Head-to-head: how many categories for grading urothelial carcinoma?

Tumour grade is a critical prognostic parameter for guiding the management of patients with non-muscle invasive bladder cancer. In 2004, the World Health Organisation (WHO) adopted a binary (low-grade/high-grade) grading system to replace the three-tier (grades 1-3) system used to grade urothelial carcinoma since 1973. However, there is significant global variation in the grading of urothelial carcinoma. Some pathology and clinical guidelines recommend reporting of the WHO 1973 and 2004 grades in parallel, while others require reporting only of the WHO 2004 grade. This variation in pathology practice is clinically significant, because the two grading systems are not readily translatable. Some experts have proposed novel systems for grading urothelial carcinoma that involve splitting of the WHO 1973 and 2004 grade categories. The arguments for and against splitting urothelial carcinomas into two-, three- and four-grade categories are independently discussed by the three authors.

Bladder cancer grading using the four-tier combination of the World Health Organization (WHO) 1973 and WHO 2004 classifications.

OBJECTIVE: To investigate the impact of grading in urothelial bladder cancer (UBC) stages Ta and T1, comparing the World Health Organization (WHO) grading classifications of 1973 (WHO73) and 2004 (WHO04) and a combination of these (WHO73/04). PATIENTS AND METHODS: All patients with primary Ta and T1 UBC in the Östergötland region, Sweden, between 1992 and 2007 were included. From 1992, we introduced a new programme for management and follow-up of UBC, including prospectively performed registration of all patients, a systematic description of the location and size of all tumours, primary resection and intravesical treatment in the case of recurrence. All tumour specimens were retrospectively reviewed in 2008 and graded according to the WHO73 and WHO04. A combination of WHO73/04, Grade 1 (G1), Grade 2 low grade (G2LG), Grade 2 high grade (G2HG) and Grade 3 (G3) was analysed in relation to clinical variables and outcomes. RESULTS: There were 769 patients with a median age of 72 years and a median follow-up duration of 74 months. Recurrence was noted in 484 patients (63%) and progression in 80 patients (10%). Recurrence was more common in multiple tumours, larger tumours and in tumours of higher grade (G2LG, G2HG and G3). Progression was more common in tumours classified as larger, T1 and G2HG and G3. Notably, in tumours classified as G2HG, recurrence and progression were more common than in the G2LG group. Harrell's concordance index for the WHO73/04 was higher for recurrence and progression than in the WHO73 or WHO04. CONCLUSION: In the four-tier combined WHO73/04 for urothelial cancer, we observed two G2 sub-groups, G2HG and G2LG. There was a better outcome in the latter group, and the importance of G1 and G3 tumours could be fully evaluated. The WHO73/04 had greater accuracy for recurrence and progression than either the WHO73 or WHO04.

Biological distinction between grades 2 and 3 with respect to intravesical recurrence in T1 high-grade bladder tumors: a retrospective study.

BACKGROUND: The pathological grading system for non-muscle-invasive bladder cancer is based on the WHO 2004/2016 classification system (low-grade: LG/high-grade: HG) and the WHO 1973 classification system (Grade 1: G1/Grade 2: G2/Grade 3: G3). Recently, the usefulness of combining both systems and classifying the tumors as LG/G1, LG/G2, HG/G2, and HG/G3 has been demonstrated. In this study, we compared the prognosis of intravesical recurrence in relation to different treatment intensities between HG/G2 and HG/G3 bladder cancers. METHODS: We retrospectively evaluated the clinical and therapeutic outcomes of 145 patients diagnosed with T1 HG bladder cancer between 2000 and 2020. We classified 145 patients into three groups: (1) patients with T1 HG/G2 and HG/G3 who received intravesical instillation therapy (n = 76), (2) patients with T1 HG/G2 who did not receive intravesical instillation therapy (n = 32), and (3) patients with T1 HG/G3 who did not receive intravesical instillation therapy (n = 37). RESULTS: The median intravesical recurrence-free survival for all patients was 34.2 months. The number of tumors, the presence of intravesical instillation therapy, and tumor grade were significant prognostic factors for intravesical recurrence in all cases. Groups 2 and 3 showed significantly worse prognosis than group 1 in the multivariate analysis. CONCLUSIONS: Regarding intravesical recurrence, intravesical instillation therapy is necessary for both T1 HG/G3 and T1 HG/G2 bladder cancers.

International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members.

Background: Grade of non-muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1-3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design setting and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non-muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the "old" World Health Organization (WHO) 1973 and the "new" WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.

