A Review of Outcomes for Stage Ta Bladder Tumors

AJCP /ORIGINAL ARTICLE A Review of Outcomes for Stage Ta Bladder Tumors Robin T. Vollmer, MD From the VA and Duke University Medical Centers, Durham, NC. Key Words: Urothelial tumors; Tumor grade; Outcomes; Evidence based; Survival times Am J Clin Pathol August 2016;146:215-220 DOI: 10.1093/AJCP/AQW103 ABSTRACT Objectives: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with stage Ta bladder tumors. Methods: Data were collected from 19 longitudinal studies of outcomes after the first diagnosis of tumor and collected as individual patient results, that is, as failure times from the first tumor to any of the three outcomes. Altogether, there were 14,252 patients, including 4,050 for the outcome of tumor recurrence, 2,937 for the outcome of tumor progression, and 11,595 for the outcome of disease-specific survival (some patients were available for more than one outcome). Results: In these data, the mean time to additional tumors was 7.8 years, the mean time to an invasive tumor was 19.5 years, and the mean tumor-specific survival time was 27.2 years. All three outcomes were significantly related to the 2004 World Health Organization (WHO) tumor grades. Conclusions: Although greater than 50% of those with stage Ta bladder tumors have additional bladder tumors, approximately 80% appear to follow a benign course without developing invasive tumors or dying of bladder cancer. The 2004 WHO grading scheme accounts for some but not all of the prognostic information. There has been continuing controversy about the nomenclature of noninvasive bladder tumors. Several studies have opined that some noninvasive bladder tumors may be considered benign. For example, in 1987, Jordan et al 1 wrote that the low grade lesions (usually designated transitional cell carcinoma, Grade I) are benign and should be called papillomas rather than carcinomas, a notion that was not popular. 2 Jordan et al 1 also wrote that the confusion of the risk of carcinoma with the presence of carcinoma seems to be a mind-set peculiar to the discussion of urothelial neoplasms, and in 1999, Murphy 3 wrote, Considering the accumulating evidence, the seeming reluctance of many to conclude that these low grade, noninvasive, papillary urothelial tumors are not themselves malignant is hard to fathom. In 2002, Bostwick and Mikuz 4 explained that the chief motivation for a new classification was to avoid use of the cancer for neoplasms with a low likelihood of invasion, recurrence and death. Consequently, the category of papillary urothelial neoplasm of low malignant potential in the 2004 World Health Organization (WHO) classification has become a popular way to address the issue. 5,6 Here, I review and analyze data from several previously published longitudinal studies to examine the outcomes of tumor-free survival time, time to progressive (ie, invasive) tumor, and time to tumor-specific death for stage Ta bladder tumors as well as to see how these outcomes relate to the 2004 WHO grading scheme. Materials and Methods The data for this study come from 19 previously published longitudinal studies of stage Ta bladder tumors. 7-25 Studies or subsets of patients with either urothelial papilloma American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 215 Am J Clin Pathol 2016;146:215-220 215 DOI: 10.1093/ajcp/aqw103

Vollmer /OUTCOMES FOR STAGE TA BLADDER TUMORS or urothelial carcinoma in situ were excluded, and many studies were excluded because they provided results for the combination of stage Ta and T1 tumors rather than for stage Ta alone. Studies were included only if they documented outcomes after the first episode of tumor and only if all tumors were completely removed. Data on tumor grade were included only if the 2004 WHO grading scheme was used: papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) urothelial carcinomas, and highgrade (HG) urothelial carcinomas. The outcomes studied comprised the occurrence of additional tumors (tumor-free survival), progression to invasive tumor, and disease-specific survival. Outcomes were collected as failure times for specific patients. Two of the studies provided specific patient results. Others provided survival curves that were digitized and then used to estimate individual outcomes. For example, if the survival probability at time t is symbolized as S(t) and the survival probability after an interval of Dt is symbolized as S(t þ Dt), then the number of patients who failed (nf) in the time interval Dt can be estimated as nf ¼ na fst ðþ Stþ ð DtÞg (1) Here, na symbolizes the number of patients available at time t, and na was estimated using an exponential model as follows: na ¼ no expð b tþ (2) where no symbolizes the number of patients at the beginning of a study when t ¼ 0. The model of equation 2 was chosen because it closely fit reported numbers of patients available in five previously reported studies 15,18,22,23,26 involving collectively 4,238 patients with Ta stage bladder tumors. Figure 1 summarizes this fit by plotting the observed number of patients available at times of follow-up on the x-axis vs the number predicted by equation 2 on the y-axis. The straight line shows where points of perfect agreement should occur. Finally, the number of censored patients, nc, in the time interval Dt was estimated as follows: nc ¼ ðno RnfÞfexp ð b tþ expð b ½t þ DtŠÞg (3) Here, Rnf symbolizes the sum of patients who failed. For five of the studies, values of b were chosen to fit the tabulated data on numbers of patients followed, as demonstrated in Figure 1. For 11 studies, b was derived from either the median or mean of follow-up times for the study, because equation 2 implies that and b ¼ log ð:5þ=median time of follow-up (4) b ¼ 1=mean time of follow-up (5) No. of Patients Expected 2,000 1,500 1,000 500 0 For the final four studies, the value of b was imputed as the inverse of the mean of follow-up times for the studies that provided mean follow-up times. The above approach was used to derive individual patient failure times for each outcome. The primary goal was to obtain graphical comparisons as well as mean failure times for outcomes, although a secondary goal was to study the influence of the 2004 WHO grading scheme on outcomes. Altogether, the studies contributed 14,439 individual patients (see Table 1 for a summary). 7-25 Because the data were in the public domain and de-identified, neither ethics approval nor informed consent was necessary or obtained. Results 0 500 1,000 1,500 2,000 No. of Observed Patients Available Figure 1 Plot of the observed number of patients available at times of follow-up on the x-axis vs the number predicted by equation 2 on the y-axis. The straight line shows where points of perfect agreement should occur. Recurrence-Free Survival Figure 2 shows a Kaplan-Meier plot of the probability of being tumor free vs years of follow-up for all the patients, regardless of their tumor grade. For this analysis, there were 4,050 patients. Figure 3 shows Kaplan-Meier plots of the probability of being tumor free vs years of follow-up stratified according to the 2004 WHO grades. Further details are provided in Table 2, which includes the long-term estimate of the percentage of patients who failed (symbolized as FR). For example, overall 56% of patients had additional tumors during follow-up. In general, grade significantly affected tumor-free recurrence times (P 0by log-rank test); however, in the subset of patients with either LG or HG tumors, there was no significant difference in tumor-free survival times (P >.1 by log-rank test), and the percentage who failed for these two grades was nearly the same. 216 Am J Clin Pathol 2016;146:215-220 American Society for Clinical Pathology 216 DOI: 10.1093/ajcp/aqw103

