Up to 80% of bladder cancers are nonmuscle invasive (NMI) at initial diagnosis . The nature of NMI bladder cancer (NMI-BC) is heterogeneous: Low grade, superficial (Ta) carcinomas rarely progress to life-threatening disease but require frequent endoscopic treatment and surveillance. Conversely, high grade/grade 3 NMI-BCs show significant progression and death rates.
Especially for T1 urothelial bladder cancer (T1-BC), which comprises 25% of NMI-BCs, discrimination of potentially progressive and fatal disease is challenging , as 5-year progression rates vary between 21 and 50% [3,4]. Conservative management leads to cancer-specific mortality in up to 34% . Therefore, various experts recommend upfront radical cystectomy for all T1-BCs [4–6]. On the contrary, radical cystectomy is overtreatment for nonprogressive T1-BC and associated with considerable morbidity and mortality . Although risk factors for T1-BC progression have been explored extensively, no definitive criteria for radical cystectomy timing exist [8,9].
For NMI-BC, risk assessment models for progression include presence of Carcinoma in situ (CIS), histological grade and T1-stage as the main prognostic factors [10,11]. However, the definition of histological grade is complicated by simultaneous use of several classification systems . The assessment of T1-stage is complicated by a considerable interobserver and intraobserver variability among pathologists [12,13]. Moreover, the prognostic value of current risk assessment models specifically for T1-BC is limited [14,15].
A recent meta-analysis concerning high-grade T1-BC reported substage, lymphovascular invasion, CIS, size, age and adjuvant Bacillus Calmette-Guérin (BCG) treatment as important prognostic factors . T1 sub-stage (T1a–T1c) was the most important prognostic variable. The main objective of this review was to analyze the prognostic significance of T1 sub-stage and T1 grade. We also explored the reliability of the T1 diagnosis itself.
RELIABILITY OF T1 STAGE
Pathological stage is the gold standard for diagnostic and prognostic purposes. Initial bladder cancer stage is based on histological evaluation of endoscopic specimens, differentiating involvement of the lamina propria (T1) from noninvasive papillary carcinoma (Ta) and invasion of the muscularis propria (≥T2). It is well known that T1-BC is upstaged to muscle invasive in 27–51% patients at radical cystectomy . Possible explanations for staging errors based on transurethral resection (TUR) specimens include thermal artifacts, tangential sectioning, absence of muscularis propria in specimens with tumor invasion, desmoplastic reactions and the presence of nested cancer variants [16,17]. In order to improve T1-BC staging, several studies have explored the effect of pathological stage review. These studies report downstaging rates to Ta of 15–56% and upstaging rates to muscle invasive bladder cancer (MI-BC) of 0–17% [13,18–23]. As the reviewed stage was a strong prognostic factor, many studies advocate standard disease review in T1-BC [13,18,20–23]. However, misinterpretation of tissue architecture does not fully explain all under-staging at initial diagnosis. Another factor is incomplete resection. Therefore, others have investigated T1-BC restaging by means of a second TUR. This resulted in upstaging to at least pT2-BC in 2–30% of patients [24,25]. The European Association of Urology (EAU) Guidelines now recommend a standard restaging TUR when T1-BC is diagnosed . In addition, Herr and Donat  established the importance of muscularis propria inclusion in TUR specimens as a quality parameter. They stratified T1-BC progression in 701 patients by the presence of muscularis propria in initial TUR specimens. If muscularis propria was present, 15% were upstaged to MI-BC in the follow-up TUR as compared with 45% when the muscularis propria was absent . The importance of deep resection was confirmed by Mariappan et al., who found that muscularis propria absence is associated with a high risk of early recurrence. Hence, endoscopic resection for T1-BC without muscularis propria is regarded incomplete .
Although a second histological analysis or resection can improve stage accuracy, T1-BC remains a heterogeneous disease with variable clinical outcomes. In search for methods to stratify progression risk, several sub-staging systems have been developed.
