects model.

Results

Overall 36 studies published between 1994 and 2018 including a total of 6781 bladder cancer patients with T1(or pT1) stage were selected for the systematic review and meta-analysis. Twenty-nine studies reported significant association between tumor infiltration depth or muscularis mucosa (MM) invasion and oncological outcomes. Totally 12 studies were included in the meta-analysis. MM invasion (T1a/b/c [or pT1a/b/c] or T1a/b [or pT1a/b] substaging system) was associated with DR (pooled HR: 1.23, 95%CI: 1.01–1.49) and DP (pooled HR: 2.61, 95%CI: 1.61–4.23). Tumor infiltration depth (T1 m/e [or pT1 m/e] substaging system) was also associated with DR (pooled HR: 1.49, 95%CI: 1.11–2.00) and DP (pooled HR: 3.29, 95%CI: 2.39–4.51).

Conclusions

T1(or pT1) substaging in patients with bladder cancer is of prognostic value as it is associated with oncologic outcomes. Inclusion of this factors into the clinical decision-making process of this heterogeneous tumor may improve outcomes, while avoiding over- and under-treatment for T1(or pT1) bladder cancer.

Keywords

Staging Substage pT1 T1 Bladder cancer Progression Prognosis Urothelial carcinoma 

Introduction

T1 carcinoma of the urinary bladder is a heterogeneous disease with potentially aggressive behavior leading to lethality [1]. Indeed, despite sharing many of the genetic and epigenetic factors of muscle-invasive bladder cancer, it is classified as non-muscle invasive. Yet, patients with T1 bladder cancer have an overall mortality of 33% and a cancer-specific mortality of 14% at three years after diagnosis, suggesting that these patients have a high risk of disease progression and, accordingly, require meticulous surgery, endoscopic surveillance and informed clinical decision-making [2].

The variability in the outcomes of patients with T1 bladder cancer is a result of both tumor heterogeneity and pathological staging, as well as inconsistencies in risk stratification, endoscopic resection and schedules of delivery of BCG [3]. Owing to limitations in clinical staging, patients with T1 bladder cancer are at risk of both under-treatment with use of BCG despite recurrence, and overtreatment with early radical cystectomy. Understanding the pathologic features of T1 bladder cancers and how they impact prognosis and, therefore, could improve risk stratification to align therapy with biological risk and clinical behavior of the individual tumor [4, 5]. While novel prognostic features such as variant histology and lymphovascular invasion have been included in the clinical decision-making, more features are needed to improve our prognostic accuracy [5, 6, 7].

There is a growing evidence that tumor depth and extension could be such a feature for patients with T1(or pT1) bladder cancer [8, 9]. To test this hypothesis, we performed a systematic review and meta-analysis to evaluate the value of T1(or pT1) substaging for predicting oncological outcomes in patients with T1(or pT1) urothelial carcinoma of the bladder. T1 and pT1 were referred to disease stage in patients who underwent trans-urethral resection of bladder tumor (TURBT) and radical cystectomy, respectively.

Materials and methods

Search strategy

A full electronic literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted by two independent authors on March 2019 to find relevant studies for this systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [10]. The search terms used were (“T1” OR “T1a” OR “T1b” OR “T1 m” OR “T1e” OR “muscularis mucosa invasion” OR “subclassification” OR “substage” OR “substaging”) AND (“bladder cancer” OR “bladder carcinoma” OR “bladder neoplasm”). The protocol for this systematic review was registered in PROSPERO (Prospective Register of Systematic Reviews, CRD42019129661) and is available in full on the University of York website.

Inclusion criteria

The following criteria were considered to select eligible studies: prospective or retrospective studies including full text regarding T1(or pT1) substaging in patients with non-muscle-invasive bladder cancer (NMIBC) with oncological outcomes including disease recurrence (DR) and disease progression (DP). We excluded studies in other than English, meeting abstract, case reports, review articles, replies, expert opinions, and comment letters.

Data extraction

Data were extracted on first author, year of publication, patients, region of study, recruitment period, study design, total number of T1(or pT1) patients, number of substaged T1(or pT1) patients, substaging system, patients’ age, and follow-up duration. Oncological outcomes including DR and DP were the primary outcomes of interest. DR was defined as histological detection of bladder cancer and DP was defined as development of muscle-invasive disease or distant metastasis after primary treatment. Two independent reviewers assessed all full text studies and excluded inappropriate ones after screening based on the study title and abstract. The muscularis mucosa (MM) invasion substaging was defined as T1a/b (or pT1a/b) or T1a/b/c (or pT1a/b/c). According to the T1a/b (or pT1a/b) staging, T1a (or pT1a), where tumors cells invade the lamina propria but are still located above the level of the MM and T1b (or pT1b), where tumors cells are seen invading into or beyond the MM. In T1a/b/c (or pT1a/b/c) staging system, T1a (or pT1a) was defined as invasion into the stroma but not to MM, T1b (or pT1b); invasion into MM but not beyond MM, and pT1c (or pT1c); invasion beyond the MM but not to muscularis propria. Infiltration depth substaging system was defined as T1 m/e (or pT1 m/e). T1 m, or pT1 m (micro infiltration) was a single focus of lamina propria invasion with a maximum depth of 0.5 mm (within one high power field; objective × 40). T1e or pT1/e (extensive infiltration) was defined as a larger area with invasion or multiple micro-invasive areas.

Statistical analyses

We extracted reported HRs and 95%CIs to calculate cumulative effect size of studies which presented the association between T1(or pT1) substaging and DR and DP. Studies presented HR using multivariate Cox proportional hazard regression model were included in meta-analysis. STATA/MPTM, version 14.2 (Stata-Corp., College Station, TX, USA) was used to perform meta-analysis. Heterogeneity between the studies included in the meta-analysis was assessed by Cochrane Q test and I2 statistics. An I2 > 50% and p value < 0.05 in Cochrane Q test implied that the heterogeneity existed. With no heterogeneity among selected studies, we considered fixed effect models to calculate pooled HRs. In case of significant heterogeneity, we used random effect model. Visual inspection of funnel plot was carried out to identify publication bias in our meta-analysis.