AJCP /ORIGINAL ARTICLE Table 1 Summary of Studies and Numbers of Patients First Author No. of Patients LMP, No. LG, No. HG, No. Anderstrom 7 77 Lutzeyer 8 185 Heney 9 314 Malmstrom 10 94 Parmar 11 254 Witjes 12 254 Fleshner 13 9,786 Chen 14 140 Leblanc 15 152 152 Cheng 16 112 112 Millan-Rodriguez 17 546 Oosterhuis 18 139 Herr 19 148 Pich 20 62 62 Holmang 21 363 95 160 108 Mariappan 22 515 515 Pan 23 1,006 212 603 191 Cao 24 187 51 8 De Nunzio 25 105 105 HG, high-grade tumors; LG, low-grade tumors; LMP, low malignant potential;, no patients with that grade were available or another grading scheme was used. Table 2 Tumor-Free Survival Times for Stage Ta Bladder Tumors 2004 WHO Grade No. of Patients Median, y Mean, y FR, % All grades a 4,050 7.5 7.8 56 LMP 419 NA 11.6 28 LG 1,648 7.5 7.6 54 HG 307 7.7 6.2 53 FR, expected long-term failure rate (ie, the percentage of patients expected to develop additional bladder tumors); HG, high-grade tumors; LG, low-grade tumors; LMP, low malignant potential; NA, time for median tumor-free survival was not reached; WHO, World Health Organization. a All grades indicates that either the 2004 WHO grading scheme was not used or that the tumor grades were not given. Progression-Free Survival Figure 4 shows a Kaplan-Meier plot of the probability of being free of invasive tumor vs years of follow-up for all patients, regardless of their tumor grade. For this analysis, there were 2,937 patients. Figure 5 shows Kaplan-Meier plots of the probability of being free of invasive tumor vs years of follow-up stratified according to the 2004 WHO grades. Further details are provided in Table 3, which includes the long-term estimate of the percentage of patients who failed (symbolized as FR). For example, overall 21% of patients had invasive tumors during follow-up. Grade significantly affected progression to invasive tumor (P 0 by log-rank test), and the percentage who eventually progressed steadily increased with tumor grade. Tumor-Specific Survival Figure 6 shows a Kaplan-Meier plot of the probability of tumor-specific survival vs years of follow-up for all the Tumor-Free Survival 0 2 4 6 8 10 12 14 Figure 2 A Kaplan-Meier plot of the probability of being tumor free vs years of follow-up for all patients, regardless of their tumor grade. For this analysis, there were 4,050 patients. Tumor-Free Survival HG LG LMP 0 2 4 6 8 10 12 14 Figure 3 Kaplan-Meier plots of the probability of being tumor free vs years of follow-up stratified according to the 2004 World Health Organization grades. HG, high grade; LG, low grade; LMP, papillary tumors of low malignant potential. patients, regardless of their tumor grade. For this analysis, there were 11,595 patients. Figure 7 shows Kaplan-Meier plots of the probability of tumor-specific survival vs years of follow-up stratified according to the 2004 WHO grades. Further details are provided in Table 4, which includes the long-term estimate of the percentage of patients who failed (symbolized as FR). For example, overall 18% of patients died of bladder cancer. Grade significantly affected tumor specific survival (P ¼ 3 10 1 by log-rank test), and those with HG had the highest rate of failure. Nevertheless, there was not a significant difference in tumor-specific survival between LMP and LG tumors (P >.09 by log-rank test). American Society for Clinical Pathology Am J Clin Pathol 2016;146:215-220 217 217 DOI: 10.1093/ajcp/aqw103