T1 SUB-STAGING: MUSCULARIS MUCOSAE INVASION
The most extensively studied sub-staging system for T1-BC is based on muscularis mucosae invasion. The muscularis mucosae is a discontinuous layer of smooth muscle bundles, situated, approximately, midway between the urothelium and the muscularis propria [27,28]. The muscularis mucosae is accompanied by a plexus of large vessels, running along the lamina propria. We searched PubMed using the keywords ‘urinary bladder cancer’, ‘T1’ and ‘substage’. Only English literature was selected, no time restrictions were applied. After exclusion of obvious duplications, we found 28 reports on the utility of the muscularis mucosae to predict T1-BC progression [29–54,55▪,56▪▪] (Table 1). Originally developed as a three-tier system , the most investigated method is based on two stages: invasion above the muscularis mucosae (T1a) and invasion in or through the muscularis mucosae (T1b). The two-tiered system was explored in 23 studies. Twelve showed a significant association between substage and progression on multivariable analysis, whereas 11 did not (Table 1). Between these studies, no evident differences existed regarding cohort sizes or inclusion criteria.
We identified only one prospective study. In this study by Orsola et al.[55▪], 111 patients with high-grade T1b-BC received a second TUR after intravesical treatment, whereas 89 T1a-BC patients were followed by cystoscopy. Although 5-year cancer-specific survival (CSS) rates were high for both groups (99% for T1a-BC and 95% for T1b-BC), T1b-BCs showed a significantly higher progression rate than T1a (23.6 versus 5.6%, P < 0.01). Regarding the retrospective reports, the largest study was conducted by Rouprêt et al.. Six different hospitals identified T1-BC substage in 587 patients, followed by central pathology review. Substage was significantly associated with recurrence-free survival [odds ratio (OR) 1.28, 95% confidence interval (CI) 1.02–1.61], progression-free survival (PFS) (OR 1.93, 95% CI 1.35–2.74) and CSS (OR 2.03, 95% CI 1.22–3.39). Notably, the reported sub-stage identification rate was 100% with central reclassification in only 16% of patients. Identification rates reported by other study groups, however, were less convincing: for example, in a series of 170 samples sub-stage could not be determined in up to 68% of TUR specimens . This variation could partly be attributable to the general challenges in histological evaluation of TUR-specimens. Another explanation is the discontinuous nature of the muscularis mucosae . Although muscularis mucosae is identified in 94% of cystectomy specimens, in biopsy specimens this ranges from 12 to 83% [27,58,59]. Another explanation is that the muscularis mucosae may be present in several TUR-chips of a resection but not in the TUR chip with the invasion front of the tumor . In order to improve sub-staging rates, the associated large vessels of the vascular plexus were proposed as a histologic substitute if the muscularis mucosae is absent [34,37]. However, the reliability of these vessels for sub-staging purposes has never been investigated. Furthermore, considerable topographical variations have been described of both the muscularis mucosae and the vessels throughout the urinary bladder . Only 16/28 studies reported how many samples were truly substaged based on identification of muscularis mucosae invasion versus the large vessels [29–31,34–37,39,40,45,47–51,54]. These proportions varied substantially (range 32–100%). This could be responsible for the fact that almost half of the studies did not find a significant prognostic value for T1a/b stage, especially in smaller cohorts. In conclusion, although the prognostic value of T1-BC substage based on muscularis mucosae invasion appears to be promising, a consensus among pathologists is lacking. Therefore, the WHO has never proposed to implement this substage system in the TNM classification system or clinical guidelines [2,9].
T1 SUB-STAGING: TUMOR DEPTH AND TUMOR DIAMETER (MICROINVASIVE VERSUS EXTENSIVE INVASIVE)
To circumvent the problems with muscularis mucosae identification, two other histopathological features have been studied to improve T1-BC substage consistency and feasibility. First, Cheng et al. investigated tumor invasion depth of the lamina propria and found a significant association with progression on univariate analysis. Millimetric depth assessment was possible in all 83 TUR samples (Table 2) [36,45,47,48,51,54,61,62]. They proposed a cutoff invasion depth of 1.5 mm as the 5-year PFS rate for invasion beyond 1.5 mm was 67 versus 93% for less than 1.5 mm (P = 0.009) . We found only one other study investigating millimetric depth as a prognosticator (Table 2). This study by Brimo et al. confirmed a strong correlation between invasion depth and progression [hazard ration (HR) 5.09, 95% CI 2.16–11.95] among 86 patients. Brimo et al. proposed a threshold invasion depth of 3 mm. Remarkably, the overall mean lamina propria thickness reported in a previous study by Cheng et al. was 1.4 mm, thus, smaller than both proposed threshold values [36,51]. This suggests that either the deep invasive fragments harbor unrecognized muscle invasion, or that thickness of the lamina propria varies significantly among patients and different regions in the bladder. Moreover, measurement of invasion depth can easily be affected by tangential TUR sections and mucosal denudation due to BCG treatment. The thresholds proposed by Brimo et al. and Cheng et al. have not been validated by other studies.
