Context.—

Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment.

Objective.—

To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression.

Design.—

We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed.

Results.—

A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9–73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3–48.3; P = .003) and 5.9 times (95% CI, 1.1–31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC.

Conclusions.—

Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Bladder tumors are the fourth most common tumors in males. More than 80 000 patients receive a diagnosis of bladder cancer and 17 000 patients die of the disease each year.1  A large portion (around 70%) of de novo bladder tumors present as non–muscle-invasive bladder carcinoma, and most of them are noninvasive papillary urothelial carcinoma (PUC).2,3  Papillary urothelial neoplasms represent a spectrum of lesions with increasing cytologic and architectural atypia, which is paralleled by an incremental risk of recurrence and progression.46  The World Health Organization (WHO) 2022 classification subcategorizes papillary urothelial neoplasms as follows: papilloma, papillary urothelial neoplasm of uncertain malignant potential (PUNLMP), low-grade papillary urothelial carcinoma (LG-PUC), and high-grade papillary urothelial carcinoma (HG-PUC).7  The hallmark of PUC is the presence of epithelial disorganization, nuclear atypia, mitotic activity, and apoptotic bodies/necrosis. The presence of these histologic findings increases from LG-PUC to HG-PUC and is mirrored by an increased risk of progression.4,6  The WHO grade for PUC is incorporated into treatment algorithms that determine the risk of the patient (low, intermediate, and high risk for recurrence/progression) and subsequently suggest the appropriate therapeutic course.8 

The WHO 2022 subclassification for papillary urothelial neoplasms, which is derived from the WHO 2004 subclassification, improves reproducibility and predictive power. However, practicing pathologists still encounter PUCs that are difficult to grade, and distinguishing LG-PUC from HG-PUC has clinical, prognostic, and therapeutic implications for the patients. We present an institutional experience of non-invasive PUC focusing on the subset with borderline features.

Patient Selection

The patient database was searched for noninvasive papillary urothelial neoplasms of the bladder from 1990 to 2010. Inclusion criteria included (1) patients with noninvasive LG-PUC or HG-PUC, (2) patients with initial de novo presentation, and (3) a minimum follow-up of 2 years for disease-free patients. Cases with a prior history of urothelial carcinoma or associated upper tract urothelial carcinoma were excluded.

Clinical and histologic data were collected on all patients, including the presence of treatment after initial diagnosis, recurrences, and progression, specifically subsequent invasion.

Histologic Evaluation

Slides were reviewed and subclassified according to the WHO 2022 classification system as LG-PUC or HG-PUC.7  All cases, including all difficult to grade/borderline cases, were reviewed by 2 pathologists. Difficult to classify cases were then scrutinized for histologic features that caused the grading difficulty. Tumors with occasional nuclear pleomorphism, without associated mitoses, severe disorganization, or necrosis were labeled borderline for nuclear pleomorphism. Nuclear pleomorphism was defined as 3 times the nuclear size difference. Nuclear pleomorphism was noticeable on low power (×4 objective) and usually seen in more than 1 focus. Pleomorphism within umbrella cells was discounted and not included in the borderline category.

Tumors with elevated mitotic count (≥5 mitoses per 10 high-power fields [HPFs]) but without nuclear atypia, severe disorganization, or necrosis were labeled borderline for mitotic count. Mitoses were counted starting with a hot spot and its adjacent 9 neighboring fields to result in a mitotic count per 10 HPFs. The cutoff of 5 or more mitoses per 10 HPFs was extrapolated from data in Table 1, by recording the mitotic figures per 10 HPFs in straightforward LG-PUC and HG-PUC; the maximum mitotic count for LG-PUC was up to 4 mitoses per 10 HPFs. Tumors with side-by-side LG-PUC and HG-PUC were labeled as borderline mixed. At the end of the review, 3 borderline categories were identified and defined as follows: (1) PUC with occasional focal moderate to marked nuclear pleomorphism (BORD-NUP), but which lacked significant architectural disorganization, mitotic count, or tumor necrosis (nuclear pleomorphism defined as 3 times variation in size); (2) PUC that architecturally and cytologically resembles LG-PUC, but with a mitotic count of 5 or more per 10 HPFs (BORD-MIT); and (3) PUC with a mixture of distinct LG and HG, with the HG component representing <50% (BORD-MIXED). Although it is common practice to render a diagnosis of HG-PUC when the HG component is 5% or more, little is known regarding the behavior of PUC when the HG component is 5% or more. We recorded the specific percentage of HG-PUC up to 50% in cases with mixed LG-PUC and HG-PUC components.