Vollmer /OUTCOMES FOR STAGE TA BLADDER TUMORS LMP Progression-Free Survival Progression-Free Survival HG LG 0 5 10 15 20 Figure 4 A Kaplan-Meier plot of the probability of being free of invasive tumor vs years of follow-up for all the patients, regardless of their tumor grade. For this analysis, there were 2,937 patients. 0 5 10 15 20 25 30 Figure 6 A Kaplan-Meier plot of the probability of tumorspecific survival vs years of follow-up for all the patients, regardless of their tumor grade. For this analysis, there were 11,595 patients. Table 3 Progression-Free Survival Times for Stage Ta Bladder Tumors 2004 WHO Grade No. of Patients Median, y Mean, y FR, % All grades a 2,937 NA 19.5 21 LMP 419 NA 22.1 7 LG 966 NA 12.8 10 HG 307 NA 9.3 28 FR, expected long-term failure rate (ie, the percentage of patients expected to develop invasive tumors); HG, high-grade tumors; LG, low-grade tumors; LMP, low malignant potential; NA, time for median tumor-free survival was not reached; WHO, World Health Organization. a All grades indicates that either the 2004 WHO grading scheme was not used or that the tumor grades were not given. 0 5 10 15 20 Figure 5 Kaplan-Meier plots of the probability of being free of invasive tumor vs years of follow-up stratified according to the 2004 World Health Organization grades. HG, high grade; LG, low grade; LMP, papillary tumors of low malignant potential. HG LG LMP 0 5 10 15 20 25 30 Figure 7 Kaplan-Meier plots of the probability of tumorspecific survival vs years of follow-up stratified according to the 2004 World Health Organization grades. HG, high grade; LG, low grade; LMP, papillary tumors of low malignant potential. Table 4 Tumor-Specific Survival Times for Stage Ta Bladder Tumors 2004 WHO Grade No. of Patients Median, y Mean, y FR, % All grades a 11,595 NA 27.2 18 LMP 324 NA 3 7 LG 654 NA 13.6 2 HG 199 NA 1 13 FR, expected long-term failure rate (ie, the percentage of patients expected to die of bladder cancer); HG, high-grade tumors; LG, low-grade tumors; LMP, low malignant potential; NA, time for median tumor-free survival was not reached; WHO, World Health Organization. a All grades indicates that either the 2004 WHO grading scheme was not used or that the tumor grades were not given. 218 Am J Clin Pathol 2016;146:215-220 American Society for Clinical Pathology 218 DOI: 10.1093/ajcp/aqw103

AJCP /ORIGINAL ARTICLE Discussion This study uses the data from 19 prior longitudinal studies of stage Ta bladder tumors to analyze more than 14,000 patients and their outcomes. It demonstrates that greater than 50% of those with stage Ta bladder tumors have additional bladder tumors. Despite these additional tumors, approximately 80% of these patients follow a benign course without developing invasive tumors or dying of bladder cancer. This result suggests that the LMP group is not large enough to account for all the benign-behaving bladder tumors, because in six previous studies involving collectively 2,271 patients, LMP tumors composed no more than 25% (weighted mean). 21,23,27-30 Thus, the results suggest that many patients who initially have LG tumors, and perhaps some who initially have HG tumors, follow a benign course. Regarding the effects of the 2004 WHO grading scheme, the results are limited, because only a few of the 19 studies with follow-up provided the 2004 grade information. Nevertheless, the results suggest that patients with LMP tumors have on average the longest times to additional tumors, the longest times to progression, and the longest times to disease-specific death. By contrast, those with HG tumors on average experience the shortest times to additional tumors, progression, or disease-specific death. Times to outcomes for those with LG tumors vary from matching those with HG tumors, to having failure times intermediate between LMP and HG tumors, to matching those with LMP tumors. The noise in the grade effects on outcomes may be due in part to the magnitude of time lapse from the first tumor to the outcomes. For these patients, the grade of the first tumor may have less impact on their status years later. In addition, the noise in grade effects could be partly due to variance between pathologists in their use of the 2004 grading scheme. For example, in the six studies mentioned above, 21,23,27-30 the prevalence of LMP tumors ranged from 14% to 38% (P 0 by test for equality of proportions). To me, as well as to one reviewer of this article, these rates of LMP seem unusually high. The prevalence of LG tumors ranged from 44% to 63% (P 0), and the prevalence of HG tumors ranged from 16% to 30% (P 0). Such significant differences between institutions suggest that pathologists may be grading these tumors differently or that the histologic distinction between some of the grades is too subtle to reproducibly accomplish. Additional studies using the new grading scheme and patients with longer follow-up will be needed to more thoroughly examine the effects of the 2004 WHO grading scheme. Corresponding author: Robin T. 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