The impact of grading scheme on non-muscle invasive bladder cancer progression: potential utility of hybrid grading schemes.

Non-muscle invasive bladder cancer (NMIBC) grade is a major determinant of progression risk. The most widely utilised grading systems are the World Health Organization (WHO) 1973 and 2004 schemes. Recent publications suggest the utility of combining both into a four-tier or a hybrid three-tier system, subdividing WHO 2004 high grade into two separate categories while maintaining low grade as a single group. We identified two retrospective cohorts of bladder resections/biopsies of papillary urothelial NMIBC with long term clinical follow-up. The sentinel specimen was assessed for WHO 2004 and 1973 grade, along with pathological stage and carcinoma in situ. Each case was additionally stratified into a hybrid three-tier system (low grade; high grade, grades 2 and 3) and a four-tier system (low grade, grades 1 and 2; high grade, grades 2 and 3). Uni- and multivariable analysis for progression and event free survival (PFS/EFS) were calculated along with the time dependent area under the curve (AUC) for each grading scheme. There were 609 cases (Cohort A, n=343; Cohort B, n=266), including 449 (74%) pTa, 156 pT1 (26%) and four pTx with 338 (56%) low grade (177, grade 1; 161, grade 2) and 271 (44%) high grade (137, grade 2; 134, grade 3). A total of 108 patients progressed (17.7%): 97 high grade, (grade 3, n=59; grade 2, n=38). Multivariable analyses of PFS with the hybrid 3- and 4-tier systems showed higher Harrell's concordance indices (0.851 and 0.853, respectively) than WHO 1973 (0.844) and WHO 2004 (0.846). In both cohorts AUC values were higher (0.77-0.85) for the two hybrid grading systems compared to WHO 1973 or WHO 2004 (0.72-0.82). Similar results were seen on analysis of EFS. The data support the use of a hybrid three-tier or four-tier grading system to improve stratification of NMIBC patients.

International Society of Urological Pathology Expert Opinion on Grading of Urothelial Carcinoma.

CONTEXT: Grading is the mainstay for treatment decisions for patients with non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To determine the requirements for an optimal grading system for NMIBC via expert opinion. EVIDENCE ACQUISITION: A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer. EVIDENCE SYNTHESIS: Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion. CONCLUSIONS: Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or-as a preferred option-a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC. PATIENT SUMMARY: Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer.

Is there a role for second transurethral resection in pTa high-grade urothelial bladder cancer?

INTRODUCTION: Evidence for second transurethral resection of bladder tumour (TURBT) for pTa high-grade lesions is limited. This study aims to examine the role of a second TURBT in the pTa high-grade group and to generate recurrence and progression data for this group. MATERIAL AND METHODS: We retrospectively studied the clinical profiles and outcomes of all patients diagnosed with high-grade pTa lesions at first TURBT, between the years 2006-2015. Firstly, in patients who underwent a complete first TURBT, we calculated the proportion of patients with positive findings on second TURBT. Secondly, we assessed whether those who underwent a second TURBT had a longer recurrence-free survival compared to those who underwent a single TURBT. RESULTS: One hundred and twelve patients had a pTa high-grade urothelial bladder tumor (WHO 2004 classification) at first TURBT, out of whom 43 (38.3%) had a second TURBT. Indications for second TURBT were high-grade lesions (n = 36), absence of detrusor muscle (n = 2), and incomplete resection (n = 5). Out of the 36 patients who had a complete first TURBT and underwent a second look TURBT, 7 patients had positive findings (3 carcinoma in situ, 2 pTa low-grade lesions and 2 pTa high-grade lesions) and there was no upstaging. Of the 5 patients with an incomplete first TURBT, one upstaged to pT1 on second TURBT. Of the 81 patients who followed up with us, 25.9% had a recurrence and 8.6% progressed. The estimated median recurrence free survival was 60 months (95% CI 29.2-90.7) for the whole group and 76 months vs. 45 months for the second and single TURBT group respectively - a difference that was clinically, though not statistically, significant. Multiple (≥2) tumours had a lower recurrence free survival (HR of 4.60, CI 1.67-12.63, p = 0.003). CONCLUSIONS: Of the patients with pTa high-grade tumours who had a second TURBT after a complete first TURBT, 19.4% had a positive finding. Multiple tumours are four times as likely to recur as solitary tumours. The role of a second TURBT in this group needs to be studied in larger patient cohorts before a recommendation regarding its lack of clinical utility can be made conclusively.