Table 1

Histopathologic Findings in Our 138 Patients, Stratified by the Noninvasive Papillary Urothelial Carcinoma Categories

Histopathologic Findings in Our 138 Patients, Stratified by the Noninvasive Papillary Urothelial Carcinoma Categories
Histopathologic Findings in Our 138 Patients, Stratified by the Noninvasive Papillary Urothelial Carcinoma Categories

Statistical Analysis

All statistical analyses were performed with R: A language and environment for statistical computing (version 4.2.0, R Foundation for Statistical Computing, http://www.R-project.org) with the “survival” (version 3.3–1) and “survminer” (version 0.4.9) packages. Medians and interquartile ranges (IQRs) were used to report continuous variables. The primary end points were recurrence-free, total progression-free, and specific invasion-free survivals, defined respectively as the time from the date of initial transurethral biopsy or resection to the date of recurrence (with a minimum interval of 2 months), progression (by increment in grade or stage), and the subsequent presence of invasion. Recurrence, total progression, and invasion-free survival curves were derived from the Kaplan-Meier method, differences in disease-free survival between groups were compared using the log-rank test, and pairwise comparisons were performed using the Benjamini-Hochberg procedure. Odds ratios were estimated by univariate Cox proportional hazards regression analysis, and multivariable analysis was performed using Cox proportional hazard models. The Schoenfeld residuals test was used to verify the proportional hazards assumption. These tests were 2-tailed, and significance was set at 5%.

A total of 138 patients were included (median age [IQR], 70.5 years [61.0–76.0 years]; men, 103 of 138 [75%]). Noninvasive PUCs were classified as LG-PUC (52 of 138; 38%), HG-PUC (34 of 138; 25%), BORD-NUP (21 of 138; 15%), BORD-MIT (14 of 138; 10%), and BORD-MIXED (17 of 138; 12%; Figure 1). For BORD-MIXED tumors, the median (IQR) percent of HG component was 20% (10%–30%). Only 1 case comprised a mixture of LG-PUC and HG-PUC with more than 50% of HG component, and it was regarded as HG-PUC.

Figure 1

Example cases of low-grade papillary urothelial carcinoma (A and B), high-grade papillary urothelial carcinoma (C and D), borderline for nuclear pleomorphism (E and F), borderline for mitoses (G and H), and borderline mixed distinct low- and high-grade papillary urothelial carcinoma (I and J) (hematoxylin-eosin, original magnifications ×100 [A, C, E, G, and I] and ×200 [B, D, F, H, and J]).

Figure 1

Example cases of low-grade papillary urothelial carcinoma (A and B), high-grade papillary urothelial carcinoma (C and D), borderline for nuclear pleomorphism (E and F), borderline for mitoses (G and H), and borderline mixed distinct low- and high-grade papillary urothelial carcinoma (I and J) (hematoxylin-eosin, original magnifications ×100 [A, C, E, G, and I] and ×200 [B, D, F, H, and J]).

Close modal

Histologic Characteristics

Histologic features, such as increased epithelial layer thickness, presence of fused papillae, necrosis, inverted growth pattern, and mitotic count, were recorded (Table 1). An incremental increase in mitotic figures was observed: the average mitotic figures per 10 HPFs was 1.5 in LG-PUC versus 12.8 in HG-PUC. The average highest mitotic density, defined as the average of highest mitotic count observed in 1 HPF, was higher for HG-PUC (3.5 mitoses per 1 HPF) compared with LG tumors (1.0 mitosis per 1 HPF).