Another relatively new sub-staging system was developed by van der Aa et al.. This method is based on the diameter of the lamina propria invasion. The authors stratified T1-BC into microinvasive (T1m) and extensive invasive (T1e). T1m was defined as a single spot of invasion with a diameter 0.5 mm or less (one high-power field). Specimens with a larger area of invasion or multiple microinvasive areas were defined as T1e. We identified eight retrospective studies on the T1m/e system (Table 2). In all reports, the sub-stage identification rate was 100%. In the smallest cohort (n = 40) no prognostic value for T1m/e sub-stage was detected . All other studies, with cohort sizes varying from 53 to 509 patients, reported a significant association between T1m/e and progression on univariable  and on multivariable analysis [15,45,47,48,51,61]. All were single-center reports, apart from the study by van Rhijn et al.. In this two-center study, TUR specimens of 134 patients were reviewed for sub-stage by one pathologist based on diameter (T1m/e) and muscularis mucosae invasion (Ta/b/c). T1e-BC was associated with progression (HR 3.0, 95% CI 1.5–5.9) and a shorter CSS (HR 2.7, 95% CI 1.1–6.8) on multivariable analysis. For T1a/b/c stage, no prognostic value was detected in multivariable analyses . Moreover, muscularis mucosae could not be identified in 37% of tumors (Tables 1 and 2). Another head-to-head comparison between T1m/e and T1a/b stage was performed by Bertz et al.. Among 309 patients, T1m/e stage was associated with recurrence (HR 2.03, 95% CI 1.16–3.56) and progression (HR 3.38, 95% CI 1.66–6.87), whereas T1a/b sub-stage was not prognostic . Sub-stage based on tumor diameter was feasible in 100% of tumors, whereas muscularis mucosae could be identified in only 83% (Tables 1 and 2).
All authors used an invasion diameter of one microscopic high-power field (range 5–6 mm) as threshold value for T1m/e identification, except for Chang et al.. They investigated the impact of other threshold values (0.5 versus 1.0 versus 1.5 mm) among 509 patients and found comparable statistical results for all cutoff points.
In conclusion, substage determination based on millimetric depth of lamina propria invasion has similar shortcomings as the system that uses the muscularis mucosae as orientation. T1m/e substage (based on tumor diameter) proved a user-friendly and more consistent method, showing an identification rate of 100% in all reports. However, multicenter studies with pathology review are warranted to investigate interobserver variation. If such studies confirm the initial promising reports, T1m/e may be incorporated in the TNM classification system for urinary bladder cancer.
GRADING NONMUSCLE INVASIVE BLADDER CANCER: AN HISTORICAL OVERVIEW
In addition to T1 stage and sub-stage, histological grade is an important prognosticator for NMI-BC. The first official grading system for bladder cancer was adopted by the WHO in 1973 . The 1973, WHO classification is a three-tier system, which defines Grades 1–3 (G1–3). G1 bladder cancer has minimal architectural abnormalities with little or no mitotic figures . G3 bladder cancer demonstrates extreme nuclear abnormalities, disordered architecture, loss of polarity and frequent mitotic activity. Although definitions of G1 and G3 tumors are explicit, G2 remains a diagnosis of exclusion . Hence, most of NMI-BC end up being classified as G2, ‘the default diagnosis’ [66,67]. In 2004, the WHO adopted a new grade classification [67,68]. The 2004 WHO classification system defines urothelial neoplasms of low-malignant potential, low-grade urothelial bladder cancer and high-grade urothelial bladder cancer . Taking into account only NMI-BCs, neither the 1973 nor the 2004 WHO system has been proven superior , although both provide independent information regarding disease outcome .
For both WHO classifications attempts were made to increase prognostic value by creating four-tiered systems. Regarding the 1973 WHO system, G2 was divided into a/b categories, also known as the modified Bergkvist criteria . The high-grade category of the 2004 WHO system was originally divided into high grade/G2 and high grade/G3. This system was adopted by the WHO in 1999 . However, neither of the four-tier grading systems are implemented in clinical guidelines due to the inherent increased observer variability compared with the three-tier systems .