Risk of bias (RoB) assessment

The RoB assessment of each study was done according to the Cochrane Handbook for Systematic Reviews of Interventions for including nonrandomized studies [11, 12]. The confounding factors including treatment modality, tumor grade, carcinoma in situ (CIS), multifocality, T1 (or pT1) substaging, and tumor size were identified as the most important prognostic factors. The presence of confounders was determined by consensus. The RoB assessment for each study was performed by two independent authors and the overall RoB level was presented as “low”, “intermediate”, or “high” risk.

Results

Literature search process

A total of 4999 studies were found after an initial search; 3036 records remained after exclusion of duplicates (Fig. 1). After exclusion of non-relevant studies, review articles, case reports, comments, replies, meeting abstracts, and studies in other than English, 57 studies remained. Finally, 36 and 12 studies were included for qualitative and quantitative evidence synthesis, respectively.
Fig. 1

PRISMA flow chart for article selection process to analyze the prognostic value of T1 substaging on oncological outcomes in patients with non-muscle-invasive bladder urothelial carcinoma

Characteristics of the included studies

Tables 1 and 2 summarize the studies’ characteristics and patients’ clinical data, respectively. Four studies were designed prospectively [13, 14, 15, 16] and 32 studies were retrospective in design [8, 9, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46]. All studies were published between 1994 and 2018. In total, 6781 patients were included in 36 studies with 5964 patients who underwent T1 (or pT1) substaging and outcomes analysis. Twenty-three studies came from Europe, five from North America, six from Asia, and two from Europe/Canada region.
Table 1

Study characteristics of 40 studies assessing the prognostic value of T1 substaging in patients with bladder urothelial carcinoma

Author

Year

Region

Recruitment period

Design

No.pT1 Pts

Substaged T1 Pts

Substaging system

Oncological end point

Hasui [23]

1994

Japan

1980–1991

Retrospective

88

88

MM invasion (T1a/T1b)

DR, DP

Holmäng [24]

1997

Sweden

1987–1988

Retrospective

121

113

MM invasion (T1a/T1b)

DP, CSS, OS

Smits [40]

1998

The Netherlands

1987–1990

Retrospective

133

124

MM invasion (T1a/T1b/T1c)

DR, DP

Cheng [22]

1999

USA

1987–1992

Retrospective

83

83

Depth of lamina propria invasion

DP

Kondylis [26]

2000

USA

1981–1997

Retrospective

55

49

MM invasion (T1a/T1b)

DR, DP

Shariat [39]

2000

USA

N/A

Retrospective

47

36

MM invasion (T1a/T1b)

DR, DP, OS

Bernardini [17]

2001

France

1973–1996

Retrospective

149

94

MM invasion (T1a/T1b)

PFS

Sozen [42]

2002

Turkey

1983–1997

Retrospective

90

50

MM invasion (T1a/T1b)

DR, DP

Orsola [32]

2005

Spain

1996–2001

Retrospective

97

85

MM invasion (T1a/T1b/T1c)

RFS, PFS

van der Aa [45]

2005

The Netherlands

N/A

Retrospective

63

53

Tumor infiltration depth (T1 m/T1e)

DP

Chaimuangraj [20]

2006

Thailand

1990–2004

Retrospective

192

192

Muscularis mucosa invasion

DR

Andius [13]

2007

Sweden

1987–1988

Prospective

121

121

MM invasion (T1a/T1b)

PFS, CSS

Mhawech-Fauceglia [29]

2007

Switzerland

N/A

Retrospective

45

45

MM invasion (T1a/T1b)

DR, DP

Queipo-Zaragoza [37]

2007

Spain

1986–2003

Retrospective

91

83

MM invasion (T1a/T1b)

DP

Soukup [16]

2008

Czech Republic

2001–2005

Prospective

105

99

MM invasion (T1a/T1b)

DR, DP (PFS)

Orsola [14]

2010

Spain

N/A

Prospective

159

138

MM invasion (T1a/T1b)

DR, DP

Bertz [18]

2011

Germany

1989–2006

Retrospective

309

309

MM invasion (T1a/T1b), Infiltration depth (≤ 1 HPF/> 1 HPF)

CSS, RFS, PFS

Palou [34]

2012

Spain/Belgium

1985–1996

Retrospective

146

93

MM invasion (T1a/T1b/T1c)

DR, DP, CSM

Lee [27]

2012

Korea

1999–2009

Retrospective

183

183

MM invasion (T1a/T1b/T1c)

DR, DP, CSM

Chang [21]

2012

Taiwan

1991–2005

Retrospective

509

509

Muscularis mucosa invasion, Infiltration depth (3 cut-off values to substage the T1 tumors: 0.5 mm, 1.0 mm, and 1.5 mm)

DR, DP, CSD, OM

van Rhijn [46]

2012

The Netherlands/Canada

1984–2006

Retrospective

129

129

MM invasion (T1a/T1b/T1c), tumor infiltration depth (T1 m/T1e)

DR, DP

Brimo [19]

2013

Canada

2004–2012

Retrospective

86

86

Muscularis mucosa invasion, Maximum tumor depth (mm)

DR,DP,WFS

Olsson [31]

2013

Sweden

1992–2001

Retrospective

285

211

MM invasion (T1a/T1b/T1c)

DR, DP

Nishiyama [30]

2013

Japan

1995–2010

Retrospective

79

79

Tumor infiltration depth (T1 m/T1e)

DR, DP

Rouprêt [38]

2013

France

1994–2010

Retrospective

612

587

MM invasion (T1a/T1b)

RFS, PFS, CSS

Soukup [41]

2014

Czech Republic

2002–2009

Retrospective

200

176

MM invasion (T1a/T1b)

RFS, PFS, CSS, OS

Hu [25]

2014

USA

1997–2005

Retrospective

39

23

Focality, Percentage of tumor invasion, and aggregate length of invasion

DR

D. E. Marco [44]

2014

Italy

2000–2006

Retrospective

40

40

MM invasion (T1a/T1b/T1c), tumor infiltration depth (T1 m/T1e)