Similarly, extensive necrosis (beyond punctate necrosis) was incrementally present; 2 of 52 patients (4%) with LG-PUC, 7 of 52 patients (13%) in all borderline cases, and in 19 of 34 patients (56%) with HG-PUC.

Of note, of the HG-PUC tumors, 3 cases had anaplastic nuclear features, 1 had focal squamous differentiation, and 1 showed focal in situ micropapillary features.

Intravesical Therapy Following Initial Diagnosis

Patients with HG-PUC had the highest percentage of intravesical therapy with Bacillus Calmette–Guérin (BCG; 9 of 30; 30%), followed by BORD-NUP (3 of 18; 17%) and BORD-MIT (2 of 14; 14%). Overall, the number of patients treated with BCG for LG-PUC and all 3 borderline categories was low, ranging from n = 1 patient for BORD-MIXED to n = 4 patients for LG-PUC.

In addition, a single dose of intravesical therapy was sometimes instilled the day of transurethral resection of the tumor, most commonly mitomycin, ranging from 3 of 14 (21%) in BORD-MIT patients to 7 of 16 (44%) in BORD-MIXED patients. Rare patients received a single instillation of intravesical adriamycin on the day of resection. Detailed intravesical treatment data can be found in Supplemental Table 1 (see supplemental digital content at https://meridian.allenpress.com/aplm in the February 2024 table of contents).

Survival Analysis

Median (IQR) follow-up was 44.2 months (29.9–73.1 months). Figures 2 and 3 depict recurrence-free, total progression-free, and invasion-free survivals. Overall median recurrence-free and total progression-free survivals were 17.3 months (95% CI, 12.2–27.0 months) and 155 months (lower 95% CI limit, 116 months; upper 95% CI not assessable). Invasion-free survival remained above the 50% threshold throughout follow-up, and therefore median invasion-free survival could not be estimated. Log-rank comparison did not reveal any difference between the 5 groups in terms of recurrence-free (P = .63) and total progression-free survivals (P = .17). Invasion-free survivals were overall different between the 5 groups (P = .004), with HG-PUC having a worse outcome compared with LG-PUC (P < .001, details regarding pairwise comparisons in Table 2).

Figure 2

Overall recurrence-free (A), total progression-free (B), and invasion-free (C) survival rate for our 138 patients with noninvasive papillary urothelial carcinoma. Tick marks along the curves indicate censored data. The vertical dash lines represent the median survival. The gray ribbon represents the 95% CI of the curve.

Figure 2

Overall recurrence-free (A), total progression-free (B), and invasion-free (C) survival rate for our 138 patients with noninvasive papillary urothelial carcinoma. Tick marks along the curves indicate censored data. The vertical dash lines represent the median survival. The gray ribbon represents the 95% CI of the curve.

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Figure 3

Comparison of recurrence-free (A), total progression-free (B), and invasion-free (C) survival rate for our 138 patients with noninvasive papillary urothelial carcinoma stratified by histopathologic categories. P values for the log-rank test are displayed at the bottom left of each panel.

Figure 3

Comparison of recurrence-free (A), total progression-free (B), and invasion-free (C) survival rate for our 138 patients with noninvasive papillary urothelial carcinoma stratified by histopathologic categories. P values for the log-rank test are displayed at the bottom left of each panel.