Currently, the American Urological Association and the European Association of Urology advocate simultaneous use of the 1973 and the 2004 WHO classifications [9,74,75]. In practice, simultaneous use of both systems results in another four-tier classification. Although this combination of classifications is associated with a significant stepwise increase of progression in NMI-BC , its prognostic value for T1-BC specifically is unclear. We have compared the different prognostic values of each existing grading system for T1-BC.
PROGNOSTIC VALUE OF DIFFERENT GRADING SYSTEMS IN T1 BLADDER CANCER
We searched PubMed using the keywords ‘urinary bladder cancer’ ‘T1’ and ‘grade’, no time restrictions were applied. Many studies had to be excluded because they did not differentiate between Ta and T1-BC [10,76]. In total, 16 retrospective reports were found and analyzed, including nine reports on the 1973 WHO classification (Table 3) [38,39,45,47,50,53,77–79] and six reports on the 2004 WHO classification (Table 4) [34,46,47,62,78,80]. Most studies that compared the 1973 and 2004 WHO classifications used retrospective data and did pathology review for the WHO 2004 classification . Only two were real comparative studies [47,78].
The 1973, WHO classification was the most applied and examined grading system (Table 3). For T1-BC, G1 disease is practically nonexistent . The reported prevalence of T1G2-BC is 25–60% and of T1G3-BC 28–71% [38,39,45,47,50,53,78,77,79]. Stratifying for G2 versus G3 disease, six of nine studies showed a significant difference in progression or CSS (Table 3). The three studies that were not significant comprised relatively small cohorts [38,47,77].
Regarding the 2004 WHO classification, only one of four studies identified grade as a prognostic factor for T1-BC progression (Table 4). This could be explained by the fact that almost all T1 tumors, formerly graded G2 or G3 according to the 1973 WHO, were referred to the 2004 WHO high-grade category [75,81]. Because of this grade shift less than 5% of T1-BCs were defined low grade, resulting in a near one-tiered system . The two available head-to-head comparisons between the 1973 and 2004 grading systems confirmed the superior prognostic value for the 1973 WHO classification in T1-BC [47,78]. Both studies did not detect any prognostic value for the 2004 WHO classification (Table 4). One found a near-significant association between 1973 WHO grade and progression (P = 0.081) among 134 patients . The other study demonstrated a significantly better 10-year CSS rate for T1G2-BC (95.5%) than for T1G3-BC (77.8%, P < 0.001) in 310 patients .
Regarding the two four-tier systems, we found only three studies that assessed the prognostic value for T1-BC (Table 5) [42,52,56▪▪]. Andius et al. investigated both the modified Bergkvist criteria and the 1999 WHO classification system. Although they found a significant association with progression for both systems on univariable analysis, no long-term prognostic value for grade could be detected on multivariable analysis . Two other relatively large cohorts failed to identify the 1999 WHO classification as a prognosticator (Table 5). Although observer variability remains an issue, long-term results showed no improved prognostication unless combined with molecular markers .
In conclusion, the 1973 WHO classification has been shown to be a significant prognosticator for T1-BC specifically. In contrast, the 2004 WHO classification appears to be inapplicable for T1-BC due to the low number of low-grade tumors. The creation of four-tiered systems by dividing the G2 or the high-grade category failed to improve prognostic accuracy.
Sub-staging is a promising method for progression-risk assessment in T1-BC. The most extensively studied system stratifies by muscularis mucosae invasion (T1a/b). Although its prognostic value has been validated in several studies, an important limitation is interobserver variability of muscularis mucosae identification. Due to a lack of consensus among pathologists, the T1a/b system has not been implemented in clinical guidelines. T1m/e stratification proved prognostic in multivariable analyses, user-friendly and a more consistent method to substage T1-BC. If the promising identification rates and low interobserver variation are confirmed by multicenter studies, the T1m/e classification may be incorporated in the TNM classification system for urinary bladder cancer.
Remarkably few studies have investigated the applicability of the WHO grading systems for T1-BC. Although both WHO classifications provide independent information in NMI-BC, for T1-BC specifically, the 1973 WHO classification is a superior prognosticator to the 2004 WHO system due to a low number of low-grade T1-BCs. The creation of four-tier grading systems by dividing the G2 or the high-grade category does not improve prognostic accuracy for NMI-BC in general, nor for T1-BCs specifically.
Financial support and sponsorship
M.A. Behrendt has received a Sponsorship Grant from the European Sponsorship Programme (EUSP, part of the EAU) and a restricted material grant from the department of urology, University of Basel, Switzerland.
Conflicts of interest
There are no conflicts of interest.
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