CSS, DP

Lim [28]

2015

Korea

1998–2012

Retrospective

177

141

MM invasion (T1a/T1b/T1c)

RFS, PFS

Orsola [15]

2015

Spain

N/A

Prospective

200

200

MM invasion (T1a/T1b)

DR, DP

Patschan [36]

2015

Sweden

1997–2003

Retrospective

167

152

MM invasion (T1a/T1b/T1c)

PFS

Patriarca [35]

2016

Italy

2011–2007

Retrospective

450

314

MM invasion (T1a/T1b), tumor infiltration depth (T1 m/T1e), ROL substaging

DR, DP

Colombo [8]

2018

Italy

2007–2011

Retrospective

502

250

MM invasion (T1a/T1b/T1c), microinfiltration and extended infiltration of LP (T1 m/T1e), ROL substaging

DR, DP

Fransen van de Putte [9]

2018

Europe/Canada

1982–2010

Retrospective

601

601

MM invasion (T1a/T1b), microinfiltration and extended infiltration of LP (T1 m/T1e)

PFS, CSS

Otto [33]

2018

Germany/The Netherlands

1989–2012

Retrospective

322

322

Metric T1 substage (tumor infiltration depth)

PFS, CSS, OS

Turan [43]

2018

Turkey

2009–2014

Retrospective

106

106

MM invasion (T1a/T1b), tumor infiltration depth (T1 m/T1e)

DR, DP

N/A not available, LP lamina propria, MM muscularis mucosa, PFS progression-free survival, CSM cancer-specific mortality, CSS cancer-specific survival, OS overall survival, WFS worsening-free survival, DR disease recurrence, DP disease progression, RFS recurrence-free survival, OM overall mortality, HPF high power field

ROL substaging ROL1 < 1 power field (objective 20×, ocular 10×/field 22, diameter 1.1 mm) of invasion, approximately corresponding to invasion of the lamina propria 1 mm thick or less; ROL2: > 1 power field (objective 20×), approximately corresponding to invasion of the lamina propria more than 1 mm thick, or multifocal invasion with foci cumulatively amounting to invasion of the lamina propria more than 1 mm thick

Table 2

Patient characteristics in 40 studies assessing the prognostic role of T1 substaging in patients with bladder urothelial carcinoma

Author

Age, year (range)

Independent correlation with oncologic outcomes

Follow-up duration

Hasui [23]

Mean: 68 (37–95)

S

N/A

Holmäng [24]

Mean: 73.1 (48–97)

S (for DP and CSS)

≥ 5 years

Smits [40]

N/A

S (for PFS)

Minimal follow-up: 3 years

Cheng [22]

Mean: 71 (47–94)

S

Mean: 5.2 years (range, 1 day–10.4)

Kondylis [26]

N/A

NS

Median 71 months (range, 4–147)

Shariat [39]

Median: 67 (30–86)

NS

Median: 79 months

Bernardini [17]

Mean: 68.9 (42–90)

S

Mean: 64.9 months (range, 5–288)

Sozen [42]

Median: 62 (33–84)

S

Mean: 68 months (range, 24–120)

Orsola [32]

Mean: 66.4(30.3–86.8)

S (in T1b/c vs T1a substaging for RFS and PFS)

Mean: 53 months

van der Aa [45]

Mean: 68 (47–90)

S

Median: 55 months (range, 9–228)

Chaimuangraj [20]

Mean: 60 (43–83)

S

N/A

Andius [13]

Median: 74 (48–98)

NS

Median: 15 years for alive cases

Mhawech-Fauceglia [29]

Mean: 70

S (for DP)

Median: 12 months

Queipo-Zaragoza [37]

Mean: 68.1

S

Mean: 57.8 months (range, 13–24)

Soukup [16]

Mean: 68.43 (38–87)

S (for PFS)

Mean: 23.31 months

Orsola [14]

Mean: 69

S (for DP)

Median: 20.3 months

Bertz [18]

Median: 71.7 (38–87 years).

S (in Infiltration depth: ≤ 1 HPF vs > 1 HPF for RFS and PFS)

Mean: 49 months (range, 5–172)

Palou [34]

Mean: 64.9 (25–81)

NS

Median: 8.7 years

Lee [27]

Mean: 63.5 years (27–93)

S (for DP and CSM)

Mean: 43.5 months (range, 12–146)

Chang [21]

Mean: 71 (23–92)

S (MM invasion: S for DP, CSM, and OM) (depth of high-grade tumor: S for DR, DP, CSM, OM)

Mean: 88 months (range, 1–240) for patients who were alive

Mean: 39 months (range, 1–193) for patients who died

van Rhijn [46]

Mean: 68.8

S (in T1 m/T1e for DP)

Median: 6.5 years

Brimo [19]

Mean: 71

S

Mean: 29 months

Olsson [31]

Median: 74

S (in T1b/c vs T1a substaging for DP in patients older than 73 years)

Median: 60 months

Nishiyama [30]

Mean: 68.5

S (for DR)

Mean: 74.0 months

Rouprêt [38]

Median: 70

S

Mean: 44 months (range, 6–161)

Soukup [41]

Median: 68.83 (17.55–86.94)

S (for PFS, CSS, OS)

Median: 3.13 years (0.1–10.5)

Hu [25]

Mean: 70 years (56–94)

S (in aggregate length of invasion; > 0.5 cm)

N/A

D. E. Marco [44]

Mean: 69.9

NS

Median: 9.5 years

Lim [28]

Mean: 68.9 (20–93)

S (for PFS)

Mean: 73.3 months (range, 3.9–187.9)

Orsola [15]

Median: 71

S (for DP)

Median: 71 months (range: 5–107)

Patschan [36]

Median: 74

NS

(3 years follow-up in analysis)

Patriarca [35]

Mean: 71.3 (64–79)

S (in ROL1 VS ROL 2 substaging for DP)

Mean: 46 months

Colombo [8]

Mean: 70 (64–77)

S (for DP in ROL2 vs ROL1 substaging)

Median: of 60 months

Fransen van de Putte [9]

Median: 71

S (for PFS and CSS in T1e vs T1 m substaging)