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Table 2

Pairwise Comparison of the Disease-Free Survival of Patients With Different Combinations of Categories of Noninvasive Urothelial Papillary Carcinoma

Pairwise Comparison of the Disease-Free Survival of Patients With Different Combinations of Categories of Noninvasive Urothelial Papillary Carcinoma
Pairwise Comparison of the Disease-Free Survival of Patients With Different Combinations of Categories of Noninvasive Urothelial Papillary Carcinoma

On univariate Cox analysis, patients aged 70 years or older and with HG-PUC (compared with LG-PUC) were 2.2 times (95% CI, 1.1–4.7 times; P = .04) and 2.8 times (95% CI, 1.1–7.0 times; P = .03) more likely to progress, respectively; HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3–48.3 times; P = .003) and 5.9 times (95% CI, 1.1–31.9 times; P = .04) more likely to subsequently invade, respectively (Table 3). Our results regarding the risk of progression of HG-PUC and the risk of invasion of HG-PUC and BORD-NUP were overall unchanged after controlling for age and sex (Table 3).

Table 3

Univariable and Multivariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion

Univariable and Multivariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion
Univariable and Multivariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion

In addition, on univariate and multivariate analyses, a trend was observed: BORD-MIXED tumors are approximately 4 times more likely to invade compared with LG-PUC. The small size of this group (17 of 138) may have precluded statistical significance (Table 3). To have a better insight on the impact of the percentage of HG-PUC on the risk of recurrence, total progression, and invasion in BORD-MIXED, different cutoffs of high-grade component, by increments of 10 percentage points (between 10% and 40%) were compared (Table 4). A trend for higher risk of invasion (∼4 times higher than LG-PUC) was seen in BORD-MIXED cases when the HG-PUC component was 20% or higher.

Table 4

Univariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion With Different Cutoffs (10%–40%) of High-Grade Component in Mixed Low- and High-Grade Papillary Urothelial Carcinoma

Univariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion With Different Cutoffs (10%–40%) of High-Grade Component in Mixed Low- and High-Grade Papillary Urothelial Carcinoma
Univariable Cox Proportional Hazards Models for Recurrence, Total Progression, and Invasion With Different Cutoffs (10%–40%) of High-Grade Component in Mixed Low- and High-Grade Papillary Urothelial Carcinoma

A continuous wide spectrum of noninvasive PUC exists, displaying variable combinations of cytologic atypia, mitoses, necrosis, and architectural disorganization. Similar to other studies, approximately a third of PUC cases in our study showed features borderline between LG-PUC and HG-PUC and were difficult to classify.9  The distinction is important because PUC grade is used as part of a clinical algorithm that classifies tumors into low, intermediate, and high risk of recurrence/progression subcategories.3  Although treatment algorithms can vary for patients with intermediate risk depending on the clinician and institution’s preferences, most high-risk patients are treated with intravesical therapy. Therefore, distinguishing LG-PUC versus HG-PUC is pivotal for dictating subsequent therapeutic course.

Our study aimed to objectively quantify the important histologic diagnostic parameters in cases with borderline features and report the associated risk of recurrence, total progression, and invasion compared with LG-PUC.

Recurrence rates were not statistically different across all subcategories, including LG-PUC, BORD-PUC, and HG-PUC. Total progression data showed a statistically significant difference between LG-PUC and HG-PUC on both univariate and multivariate analysis. HG-PUCs were almost 3 times more likely to progress compared with LG-PUCs. BORD-NUP cases showed a trend toward a higher rate of total progression. These findings were confirmed by the invasion-free survival data, where both HG-PUC and BORD-NUP showed significant rates of invasion, when compared to LG-PUC, on both univariate and multivariate analysis. Our data suggest that the presence of nuclear pleomorphism, defined as 3 times the nuclear size difference, could predispose the patient for subsequent progression, despite the absence of increased mitotic activity. Our results mirror findings from prior studies that highlight the importance of nuclear pleomorphism as a prognostic indicator of progression and invasion.10 