Median: 5.9 years

Otto [33]

Median: 72

NS

Median: 42 months

Turan [43]

Mean: 67.9

S (in T1a/b substaging for DR)

Mean: 54 months

N/A not available, S significant, NS non-significant, MM muscularis mucosa PFS progression-free survival, CSM cancer-specific mortality, CSS cancer-specific survival, OS overall survival, OM overall mortality, DR disease recurrence, DP disease progression, RFS recurrence-free survival, HPF high power field

S statistical significance p value < 0.05

Nine studies included patients who had been substaged with both MM and tumor infiltration depth staging systems. Twenty-two studies included MM invasion substaging system only and five included patients substaged with tumor infiltration depth staging system only. TURBT with or without intravesical BCG or chemotherapy agents was reported as initial therapy in 6677 patients. Radical or partial cystectomy and/or radiation therapy were reported in 104 patients as initial therapeutic modality [13, 17, 24, 29, 35, 39, 45]. The prognostic value of T1(or pT1) substaging on at least one oncological outcome was established in 29 studies.

Meta-analysis

T1 (or pT1) MM invasion substaging and DP

The impact of MM invasion on DP was investigated in patients with T1(or pT1) bladder urothelial carcinoma. Overall seven studies with a total of 899 patients were identified and MM invasion was associated with a higher DP rate (pooled HR 2.61, 95%CI: 1.61–4.23) (Fig. 2A) [16, 19, 27, 28, 32, 41, 46]. A statistically significant heterogeneity was found among included studies using the Chi-square and I2 tests (I^2 = 54.1%, p = 0.042); the weights were from random effect model to analyze pooled HR. Funnel plots identified one study over the pseudo 95%CI (Fig. 2A).
Fig. 2

A Forest plots and funnel plot of studies investigating the association of T1a/b/c substaging system with disease progression (DP) and disease recurrence (DR) outcomes. B T1a/b/c substaging system RoB table, a Random sequence generation (selection bias). b Allocation concealment (selection bias). c Blinding of participants and personnel (Performance bias.). d Blinding of outcome assessment (detection bias). e Incomplete outcome data (attrition bias). f Selective reporting (reporting bias); and adjustment for the effects of the following confounders. g Treatment modality. h Tumor grade. i CIS. j Multifocality. k T1 m/e substaging. l Tumor size. Green circles: low risk of bias and confounding, red circles: high risk of bias and confounding, yellow circles: unclear risk of bias and confounding. CI confidence interval, HR hazard ratio

T1 (or pT1) MM invasion substaging and DR

Six studies in a total of 930 patients reported HR to present the prognostic value of MM invasion on DR in T1(or pT1) urothelial bladder carcinoma patients [16, 18, 19, 27, 40, 46]. The overall pooled HR was 1.23 (95%CI: 1.01–1.49) implying a significant association between MM invasion and DR (Fig. 2A). The Chi-square and I2 tests did not show any significant heterogeneity (I^2 = 41.4%, p = 0.129). Funnel plots revealed one study over the pseudo 95%CI (Fig. 2A). Figure 2B shows the RoB table of studies included in the T1(or pT1) MM invasion substaging meta-analysis.

Infiltration depth substaging and DP

Five studies with a total of 1171 patients with T1(or pT1) bladder urothelial carcinoma reported the association of tumor infiltration depth and DP [9, 18, 30, 45, 46]. Tumor infiltration depth was associated with DP (pooled HR: 3.29, 95%CI: 2.39–4.51) (Fig. 3A). There was no significant heterogeneity in the Cochrane Q or I2 tests (I^2 = 0.0%, p = 0.924). No study was detected over the pseudo 95%CI on Funnel plots (Fig. 3A).
Fig. 3

A Forest plots and funnel plot of studies investigating the association of T1 m/e substaging system with disease progression (DP) and disease recurrence (DR) outcomes. B T1 m/e substaging system RoB table, a Random sequence generation (selection bias). b Allocation concealment (selection bias). c Blinding of participants and personnel (Performance bias.). d Blinding of outcome assessment (detection bias). e Incomplete outcome data (attrition bias). f Selective reporting (reporting bias); and adjustment for the effects of the following confounders. g treatment modality. h tumor grade. i CIS. j Multifocality. k T1a/b/c substaging. l Tumor size. Green circles: low risk of bias and confounding, red circles: high risk of bias and confounding, yellow circles: unclear risk of bias and confounding. CI confidence interval, HR hazard ratio

Infiltration depth substaging and DR

The impact of infiltration depth on DR was investigated in three studies in a total of 517 patients with T1(or pT1) bladder urothelial carcinoma [18, 30, 46]. There was a significant association between infiltration depth and DR with pooled HR of 1.49 (95%CI: 1.11–2.00) (Fig. 3A). The Chi-square and I2 tests did not show any significant heterogeneity (I^2 = 56.4%, p = 0.101). Funnel plots identified no study over the pseudo 95%CI (Fig. 3A). Figure 3B shows the RoB table of studies included in T1(or pT1) Infiltration depth substaging meta-analysis.

Discussion

In this systematic review and meta-analysis, we assessed the prognostic value of T1(or pT1) substaging systems on oncological outcomes in patients with T1(or pT1) bladder urothelial carcinoma. Both MM invasion and tumor infiltration depth substaging systems were strongly associated with both DR and DP after adjusting for the effects of established confounding factors (e.g., tumor grade, CIS, and multifocality).

The most widely used prognostic tools, taking into account tumor grade and stage, prior recurrences, tumor size, multifocality, and the presence of CIS, are still suboptimal to predict DR and DP. Moreover, the lack of effective bladder cancer information among general public may be as an important factor affecting patients’ outcomes and online information and social media could be effective to improve quality of patient’s care and disease management in patients with bladder cancer [47].

We and others have shown that the current prognostic and risk stratification tools are too inaccurate to guide clinical decision making safely [1, 48, 49]. In this review and meta-analysis, we confirm that tumor invasion into MM and tumor infiltration depth of more than 0.5 mm are strong predictors of disease recurrence and progression and could be used to distinguish high risk patients for recurrence and progression who might benefit from standard adjuvant therapy (e.g., intravesical immunotherapy or chemotherapy). From these who are most likely to benefit from intensification of care such as early radical cystectomy.

In patients with NMIBC, the probability of disease progression can be as high as 45% at five years [50]. Although it has been suggested that MM substaging might be helpful to identify high risk patients who are likely to suffer from disease progression despite adequate intravesical therapy, available data quality has not been of high quality and prognostic tools have not included this valuable parameter [38, 51]. Martin-Doyle et al. evaluated the prognosticators to improve selection criteria for early cystectomy in patients with high-grade T1 bladder cancer in a meta-analysis. The authors reported T1a/b substaging system as a valuable prognosticator of oncological outcomes comparable with our study with pooled HR of 1.81 (95%CI: 0.88–3.73) for DR and pooled HR of 3.55 (95%CI: 1.92–6.56) for DP in 420 and 785 patients with high-grade T1 bladder cancer, respectively [51]. We confirmed that both MM invasion and tumor infiltration depth are strong predictors of disease progression after controlling for the effect of standard prognosticators. Indeed, patients harboring T1b/c or T1e in substaging system may benefit from early radical cystectomy as their tumor carries the biologic and clinical behavior of muscle-invasive bladder cancer [51]. In patients considered candidates for radical cystectomy, pretreatment imaging modalities including magnetic resonance imaging and positron emission topography/computed tomography (CT) provide higher sensitivity and similar specificity compared to CT for detection of positive lymph nodes that might have a significant impact on clinical decision-making process [52].

A consensus among pathologists is urgent to propose T1(or pT1) substaging systems as a prognosticator in TNM classification system and guidelines. MM is identified in 12–83% of bladder biopsy specimen [53, 54]. Therefore, some studies proposed identification of large vessels of the vascular plexus as an alternative tumor extension marker in specimens without obvious MM [43, 46]. Moreover, although a cut-off point of 5 mm has been proposed in several studies to define tumor infiltration depth, other studies have utilized other definitions [8, 35]. These discrepancies between definitions may lead to low reproducibility and questionable validity. Standardization and prospective assessment in controlled studies is necessary.

According to our study, although substaging of T1(or pT1) disease is somewhat controversial and difficult to implement in all cases; the main advantage of this scoring system is to identify the high risk T1 bladder cancer patients who might benefit from more rigorous follow-up and ideally from more aggressive treatments which are appropriate for invasive bladder carcinoma.

This study is not without limitations. The majority of included studies in this systemic review were retrospective in design precluding robust conclusions about the prognostic value of T1(or pT1) substaging systems. Moreover, the heterogeneity of substaging systems was found in MM invasion and tumor infiltration depth systems as well as the outcomes assessed in the studies makes clear conclusions difficult. Indeed, further studies are needed to assess the prognostic value of T1(or pT1) substaging systems in patient counselling and risk-based selection of the personalized therapeutic modality.

Conclusion

We found that T1(or pT1) substaging systems are strong predictors of oncological outcomes (DR, DR). Although T1(or pT1) substaging systems are promising and can be used as an aid in determining the most appropriate treatment modality and intensity of follow-up, optimal T1(or pT1) substaging system definition remains to be elucidated in future well-designed prospective studies.

Notes

Acknowledgements

Open access funding provided by Medical University of Vienna.

Author contribution

Protocol/project development: S.F Shariat, M Kardoust Parizi, H Fajkovic1. Data extraction or management: M Kardoust Parizi, V Seebacher, P.V Glybochko. Data analysis: M Kardoust Parizi, D Enikeev. Manuscript writing: M Kardoust Parizi, P.L Chłosta, F Janisch. Manuscript editing and supervision: S.F Shariat, M Kardoust Parizi.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies using human participants or animals.

Informed consent

This article does not contain any studies using human participants.