Interestingly, BORD-MIXED, with less than 50% HG component, did not show a statistically significant different rate of total progression compared with LG-PUC; the current approach for these tumors is to label all tumors with HG-PUC component above 5% as HG-PUC.7  When comparing the effect of the percentage of HG-PUC on invasion in the BORD-MIXED cases, we saw a trend toward higher risk of invasion, approximately 4 times the risk of LG-PUC, when the HG-PUC component was more than 20% (Table 4). Previous studies addressing the behavior of PUC with distinct low- and high-grade components showed a more indolent clinical course compared with HG-PUC. The cutoff percentage of HG-PUC in these studies varied at 5%,11  10%,12  and less than 50%.13  The findings confirm the continuous spectrum of histologic changes and associated prognostic outcomes encountered in these lesions. Results from our studies and prior studies suggest there could be a benefit in reporting these tumors as “mixed low- and high-grade papillary urothelial carcinoma” because they may reflect more accurately the prognosis for these patients. Providing the percentage of HG-PUC would offer clinicians more granular details on the tumors of these patients. This would allow the clinician to assess the risk of progression by considering other clinical, including cystoscopic, parameters when deciding on the therapeutic course of action.

Similarly, borderline tumors with only elevated mitotic figures (BORD-MIT) did not show a significantly different rate in either total progression or invasion compared with LG-PUC (Table 2).

We believe this descriptive terminology, “borderline,” would encourage the treating clinicians to also rely on the history of the patient and other cystoscopic data points when deciding the patient’s therapeutic course.

The strengths of our study include: (1) detailed characterization of histologic parameters that pathologists use routinely to distinguish between LG-PUC and HG-PUC, resulting in 3 different subcategories of borderline PUC, (2) strict patient inclusion criteria with at least 2-year follow-up in absence of recurrence or progression, and (3) separate analysis of recurrence, total progression, and invasion, to provide detailed insight on the behavior of these borderline PUCs.

Study limitations include: (1) low number of cases in each of the borderline subcategories, (2) low number of patients with invasion, and (3) inability to meaningfully analyze data on treatment after initial diagnosis because of the low overall number of patients who received intravesical BCG in LG-PUC and all 3 borderline categories, ranging from 1 to 4 patients in each of these categories.

Many studies have investigated additional potential clinical and ancillary parameters that could help in predicting PUC progression and recurrence. Risk assessment models that were developed included cystoscopic, histopathologic, and clinical data to determine the risk of progression,8,14  and of those, the American Urological Association/Society of Urologic Oncology guidelines are widely used in the United States.

As we learn more about the genetic biology of these tumors, incorporating a panel of biomarkers that could refine further the capability of these risk assessment models to determine the risk of progression could be helpful. A few biomarkers, such as IMP3,15  p53, Ki-67, CK20,16  p27,17  Aurora-A,18  and Annexin-I,19  have shown modest predictive potential. Quantitative real-time–polymerase chain reaction for let-7c cluster has also been proposed as an independent progression predictor.20  However, none of these markers have been adopted in clinical practice. As our knowledge of the molecular mechanisms behind urothelial carcinoma tumorigenesis grows, finding biomarkers that could predict progression and prognosis and are easy to apply in clinical practice would be beneficial.

Approximately a third of PUCs show borderline features that do not neatly fit into LG-PUC or HG-PUC, and the distinction is important because it carries clinical prognostic and therapeutic implications. Our study offers detailed histologic characterization of PUC, with an emphasis on tumors with borderline histologic features between LG-PUC and HG-PUC. PUC that resembles LG-PUC but shows occasional cells with nuclear pleomorphism (BORD-NUP) appears to be associated with higher risk of invasion. PUCs with mixed LG-PUC and less than 50% HG-PUC (BORD-MIXED) do not show a statistically significant worse prognosis compared with LG-PUC. However, the presence of more than 20% HG-PUC in BORD-MIXED shows a trend toward a higher risk of invasion (∼4 times that of LG-PUC). There may be added value in labeling BORD-MIXED as mixed low- and high-grade noninvasive PUC to better reflect the associated prognosis. Additional studies to investigate the potential clinical implications and applications of the mixed terminology are necessary for patients with mixed low- and high-grade papillary urothelial carcinoma. Future studies to reproduce and validate our findings are warranted.

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Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the February 2024 table of contents.

The authors have no relevant financial interest in the products or companies described in this article.

Supplementary data