References

  1. 1.
    Soukup V, Capoun O, Cohen D, Hernandez V, Burger M, Comperat E, Gontero P, Lam T, Mostafid AH, Palou J, van Rhijn BWG, Roupret M, Shariat SF, Sylvester R, Yuan Y, Zigeuner R, Babjuk M (2018) Risk stratification tools and prognostic models in non-muscle-invasive bladder cancer: a critical assessment from the european association of urology non-muscle-invasive bladder cancer guidelines panel. Eur Urol Focus.  https://doi.org/10.1016/j.euf.2018.11.005 Google Scholar
  2. 2.
    Kluth LA, Xylinas E, Crivelli JJ, Passoni N, Comploj E, Pycha A, Chrystal J, Sun M, Karakiewicz PI, Gontero P, Lotan Y, Chun FK, Fisch M, Scherr DS, Shariat SF (2013) Obesity is associated with worse outcomes in patients with T1 high grade urothelial carcinoma of the bladder. J Urol 190(2):480–486.  https://doi.org/10.1016/j.juro.2013.01.089 Google Scholar
  3. 3.
    Fritsche HM, Burger M, Svatek RS, Jeldres C, Karakiewicz PI, Novara G, Skinner E, Denzinger S, Fradet Y, Isbarn H, Bastian PJ, Volkmer BG, Montorsi F, Kassouf W, Tilki D, Otto W, Capitanio U, Izawa JI, Ficarra V, Lerner S, Sagalowsky AI, Schoenberg M, Kamat A, Dinney CP, Lotan Y, Shariat SF (2010) Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 57(2):300–309.  https://doi.org/10.1016/j.eururo.2009.09.024 Google Scholar
  4. 4.
    Tilki D, Shariat SF, Lotan Y, Rink M, Karakiewicz PI, Schoenberg MP, Lerner SP, Sonpavde G, Sagalowsky AI, Gupta A (2013) Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy. BJU Intern 111(8):1215–1221.  https://doi.org/10.1111/j.1464-410X.2012.11455.x Google Scholar
  5. 5.
    Mari A, Kimura S, Foerster B, Abufaraj M, D’Andrea D, Hassler M, Minervini A, Roupret M, Babjuk M, Shariat SF (2019) A systematic review and meta-analysis of the impact of lymphovascular invasion in bladder cancer transurethral resection specimens. BJU Intern 123(1):11–21.  https://doi.org/10.1111/bju.14417 Google Scholar
  6. 6.
    Abufaraj M, Foerster B, Schernhammer E, Moschini M, Kimura S, Hassler MR, Preston MA, Karakiewicz PI, Remzi M, Shariat SF (2019) Micropapillary urothelial carcinoma of the bladder: a systematic review and meta-analysis of disease characteristics and treatment outcomes. Eur Urol 75(4):649–658.  https://doi.org/10.1016/j.eururo.2018.11.052 Google Scholar
  7. 7.
    Da D, Abufaraj M, Susani M, Ristl R, Foerster B, Kimura S, Mari A, Soria F, Briganti A, Karakiewicz PI, Gust KM, Roupret M, Shariat SF (2018) Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: a clinical decision-making tool. Urol Oncol 36(5):239.e231–239.e237.  https://doi.org/10.1016/j.urolonc.2018.01.018 Google Scholar
  8. 8.
    Colombo R, Hurle R, Moschini M, Freschi M, Colombo P, Colecchia M, Ferrari L, Luciano R, Conti G, Magnani T, Capogrosso P, Conti A, Pasini L, Burgio G, Guazzoni G, Patriarca C (2018) Feasibility and clinical roles of different substaging systems at first and second transurethral resection in patients with t1 high-grade bladder cancer. Eur Urol Focus 4(1):87–93.  https://doi.org/10.1016/j.euf.2016.06.004 Google Scholar
  9. 9.
    Fransen van de Putte EE, Otto W, Hartmann A, Bertz S, Mayr R, Brundl J, Breyer J, Manach Q, Comperat EM, Boormans JL, Bosschieter J, Jewett MAS, Stoehr R, van Leenders G, Nieuwenhuijzen JA, Zlotta AR, Hendricksen K, Roupret M, Burger M, van der Kwast TH, van Rhijn BWG (2018) Metric substage according to micro and extensive lamina propria invasion improves prognostics in T1 bladder cancer. Urol Oncol 36(8):e7–e13.  https://doi.org/10.1016/j.urolonc.2018.05.007 Google Scholar
  10. 10.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10):e1–e34.  https://doi.org/10.1016/j.jclinepi.2009.06.006 Google Scholar
  11. 11.
    Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, Petticrew M, Altman DG (2003) Evaluating non-randomised intervention studies. Health Technology Assessment, Winchester, pp 1–173Google Scholar
  12. 12.
    Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The cochrane collaboration (2011). Available from http://handbook.cochrane.org
  13. 13.
    Andius P, Johansson SL, Holmang S (2007) Prognostic factors in stage T1 bladder cancer: tumor pattern (solid or papillary) and vascular invasion more important than depth of invasion. Urology 70(4):758–762.  https://doi.org/10.1016/j.urology.2007.06.638 Google Scholar
  14. 14.
    Orsola A, Cecchini L, Raventos CX, Trilla E, Planas J, Landolfi S, de Torres I, Morote J (2010) Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guerin therapy and the decision for a repeat TUR. BJU Int 105(2):202–207.  https://doi.org/10.1111/j.1464-410X.2009.08694.x Google Scholar
  15. 15.
    Orsola A, Werner L, de Torres I, Martin-Doyle W, Raventos CX, Lozano F, Mullane SA, Leow JJ, Barletta JA, Bellmunt J, Morote J (2015) Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients. Br J Cancer 112(3):468–474.  https://doi.org/10.1038/bjc.2014.633 Google Scholar
  16. 16.
    Soukup V, Babjuk M, Duskova J, Pesl M, Szakaczova M, Zamecnik L, Dvoracek J (2008) Does the expression of fascin-1 and tumor subclassification help to assess the risk of recurrence and progression in t1 urothelial urinary bladder carcinoma? Urol Int 80(4):413–418.  https://doi.org/10.1159/000132700 Google Scholar
  17. 17.
    Bernardini S, Billerey C, Martin M, Adessi GL, Wallerand H, Bittard H (2001) The predictive value of muscularis mucosae invasion and p53 over expression on progression of stage T1 bladder carcinoma. J Urol 165(1):42–46.  https://doi.org/10.1097/00005392-200101000-00011 Google Scholar
  18. 18.
    Bertz S, Denzinger S, Otto W, Wieland WF, Stoehr R, Hofstaedter F, Hartmann A (2011) Substaging by estimating the size of invasive tumour can improve risk stratification in pT1 urothelial bladder cancer-evaluation of a large hospital-based single-centre series. Histopathology 59(4):722–732.  https://doi.org/10.1111/j.1365-2559.2011.03989.x Google Scholar
  19. 19.
    Brimo F, Wu C, Zeizafoun N, Tanguay S, Aprikian A, Mansure JJ, Kassouf W (2013) Prognostic factors in T1 bladder urothelial carcinoma: the value of recording millimetric depth of invasion, diameter of invasive carcinoma, and muscularis mucosa invasion. Hum Pathol 44(1):95–102.  https://doi.org/10.1016/j.humpath.2012.04.020 Google Scholar
  20. 20.
    Chaimuangraj S, Dissaranan C, Leenanupunth C, Prathombutr P, Chalermsanyakorn P (2006) Significance of muscularis mucosae in metastasis involvement of urinary bladder transitional cell carcinoma. J Med Assoc Thai 89(9):1447–1453Google Scholar
  21. 21.
    Chang WC, Chang YH, Pan CC (2012) Prognostic significance in substaging ofT1 urinary bladder urothelial carcinoma on transurethral resection. Am J Surg Pathol 36(3):454–461.  https://doi.org/10.1097/PAS.0b013e31823dafd3 Google Scholar
  22. 22.
    Cheng L, Neumann RM, Weaver AL, Spotts BE, Bostwick DG (1999) Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol 17(10):3182–3187.  https://doi.org/10.1200/jco.1999.17.10.3182 Google Scholar
  23. 23.
    Hasui Y, Osada Y, Kitada S, Nishi S (1994) Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology 43(6):782–786Google Scholar
  24. 24.
    Holmäng S, Hedelin H, Anderström C, Holmberg E, Johansson SL (1997) The importance of the depth of invasion in stage T1 bladder carcinoma: a prospective cohort study. J Urol 157(3):800–804.  https://doi.org/10.1016/S0022-5347(01)65044-4 Google Scholar
  25. 25.
    Hu Z, Mudaliar K, Quek ML, Paner GP, Barkan GA (2014) Measuring the dimension of invasive component in pT1 urothelial carcinoma in transurethral resection specimens can predict time to recurrence. Ann Diagn Pathol 18(2):49–52.  https://doi.org/10.1016/j.anndiagpath.2013.11.002 Google Scholar
  26. 26.
    Kondylis FI, Demirci S, Ladaga L, Kolm P, Schellhammer PF (2000) Outcomes after intravesical bacillus Calmette-Guerin are not affected by substaging of high grade T1 transitional cell carcinoma. J Urol 163(4):1120–1123Google Scholar
  27. 27.
    Lee JY, Joo HJ, Cho DS, Kim SI, Ahn HS, Kim SJ (2012) Prognostic significance of substaging according to the depth of lamina propria invasion in primary T1 transitional cell carcinoma of the bladder. Korean J Urol 53(5):317–323.  https://doi.org/10.4111/kju.2012.53.5.317 Google Scholar
  28. 28.
    Lim SD, Cho YM, Choi GS, Park HK, Paick SH, Kim WY, Kim SN, Yoon G (2015) Clinical significance of substaging and HER2 expression in papillary nonmuscle invasive urothelial cancers of the urinary bladder. J Korean Med Sci 30(8):1068–1077.  https://doi.org/10.3346/jkms.2015.30.8.1068 Google Scholar
  29. 29.
    Mhawech-Fauceglia P, Fischer G, Alvarez V Jr, Ahmed A, Herrmann FR (2007) Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder carcinoma using a panel of biomarkers: a high throughput tissue microarray analysis. BJU Int 100(5):1182–1187.  https://doi.org/10.1111/j.1464-410X.2007.07090.x Google Scholar
  30. 30.
    Nishiyama N, Kitamura H, Maeda T, Takahashi S, Masumori N, Hasegawa T, Tsukamoto T (2013) Clinicopathological analysis of patients with non-muscle-invasive bladder cancer: prognostic value and clinical reliability of the 2004 WHO classification system. Jpn J Clin Oncol 43(11):1124–1131.  https://doi.org/10.1093/jjco/hyt120 Google Scholar
  31. 31.
    Olsson H, Hultman P, Rosell J, Jahnson S (2013) Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours. Scand J Urol 47(3):188–195.  https://doi.org/10.3109/00365599.2012.719539 Google Scholar
  32. 32.
    Orsola A, Trias I, Raventos CX, Espanol I, Cecchini L, Bucar S, Salinas D, Orsola I (2005) Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients. Eur Urol 48(2):231–238.  https://doi.org/10.1016/j.eururo.2005.04.013 Google Scholar
  33. 33.
    Otto W, van Rhijn BW, Breyer J, Bertz S, Eckstein M, Mayr R, Lausenmeyer EM, Denzinger S, Burger M, Hartmann A (2018) Infiltrative lamina propria invasion pattern as an independent predictor for cancer-specific and overall survival of instillation treatment-naive stage T1 high-grade urothelial bladder cancer. Int J Urol 25(5):442–449.  https://doi.org/10.1111/iju.13532 Google Scholar
  34. 34.
    Palou J, Sylvester RJ, Faba OR, Parada R, Pena JA, Algaba F, Villavicencio H (2012) Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guerin. Eur Urol 62(1):118–125.  https://doi.org/10.1016/j.eururo.2011.10.029 Google Scholar
  35. 35.
    Patriarca C, Hurle R, Moschini M, Freschi M, Colombo P, Colecchia M, Ferrari L, Guazzoni G, Conti A, Conti G, Luciano R, Magnani T, Colombo R (2016) Usefulness of pT1 substaging in papillary urothelial bladder carcinoma. Diag Pathol 11:6.  https://doi.org/10.1186/s13000-016-0466-6 Google Scholar
  36. 36.
    Patschan O, Sjodahl G, Chebil G, Lovgren K, Lauss M, Gudjonsson S, Kollberg P, Eriksson P, Aine M, Mansson W, Ferno M, Liedberg F, Hoglund M (2015) A molecular pathologic framework for risk stratification of stage T1 urothelial carcinoma. Eur Urol 68(5):824–832.  https://doi.org/10.1016/j.eururo.2015.02.021 Google Scholar
  37. 37.
    Queipo-Zaragoza JA, Ruiz-Cerda JL, Vera-Donoso CD, Vera-Sempere F, Budia-Alba A, Jimenez-Cruz JF (2007) Prognostic value of p53, Ki-67, microstaging and microvessel density in pT1G3 bladder tumors: creation of risk groups for progression. Scand J Urol Nephrol 41(4):283–289.  https://doi.org/10.1080/00365590601183055 Google Scholar
  38. 38.
    Rouprêt M, Seisen T, Compérat E, Larré S, Mazerolles C, Gobet F, Fetissof F, Fromont G, Safsaf A, D’Arcier BF, Celhay O, Validire P, Rozet F, Irani J, Soulié M, Pfister C (2013) Prognostic interest in discriminating muscularis mucosa invasion (T1a vs T1b) in nonmuscle invasive bladder carcinoma: french national multicenter study with central pathology review. J Urol 189(6):2069–2076.  https://doi.org/10.1016/j.juro.2012.11.120 Google Scholar
  39. 39.
    Shariat SF, Weizer AZ, Green A, Laucirica R, Frolov A, Wheeler TM, Lerner SP (2000) Prognostic value of P53 nuclear accumulation and histopathologic features in T1 transitional cell carcinoma of the urinary bladder. Urology 56(5):735–740Google Scholar
  40. 40.
    Smits G, Schaafsma E, Kiemeney L, Caris C, Debruyne F, Witjes JA (1998) Microstaging of pT1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. Urology 52(6):1009–1013Google Scholar
  41. 41.
    Soukup V, Duskova J, Pesl M, Capoun O, Feherova Z, Zamecnik L, Hanus T, Babjuk M (2014) The prognostic value of T1 bladder cancer substaging: a single institution retrospective study. Urol Int 92(2):150–156.  https://doi.org/10.1159/000355358 Google Scholar
  42. 42.
    Sozen S, Akbal C, Sokmensuer C, Ekici S, Ozen H (2002) Microstaging of pT1 transitional cell carcinoma of the bladder. Does it really differentiate two populations with different prognoses? (pT1 subcategory). Urol Int 69(3):200–206.  https://doi.org/10.1159/000063941 Google Scholar
  43. 43.
    Turan T, Efiloglu O, Gunaydin B, Ozkanli S, Nikerel E, Atis G, Caskurlu T, Yildirim A (2018) Comparative differences between T1a/b and T1e/m as substages in T1 urothelial carcinoma of the bladder. Int Braz J Urol 44(2):267–272.  https://doi.org/10.1590/s1677-5538.ibju.2017.0424 Google Scholar
  44. 44.
    Dem V, Cerruto MA, D’Elia C, Brunelli M, Otte O, Minja A, Luchini C, Novella G, Cavalleri S, Martignoni G, Artibani W (2014) Prognostic role of substaging in T1G3 transitional cell carcinoma of the urinary bladder. Mol Clin Oncol 2(4):575–580.  https://doi.org/10.3892/mco.2014.290 Google Scholar
  45. 45.
    van der Aa MN, van Leenders GJ, Steyerberg EW, van Rhijn BW, Jobsis AC, Zwarthoff EC, van der Kwast TH (2005) A new system for substaging pT1 papillary bladder cancer: a prognostic evaluation. Hum Pathol 36(9):981–986.  https://doi.org/10.1016/j.humpath.2005.06.017 Google Scholar
  46. 46.
    van Rhijn BW, van der Kwast TH, Alkhateeb SS, Fleshner NE, van Leenders GJ, Bostrom PJ, van der Aa MN, Kakiashvili DM, Bangma CH, Jewett MA, Zlotta AR (2012) A new and highly prognostic system to discern T1 bladder cancer substage. Eur Urol 61(2):378–384.  https://doi.org/10.1016/j.eururo.2011.10.026 Google Scholar
  47. 47.
    Tariq A, Khan SR, Vela I, Williams ED (2019) Assessment of the use of the Internet and social media among people with bladder cancer and their carers, and the quality of available patient-centric online resources: a systematic review. BJU Int 123(Suppl 5):10–18.  https://doi.org/10.1111/bju.14720 Google Scholar
  48. 48.
    Rieken M, Shariat SF, Kluth L, Crivelli JJ, Abufaraj M, Foerster B, Mari A, Ilijazi D, Karakiewicz PI, Babjuk M, Gonen M, Xylinas E (2018) Comparison of the EORTC tables and the EAU categories for risk stratification of patients with nonmuscle-invasive bladder cancer. Urol Oncol 36(1):8.e17–18.e24.  https://doi.org/10.1016/j.urolonc.2017.08.027 Google Scholar
  49. 49.
    Xylinas E, Kent M, Kluth L, Pycha A, Comploj E, Svatek RS, Lotan Y, Trinh QD, Karakiewicz PI, Holmang S, Scherr DS, Zerbib M, Vickers AJ, Shariat SF (2013) Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. Br J Cancer 109(6):1460–1466.  https://doi.org/10.1038/bjc.2013.372 Google Scholar
  50. 50.
    Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49(3):466–477.  https://doi.org/10.1016/j.eururo.2005.12.031 Google Scholar
  51. 51.
    Martin-Doyle W, Leow JJ, Orsola A, Chang SL, Bellmunt J (2015) Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol 33(6):643–650.  https://doi.org/10.1200/jco.2014.57.6967 Google Scholar
  52. 52.
    Crozier J, Papa N, Perera M, Ngo B, Bolton D, Sengupta S, Lawrentschuk N (2019) Comparative sensitivity and specificity of imaging modalities in staging bladder cancer prior to radical cystectomy: a systematic review and meta-analysis. World J Urol 37(4):667–690.  https://doi.org/10.1007/s00345-018-2439-8 Google Scholar
  53. 53.
    Cottrell L, Nairn ER, Hair M (2007) Consistency of microstaging pT1 bladder transitional cell carcinoma. J Clin Pathol 60(6):735–736.  https://doi.org/10.1136/jcp.2006.045708 Google Scholar
  54. 54.
    Segal R, Yafi FA, Brimo F, Tanguay S, Aprikian A, Kassouf W (2012) Prognostic factors and outcome in patients with T1 high-grade bladder cancer: can we identify patients for early cystectomy? BJU Int 109(7):1026–1030.  https://doi.org/10.1111/j.1464-410X.2011.10462.x Google Scholar

Copyright information

© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Mehdi Kardoust Parizi
    • 1
    • 2
  • Dmitry Enikeev
    • 3
  • Petr V. Glybochko
    • 3
  • Veronika Seebacher
    • 4
  • Florian Janisch
    • 1
    • 5
  • Harun Fajkovic
    • 1
  • Piotr L. Chłosta
    • 6
  • Shahrokh F. Shariat
    • 1
    • 3
    • 7
    • 8
    Email author
  1. 1.Department of Urology and Comprehensive Cancer CenterVienna General Hospital, Medical University of ViennaViennaAustria
  2. 2.Department of UrologyShariati Hospital, Tehran University of Medical SciencesTehranIran
  3. 3.Institute for Urology and Reproductive HealthSechenov UniversityMoscowRussia
  4. 4.Department for Gynecology and Gynecologic Oncology, Gynecologic Cancer UnitComprehensive Cancer Centre, Medical University of ViennaViennaAustria
  5. 5.Department of UrologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Department of UrologyJagiellonian University, Medical CollegeCracowPoland
  7. 7.Department of UrologyWeill Cornell Medical CollegeNew YorkUSA
  8. 8.Department of UrologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations