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Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients
Original Study
Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients Marco Moschini,1,2,3 Shahrokh F. Shariat,3 Roberta Lucianò,4 David D’Andrea,3 Beat Foerster,3 Mohammad Abufaraj,3 Marco Bandini,1 Paolo Dell’Oglio,3 Rocco Damiano,2 Andrea Salonia,1 Francesco Montorsi,1 Alberto Briganti,1 Renzo Colombo,1 Andrea Gallina1 Abstract The importance of a correct histologic variant classification in the decision making of bladder cancer patients have been recently highlighted by the new World Health Organization classification of the urothelial tract. Histologic variants at the time of radical cystectomy is a common finding, accounting for almost 30% of specimens, yet only pure histologic variants but not mixed histologic variants are associated with worse survival compared to pure urothelial cancer. Physicians should consider this parameter when counseling surgical patients. Purpose: To evaluate the impact of pure and mixed histologic variant versus pure urothelial carcinoma in nonmetastatic bladder cancer (BCa) patients treated with radical cystectomy (RC). Patients and Methods: We evaluated data from 1067 patients treated with RC and pelvic lymph node dissection between 1990 and 2013 at a single institution tertiary-care referral center. All specimens were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the impact of the presence of pure and mixed histologic variants versus pure urothelial on recurrence, cancer-specific mortality, and overall mortality after accounting for all available confounders. Results: In total, 201 (19%) and 137 (13%) patients were found with mixed and pure variants at RC, respectively. Mixed preponderant variants were sarcomatoid, lymphoepitelial, squamous, and glandular; small-cell and micropapillary variants were found mostly as pure variants. With a median follow-up of 6.5 years, patients who harbored pure variant were found by multivariable analyses to have lower survival outcomes compared to pure urothelial carcinoma (all P < .01). Conversely, no differences were found between mixed variant versus pure urothelial by multivariable Cox regression analyses predicting recurrence, cancer-specific mortality, and overall mortality (all P > .1). Conclusion: The presence of histologic variants at RC is a common finding, accounting for approximately 30% of specimens. In this setting, the presence of a pure variant but not the presence of mixed variant with urothelial carcinoma is related to a detrimental effect on survival outcomes after RC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Histological variants, Mixed variants, Radical cystectomy, Urothelial carcinoma
Introduction Divergent differentiation in urothelial carcinoma is a common event, accounting for approximately 30% of bladder specimen in radical cystectomy (RC) series.1,2 The importance of a correct histologic variant classification in the decision making of bladder 1 Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, Urological Research Institute, Milan, Italy 2 Department of Urology, Magna Graecia University of Catanzaro, Catanzaro, Italy 3 Department of Urology, Medical University of Vienna, Vienna, Austria 4 Department of Pathology, Ospedale San Raffaele, Milan, Italy
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cancer (BCa) patients has been evaluated by others,3,4 and it was recently highlighted in the 4th edition of the World Health Organization (WHO) classification of the urothelial tract.5 The presence of specific variants can drive the decision for an early RC in nonemuscle-invasive BCa patients6 or can modify the indication Submitted: Oct 13, 2016; Revised: Nov 28, 2016; Accepted: Dec 3, 2016 Address for correspondence: Marco Moschini, MD, Department of Urology, University “Vita-Salute”, San Raffaele Hospital, Via Olgettina, 60-20132 Milan, Italy Fax: 02 26435659; e-mail contact: [email protected]
Clinical Genitourinary Cancer Month 2016
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Pure But Not Mixed Histologic Variants for neoadjuvant chemotherapy before surgery.7-9 Moreover, the presence of specific histologic variants at the time of transurethral resection or RC has been associated with worse survival expectations.1,10,11 However, others have failed to assess this effect on multivariable analyses.2 There is currently a paucity of data regarding characteristics associated with histologic variants. Specifically, no clear data exist regarding whether the presence of a concomitant urothelial pattern with variant histology or the presence of a pure variant alone may differently affect survival outcomes. With this in mind, we analyzed a large single-center series to assess if this parameter could affect survival. This could potentially be an important parameter to be evaluated by uropathologists and thus included in pathologic reports.
because we assumed, in conformity with previous findings, that any component of variant histology would drive outcomes.1 All removed lymph nodes (LNs) were examined for the presence of nodal metastases. LN invasion was invariably defined as 1 or more metastatic LNs. Positive soft tissue surgical margin was defined as the presence of tumor at inked areas of soft tissue on the RC specimen. Clinical and radiologic follow-up consisted of a baseline visit at 3 to 4 months after surgery. Minimum follow-up consisted of at least 2 annual visits. Examinations included radiologic imaging with computed tomography in all patients. In addition to physical examination with laboratory testing, intravenous pyelography, cystoscopy, urine cytology, urethral washings, and bone scan were carried out if indicated by the treating physician.
Statistical Analyses
Patients and Methods Study Population We evaluated data from 1067 patients with nonmetastatic BCa patients with the evaluation of histologic type assessed from dedicated uropathologists. All patients were treated with RC and pelvic lymph node dissection at a single tertiary-care referral center between 1990 and 2013. The procedures were approved by the institutional review board (Vescica/2010), an informed consent was obtained by all patients. Neoadjuvant and adjuvant chemotherapy were provided according to patient characteristics and physician preferences. Patients were evaluated preoperatively with pelvic/ abdominal computed tomography scan or magnetic resonance imaging, bone scan, and chest X-ray. Pathologic stages were classified according to the 2009 tumor, node, metastasis classification.12 Tumor grade was assessed according to 1998 WHO/International Society of Urologic Pathology consensus classification.13 When more than 1 variant histology was assessed by uropathologists, it was included as a mixed variant. Variant histology (defined as plasmacytoid, nested, or adenocarcinoma) was included in the “other” group as a consequence of the rarity of these findings in our series. We did not use a percentage of threshold for variant histology
Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges were reported for continuously coded variables. The Mann-Whitney test and chi-square test were used to compare the statistical significance of differences in medians and proportions, respectively. Kaplan-Meier analysis was used to compare recurrence-free, cancer-specific mortality (CSM)-free, and overall mortality (OM)-free rates after RC, stratified according to the presence of histologic variant. Univariable and multivariable Cox regression analyses tested the impact of the presence of variant histology on recurrence, CSM, and OM after accounting for all available confounders. Statistical significance was considered at P < .05. Statistical analyses were performed by SPSS 22.0 (IBM SPSS, Chicago, IL) and Stata 13 (StataCorp, College Station, TX).
Results Baseline Characteristics Overall, 792 patients (68%) had pure urothelial carcinoma after RC, while 201 (19%) and 137 (13%) had mixed and pure variants, respectively. Figure 1 shows the incidence of pure and mixed variants across different histologic variants. Mixed variants were
Figure 1 Incidence of Mixed and Pure Variants Stratified According to Histologic Variants
2
-
Clinical Genitourinary Cancer Month 2016
Marco Moschini et al preponderant in sarcomatoid, lymphoepitelial, squamous, and glandular variants. Conversely, small-cell and micropapillary variants were found mostly as pure variants. Table 1 lists the clinical characteristics of patients treated with RC stratified according histologic variants. Clinical and demographic characteristics were not found to be different by urothelial variant (all P .2). Table 2 shows the pathologic characteristics of patients treated with RC stratified according to histologic variants. Mixed and pure variants were found to be associated with higher extravesical disease (75.1% and 62.1% vs. 57.7%; P < .001), respectively. Differences were found in LN invasion, positive soft tissue surgical margin, and concomitant carcinoma-in-situ (all P < .03).
Cox Regression Analyses and Survival Estimates Mean (median) follow-up was 6.5 (6.2) years after surgery. During the follow-up period, 343 instances of recurrence, 365 of CSM, and 451 of OM were recorded. Kaplan-Meier analysis assessing recurrence-free (Figure 2A), CSM-free (Figure 2B), and OM-free (Figure 2C) rates stratified according histologic variants were built (mixed variant vs. pure urothelial and pure variant vs. pure urothelial). Patients who harbored pure variants had worse survival outcomes compared to patients with pure urothelial carcinoma (all P < .01). Conversely, no differences were found between pure urothelial versus mixed variants. At multivariable Cox regression
Table 1 Descriptive Characteristics of 1067 Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pathologic Variant Histology
Variable
Pure Urothelial (N [ 729, 68%)
Mixed Variant (N [ 201, 19%)
Pure Variant (N [ 137, 13%)
Age at surgery, y Mean Median (IQR)
67.4 68 (61-75)
66.3 68 (60-74)
Discussion Urothelial carcinoma with divergent differentiation is a common finding at the time of RC.1,2 Recently, the 4th edition of the WHO manual on urothelial carcinoma highlighted the importance of variant histology as an indicator of mutational landscape and subsequently acted as a driver for tailored treatment.14 However, data in the literature are scarce regarding the impact of pure histologic variants, pure urothelial variants, or mixed variants (histologic variants with urothelial component) on survival. Although several authors reported the impact of different subtypes of histologic variants on survival at the time of RC, no one has investigated whether this impact existed only in pure histologic variants or whether the concomitant presence of urothelial carcinoma mitigated or aggravated this effect. Assessing this could be pivotal, as this parameter is not always present in pathologic report,14 and currently no clear data exist regarding its influence on survival outcomes. We made several findings. First, we found that 1 out 3 patients have a histologic variant at the time of RC. Of these, approximately half were found with a mixed variant, while the remaining had a pure variant. Differences were found considering the type of histologic variant and the possibility to incur in a pure or mixed variant. Although to our knowledge no data exist in the literature about the incidence of pure histologic variants or its presence associated with urothelial carcinoma, our data confirmed existing literature considering histologic variants (mixed and pure considered together).2 Xylinas et al2 reported an incidence of 24.6% of histologic variants in a multicenter series analyzing patients treated in
67.1 68 (60-74)
Gender
.7
Male
613 (84.1%)
169 (84.1%)
112 (81.8%)
Female
116 (15.9%)
32 (15.9%)
25 (18.2%)
BMI, kg/m2 Mean
P .4
analyses predicting recurrence, CSM, and OM (Table 3), pure versus urothelial variants were found to be related to worse survival considering recurrence (hazard ratio, 2.04, confidence interval, 1.49-2.81, P < .001), CSM (hazard ratio, 1.48; 95% confidence interval, 1.09-2.00; P ¼ .01), and OM (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85; P ¼ .02). Conversely, the presence of mixed variant was not associated with survival outcomes (all P > .2).
Table 2 Pathologic Characteristics of 1067 Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pathologic Variant Histology
.9 25.8
25.8
25.9
Median (IQR) 25.3 (23.5-27.8) 25.0 (22.8-28.9) 25.8 (23.6-28.6) CCI
.8
Variable
Pure Urothelial (N [ 729, 68%)
Mixed Variant Pure Variant (N [ 201, (N [ 137, 19%) 13%)
310 (42.5%)
78 (38.8%)
64 (46.7%)
1
185 (25.4%)
52 (25.9%)
34 (24.8%)
pT0-T2
308 (42.2%)
50 (24.9%)
52 (38.0%)
2
130 (17.8%)
41 (20.4%)
24 (17.5%)
pT3
272 (37.3%)
101 (50.2%)
56 (40.9%)
pT4
149 (20.4%)
50 (24.9%)
29 (21.2%)
255 (35.0%)
90 (44.8%)
44 (32.1%)
No. of removed lymph nodes Mean Median (IQR) Neoadjuvant CT Adjuvant CT
.2
Lymph node invasion 19 17 (11-24)
21 19 (12-28)
18
Positive STSM
18 (11-25)
18 (2.5%)
5 (2.5%)
6 (4.4%)
.8
Concomitant CIS
107 (14.7%)
33 (16.4%)
19 (13.9%)
.5
LVI
Abbreviations: BMI ¼ body mass index; CCI ¼ Charlson comorbidity index; CT ¼ chemotherapy; IQR ¼ interquartile range.
P <.001
Pathologic stage
0
.02
60 (8.2%)
32 (15.9%)
13 (9.5%)
.006
211 (28.9%)
44 (21.9%)
12 (8.8%)
<.001
193 (26.5%)
57 (28.4%)
29 (21.2%)
.3
Abbreviations: CIS ¼ carcinoma-in-situ; IQR ¼ interquartile range; LVI ¼ lymphovascular invasion; STSM ¼ soft tissue surgical margin.
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Pure But Not Mixed Histologic Variants Figure 2 Kaplan-Meier Analysis of Patients With Nonmetastatic Bladder Cancer. Recurrence-free (A), Cancer-specific Mortalityefree (B), and Overall Mortalityefree (C) Rates in Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pure Urothelial Versus Mixed Variant Versus Pure Variant
referral centers. Our findings are in line with these results. In this regard, the association between the type of institution and the incidence of histologic variant is confirmed by these results, as the diagnosis of histologic variants is reduced in small community practice centers.15 No differences in demographic characteristics were found for patients diagnosed with histologic variants compared to those diagnosed with urothelial carcinoma. However, considering pathologic characteristics, patients diagnosed with mixed variants were found at increased risk of developing LN metastases. These
results need to be confirmed by high-quality data to evaluate the impact of histologic variants on different metastatic patterns. Second, considering survival outcomes after RC, we found that the presence of a pure variant and not the presence of mixed variant was related to a detrimental effect on survival compared to urothelial pure patients outcomes. These results were confirmed by multivariable analyses adjusting for all available confounders. Several authors previously assessed the impact of histologic variants at the time of RC on survival outcomes,1,2 although controversial results
Table 3 Multivariable Cox Regression Analyses Predicting Risk of Recurrence, CSM, and OM in Patients Treated With Radical Cystectomy Multivariable Recurrence Variable Age, y
Multivariable CSM
HR (CI 95%)
P
HR (CI 95%)
1.01 (0.99-1.02)
.3
1.02 (1.01-1.03)
Multivariable OM P .006
HR (CI 95%)
P
1.02 (1.01-1.04)
<.001
Year of surgery
0.98 (0.95-1.00)
.08
0.97 (0.95-0.99)
.004
0.98 (0.96-0.99)
.02
Gender (Ref: female)
1.01 (0.72-1.42)
.9
1.10 (0.80-1.52)
.5
1.12 (0.84-1.49)
.4
0
Ref
Ref
Ref
Ref
Ref
Ref
1
1.48 (1.10-1.99)
.009
1.54 (1.16-2.04)
.003
1.54 (1.19-1.99)
.001
2
1.44 (1.04-2.00)
.03
1.58 (1.16-2.14)
.003
1.81 (1.38-2.37)
<.001
CCI
Mixed variant vs. urothelial
1.21 (0.87-1.68)
.3
0.92 (0.66-1.29)
.6
0.97 (0.72-1.30)
.8
Pure variant vs. urothelial
2.04 (1.49-2.81)
<.001
1.48 (1.09-2.00)
.01
1.40 (1.06-1.85)
.02
Pathologic stage pT0-T2 pT3
-
Ref
Ref
Ref
Ref
Ref
<.001
2.60 (1.92-3.52)
<.001
1.94 (1.50-2.52)
<.001 <.001
2.34 (1.59-3.46)
<.001
3.22 (2.25-4.60)
<.001
2.46 (1.81-3.35)
LVI
1.43 (1.09-1.88)
.009
1.22 (0.94-1.57)
.1
1.25 (1.00-1.58)
.06
Concomitant CIS
1.21 (0.90-1.63)
.2
1.05 (0.77-1.42)
.8
0.87 (0.66-1.15)
.3
pT4
4
Ref 2.18 (1.60-2.99)
PSTSM
1.86 (1.19-2.91)
.006
1.63 (1.09-2.45)
.02
1.61 (1.10-2.34)
.01
No. of positive nodes
1.03 (1.02-1.05)
<.001
1.05 (1.03-1.06)
<.001
1.04 (1.03-1.06)
<.001
No. of removed nodes
0.98 (0.97-0.99)
.007
0.98 (0.97-0.99)
.002
0.98 (0.97-1.00)
.007
Neoadjuvant chemotherapy
1.02 (0.47-2.20)
.9
0.98 (0.45-2.09)
.9
0.85 (0.42-1.73)
.6
Adjuvant chemotherapy
1.52 (1.15-2.00)
.003
0.90 (0.68-1.19)
.5
0.83 (0.64-1.08)
.2
Abbreviations: CCI ¼ Charlson comorbidity index; CI ¼ confidence interval; CIS ¼ carcinoma-in-situ; CSM ¼ cancer-specific mortality; HR ¼ hazard ratio; LVI ¼ lymphovascular invasion; OM ¼ overall mortality; PSTSM ¼ positive soft tissue surgical margin.
Clinical Genitourinary Cancer Month 2016
Marco Moschini et al exist in the literature on this topic. Xylinas et al2 were unable to assess any differences in survival outcomes considering histologic variants in multivariable analyses using a multicenter database composed of 1984 patients treated with RC between 2000 and 2008 at 5 centers. This was in contrast with the findings of Monn et al,1 who found that plasmacytoid and micropapillary differentiations were associated with decreased survival after RC by multivariable analyses. Other types of histologic variants were associated with worse pathologic features compared to urothelial carcinoma at the time of RC,16-20 although when all the parameters were accounted for in a multivariable model, the effect of the presence of histologic variants on survival disappeared. This can be related to the absence of a detailed pathologic description, which should include the concomitant presence of urothelial component and possibly the percentage of histologic variant in the specimen. From a biological point of view, the presence of a histologic variant may represent the phenotype of a different mutational landscape. Therefore, the concomitant presence of several mutational patterns may affect survival.14 The importance of our study in relation to previous reports consists of several aspects. First, our investigation represents the largest single-center available cohort assessing incidence of histologic variants at the time of oncologic outcomes in BCa patients treated with RC. Moreover, all the patients included in our study were treated at a single tertiary-care referral center. Therefore, the nature of our investigation takes advantage of experienced surgeons and dedicated uropathologists. Second, we found that only the presence of the pure histologic variant is related to a detrimental effect on survival, while the presence of mixed variant had no difference. These findings highlight the importance of reporting this parameter when assessing the pathologic specimen. Our findings highlight the necessity of further treatment for patients diagnosed with these adverse pathologic features in order to increase survival. Finally, we observed that year of surgery is a strong predictor of CSM and OM. These findings can be explained by our previous report assessing changes in BCa reported as an effect of stage migration.21 Our study has several limitations. First, our study, a retrospective chart review, was not prospective or randomized, and our findings should be interpreted in this context. However, such retrospective studies are usually the precursor for more extensive prospective investigations. Second, we could not evaluate the percentage of variant histology that was not reported in pathologic specimens. However, no evidence exists about the possible implication of survival prediction of this parameter.5,19 Third, our findings should be evaluated in the context of a high-volume tertiary-care referral center, and the rate of histologic variants in our series could therefore be higher than those in noninstitutional center, where they may be underestimated.15
Conclusion Approximately one third of patients were found to have a variant histology at RC specimen (mixed or pure). Differences in adverse pathologic features were found considering pure urothelial cancer or variants. Pure variants were found to be strongly associated with worse survival outcome by multivariable analyses, while this effect disappeared when considering mixed variants. Uropathologists should assess whether histologic variants are pure or mixed with urothelial carcinoma.
Clinical Practice Points The presence of histologic variants is a common finding after
RC, accounting for approximately 30% of patients. More commonly, it is associated with the concomitant presence
of urothelial carcinoma. At multivariable analysis, only pure histologic variants were
associated with worse survival after RC.
Acknowledgment Supported by a EUSP Scholarship, European Association of Urology (to M.M.).
Disclosure The authors have stated that they have no conflict of interest.
References 1. Monn MF, Kaimakliotis HZ, Pedrosa JA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol 2015; 33:18.e15-20. 2. Xylinas E, Rink M, Robinson BD, et al. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer 2013; 49:1889-97. 3. Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? Urol Oncol 2015; 33:21.e1-9. 4. Rice KR, Koch MO, Kao CS, et al. Lymph node metastases in patients with urothelial carcinoma variants: influence of the specific variant on nodal histology. Urol Oncol 2015; 33:20.e23-9. 5. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours. Eur Urol 2016; 70:106-19. 6. Seisen T, Compérat E, Léon P, Roupret M. Impact of histological variants on the outcomes of nonmuscle invasive bladder cancer after transurethral resection. Curr Opin Urol 2014; 24:524-31. 7. Willis DL, Porten SP, Kamat AM. Should histologic variants alter definitive treatment of bladder cancer? Curr Opin Urol 2013; 23:435-43. 8. Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191:40-7. 9. Moschini M, Soria F, Klatte T, et al. Validation of preoperative risk grouping of the selection of patients most likely to benefit from neoadjuvant chemotherapy before radical cystectomy [e-pub ahead of print]. Clin Genitourin Cancer, 2016 Jul 22, http://dx.doi.org/10.1016/j.clgc.2016.07.014. 10. Willis D, Kamat AM. Nonurothelial bladder cancer and rare variant histologies. Hematol Oncol Clin North Am 2015; 29:237-52, viii. 11. Ismaili N. A rare bladder cancer—small cell carcinoma: review and update. Orphanet J Rare Dis 2011; 6:75. 12. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17:1471-4. 13. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/ International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998; 22:1435-48. 14. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. WHO Classification of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2014. Available at:http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/. 15. Shah RB, Montgomery JS, Montie JE, Kunju LP. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol 2013; 31:1650-5. 16. Kaimakliotis HZ, Monn MF, Cary KC, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urol Oncol 2014; 32:833-8. 17. Fairey AS, Daneshmand S, Wang L, et al. Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy. Urol Oncol 2014; 32:110-6. 18. Monn MF, Kaimakliotis HZ, Cary KC, et al. The changing reality of urothelial bladder cancer: should non-squamous variant histology be managed as a distinct clinical entity? BJU Int 2015; 116:236-40. 19. Kim SP, Frank I, Cheville JC, et al. The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. J Urol 2012; 188:405-9. 20. Izard JP, Siemens DR, Mackillop WJ, et al. Outcomes of squamous histology in bladder cancer: a population-based study. Urol Oncol 2015; 33:425.e7-13. 21. Moschini M, Luzzago S, Cazzaniga W, et al. Effect of stage migration on bladder cancer: a slow but steady improvement in long-term survival rates after radical cystectomy in previous 25 years [e-pub ahead of print]. Clin Genitourin Cancer, 2016 Aug 8, http://dx.doi.org/10.1016/j.clgc.2016.07.024.
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Pure but Not Mixed Histologic Variants Are Associated With Poor Survival at Radical Cystectomy in Bladder Cancer Patients Marco Moschini,1,2,3 Shahrokh F. Shariat,3 Roberta Lucianò,4 David D’Andrea,3 Beat Foerster,3 Mohammad Abufaraj,3 Marco Bandini,1 Paolo Dell’Oglio,3 Rocco Damiano,2 Andrea Salonia,1 Francesco Montorsi,1 Alberto Briganti,1 Renzo Colombo,1 Andrea Gallina1 Abstract The importance of a correct histologic variant classification in the decision making of bladder cancer patients have been recently highlighted by the new World Health Organization classification of the urothelial tract. Histologic variants at the time of radical cystectomy is a common finding, accounting for almost 30% of specimens, yet only pure histologic variants but not mixed histologic variants are associated with worse survival compared to pure urothelial cancer. Physicians should consider this parameter when counseling surgical patients. Purpose: To evaluate the impact of pure and mixed histologic variant versus pure urothelial carcinoma in nonmetastatic bladder cancer (BCa) patients treated with radical cystectomy (RC). Patients and Methods: We evaluated data from 1067 patients treated with RC and pelvic lymph node dissection between 1990 and 2013 at a single institution tertiary-care referral center. All specimens were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the impact of the presence of pure and mixed histologic variants versus pure urothelial on recurrence, cancer-specific mortality, and overall mortality after accounting for all available confounders. Results: In total, 201 (19%) and 137 (13%) patients were found with mixed and pure variants at RC, respectively. Mixed preponderant variants were sarcomatoid, lymphoepitelial, squamous, and glandular; small-cell and micropapillary variants were found mostly as pure variants. With a median follow-up of 6.5 years, patients who harbored pure variant were found by multivariable analyses to have lower survival outcomes compared to pure urothelial carcinoma (all P < .01). Conversely, no differences were found between mixed variant versus pure urothelial by multivariable Cox regression analyses predicting recurrence, cancer-specific mortality, and overall mortality (all P > .1). Conclusion: The presence of histologic variants at RC is a common finding, accounting for approximately 30% of specimens. In this setting, the presence of a pure variant but not the presence of mixed variant with urothelial carcinoma is related to a detrimental effect on survival outcomes after RC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Histological variants, Mixed variants, Radical cystectomy, Urothelial carcinoma
Introduction Divergent differentiation in urothelial carcinoma is a common event, accounting for approximately 30% of bladder specimen in radical cystectomy (RC) series.1,2 The importance of a correct histologic variant classification in the decision making of bladder 1 Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, Urological Research Institute, Milan, Italy 2 Department of Urology, Magna Graecia University of Catanzaro, Catanzaro, Italy 3 Department of Urology, Medical University of Vienna, Vienna, Austria 4 Department of Pathology, Ospedale San Raffaele, Milan, Italy
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.12.006
cancer (BCa) patients has been evaluated by others,3,4 and it was recently highlighted in the 4th edition of the World Health Organization (WHO) classification of the urothelial tract.5 The presence of specific variants can drive the decision for an early RC in nonemuscle-invasive BCa patients6 or can modify the indication Submitted: Oct 13, 2016; Revised: Nov 28, 2016; Accepted: Dec 3, 2016 Address for correspondence: Marco Moschini, MD, Department of Urology, University “Vita-Salute”, San Raffaele Hospital, Via Olgettina, 60-20132 Milan, Italy Fax: 02 26435659; e-mail contact: [email protected]
Clinical Genitourinary Cancer Month 2016
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Pure But Not Mixed Histologic Variants for neoadjuvant chemotherapy before surgery.7-9 Moreover, the presence of specific histologic variants at the time of transurethral resection or RC has been associated with worse survival expectations.1,10,11 However, others have failed to assess this effect on multivariable analyses.2 There is currently a paucity of data regarding characteristics associated with histologic variants. Specifically, no clear data exist regarding whether the presence of a concomitant urothelial pattern with variant histology or the presence of a pure variant alone may differently affect survival outcomes. With this in mind, we analyzed a large single-center series to assess if this parameter could affect survival. This could potentially be an important parameter to be evaluated by uropathologists and thus included in pathologic reports.
because we assumed, in conformity with previous findings, that any component of variant histology would drive outcomes.1 All removed lymph nodes (LNs) were examined for the presence of nodal metastases. LN invasion was invariably defined as 1 or more metastatic LNs. Positive soft tissue surgical margin was defined as the presence of tumor at inked areas of soft tissue on the RC specimen. Clinical and radiologic follow-up consisted of a baseline visit at 3 to 4 months after surgery. Minimum follow-up consisted of at least 2 annual visits. Examinations included radiologic imaging with computed tomography in all patients. In addition to physical examination with laboratory testing, intravenous pyelography, cystoscopy, urine cytology, urethral washings, and bone scan were carried out if indicated by the treating physician.
Statistical Analyses
Patients and Methods Study Population We evaluated data from 1067 patients with nonmetastatic BCa patients with the evaluation of histologic type assessed from dedicated uropathologists. All patients were treated with RC and pelvic lymph node dissection at a single tertiary-care referral center between 1990 and 2013. The procedures were approved by the institutional review board (Vescica/2010), an informed consent was obtained by all patients. Neoadjuvant and adjuvant chemotherapy were provided according to patient characteristics and physician preferences. Patients were evaluated preoperatively with pelvic/ abdominal computed tomography scan or magnetic resonance imaging, bone scan, and chest X-ray. Pathologic stages were classified according to the 2009 tumor, node, metastasis classification.12 Tumor grade was assessed according to 1998 WHO/International Society of Urologic Pathology consensus classification.13 When more than 1 variant histology was assessed by uropathologists, it was included as a mixed variant. Variant histology (defined as plasmacytoid, nested, or adenocarcinoma) was included in the “other” group as a consequence of the rarity of these findings in our series. We did not use a percentage of threshold for variant histology
Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges were reported for continuously coded variables. The Mann-Whitney test and chi-square test were used to compare the statistical significance of differences in medians and proportions, respectively. Kaplan-Meier analysis was used to compare recurrence-free, cancer-specific mortality (CSM)-free, and overall mortality (OM)-free rates after RC, stratified according to the presence of histologic variant. Univariable and multivariable Cox regression analyses tested the impact of the presence of variant histology on recurrence, CSM, and OM after accounting for all available confounders. Statistical significance was considered at P < .05. Statistical analyses were performed by SPSS 22.0 (IBM SPSS, Chicago, IL) and Stata 13 (StataCorp, College Station, TX).
Results Baseline Characteristics Overall, 792 patients (68%) had pure urothelial carcinoma after RC, while 201 (19%) and 137 (13%) had mixed and pure variants, respectively. Figure 1 shows the incidence of pure and mixed variants across different histologic variants. Mixed variants were
Figure 1 Incidence of Mixed and Pure Variants Stratified According to Histologic Variants
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Clinical Genitourinary Cancer Month 2016
Marco Moschini et al preponderant in sarcomatoid, lymphoepitelial, squamous, and glandular variants. Conversely, small-cell and micropapillary variants were found mostly as pure variants. Table 1 lists the clinical characteristics of patients treated with RC stratified according histologic variants. Clinical and demographic characteristics were not found to be different by urothelial variant (all P .2). Table 2 shows the pathologic characteristics of patients treated with RC stratified according to histologic variants. Mixed and pure variants were found to be associated with higher extravesical disease (75.1% and 62.1% vs. 57.7%; P < .001), respectively. Differences were found in LN invasion, positive soft tissue surgical margin, and concomitant carcinoma-in-situ (all P < .03).
Cox Regression Analyses and Survival Estimates Mean (median) follow-up was 6.5 (6.2) years after surgery. During the follow-up period, 343 instances of recurrence, 365 of CSM, and 451 of OM were recorded. Kaplan-Meier analysis assessing recurrence-free (Figure 2A), CSM-free (Figure 2B), and OM-free (Figure 2C) rates stratified according histologic variants were built (mixed variant vs. pure urothelial and pure variant vs. pure urothelial). Patients who harbored pure variants had worse survival outcomes compared to patients with pure urothelial carcinoma (all P < .01). Conversely, no differences were found between pure urothelial versus mixed variants. At multivariable Cox regression
Table 1 Descriptive Characteristics of 1067 Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pathologic Variant Histology
Variable
Pure Urothelial (N [ 729, 68%)
Mixed Variant (N [ 201, 19%)
Pure Variant (N [ 137, 13%)
Age at surgery, y Mean Median (IQR)
67.4 68 (61-75)
66.3 68 (60-74)
Discussion Urothelial carcinoma with divergent differentiation is a common finding at the time of RC.1,2 Recently, the 4th edition of the WHO manual on urothelial carcinoma highlighted the importance of variant histology as an indicator of mutational landscape and subsequently acted as a driver for tailored treatment.14 However, data in the literature are scarce regarding the impact of pure histologic variants, pure urothelial variants, or mixed variants (histologic variants with urothelial component) on survival. Although several authors reported the impact of different subtypes of histologic variants on survival at the time of RC, no one has investigated whether this impact existed only in pure histologic variants or whether the concomitant presence of urothelial carcinoma mitigated or aggravated this effect. Assessing this could be pivotal, as this parameter is not always present in pathologic report,14 and currently no clear data exist regarding its influence on survival outcomes. We made several findings. First, we found that 1 out 3 patients have a histologic variant at the time of RC. Of these, approximately half were found with a mixed variant, while the remaining had a pure variant. Differences were found considering the type of histologic variant and the possibility to incur in a pure or mixed variant. Although to our knowledge no data exist in the literature about the incidence of pure histologic variants or its presence associated with urothelial carcinoma, our data confirmed existing literature considering histologic variants (mixed and pure considered together).2 Xylinas et al2 reported an incidence of 24.6% of histologic variants in a multicenter series analyzing patients treated in
67.1 68 (60-74)
Gender
.7
Male
613 (84.1%)
169 (84.1%)
112 (81.8%)
Female
116 (15.9%)
32 (15.9%)
25 (18.2%)
BMI, kg/m2 Mean
P .4
analyses predicting recurrence, CSM, and OM (Table 3), pure versus urothelial variants were found to be related to worse survival considering recurrence (hazard ratio, 2.04, confidence interval, 1.49-2.81, P < .001), CSM (hazard ratio, 1.48; 95% confidence interval, 1.09-2.00; P ¼ .01), and OM (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85; P ¼ .02). Conversely, the presence of mixed variant was not associated with survival outcomes (all P > .2).
Table 2 Pathologic Characteristics of 1067 Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pathologic Variant Histology
.9 25.8
25.8
25.9
Median (IQR) 25.3 (23.5-27.8) 25.0 (22.8-28.9) 25.8 (23.6-28.6) CCI
.8
Variable
Pure Urothelial (N [ 729, 68%)
Mixed Variant Pure Variant (N [ 201, (N [ 137, 19%) 13%)
310 (42.5%)
78 (38.8%)
64 (46.7%)
1
185 (25.4%)
52 (25.9%)
34 (24.8%)
pT0-T2
308 (42.2%)
50 (24.9%)
52 (38.0%)
2
130 (17.8%)
41 (20.4%)
24 (17.5%)
pT3
272 (37.3%)
101 (50.2%)
56 (40.9%)
pT4
149 (20.4%)
50 (24.9%)
29 (21.2%)
255 (35.0%)
90 (44.8%)
44 (32.1%)
No. of removed lymph nodes Mean Median (IQR) Neoadjuvant CT Adjuvant CT
.2
Lymph node invasion 19 17 (11-24)
21 19 (12-28)
18
Positive STSM
18 (11-25)
18 (2.5%)
5 (2.5%)
6 (4.4%)
.8
Concomitant CIS
107 (14.7%)
33 (16.4%)
19 (13.9%)
.5
LVI
Abbreviations: BMI ¼ body mass index; CCI ¼ Charlson comorbidity index; CT ¼ chemotherapy; IQR ¼ interquartile range.
P <.001
Pathologic stage
0
.02
60 (8.2%)
32 (15.9%)
13 (9.5%)
.006
211 (28.9%)
44 (21.9%)
12 (8.8%)
<.001
193 (26.5%)
57 (28.4%)
29 (21.2%)
.3
Abbreviations: CIS ¼ carcinoma-in-situ; IQR ¼ interquartile range; LVI ¼ lymphovascular invasion; STSM ¼ soft tissue surgical margin.
Clinical Genitourinary Cancer Month 2016
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Pure But Not Mixed Histologic Variants Figure 2 Kaplan-Meier Analysis of Patients With Nonmetastatic Bladder Cancer. Recurrence-free (A), Cancer-specific Mortalityefree (B), and Overall Mortalityefree (C) Rates in Patients With Nonmetastatic Bladder Cancer Treated With Radical Cystectomy Stratified According to Pure Urothelial Versus Mixed Variant Versus Pure Variant
referral centers. Our findings are in line with these results. In this regard, the association between the type of institution and the incidence of histologic variant is confirmed by these results, as the diagnosis of histologic variants is reduced in small community practice centers.15 No differences in demographic characteristics were found for patients diagnosed with histologic variants compared to those diagnosed with urothelial carcinoma. However, considering pathologic characteristics, patients diagnosed with mixed variants were found at increased risk of developing LN metastases. These
results need to be confirmed by high-quality data to evaluate the impact of histologic variants on different metastatic patterns. Second, considering survival outcomes after RC, we found that the presence of a pure variant and not the presence of mixed variant was related to a detrimental effect on survival compared to urothelial pure patients outcomes. These results were confirmed by multivariable analyses adjusting for all available confounders. Several authors previously assessed the impact of histologic variants at the time of RC on survival outcomes,1,2 although controversial results
Table 3 Multivariable Cox Regression Analyses Predicting Risk of Recurrence, CSM, and OM in Patients Treated With Radical Cystectomy Multivariable Recurrence Variable Age, y
Multivariable CSM
HR (CI 95%)
P
HR (CI 95%)
1.01 (0.99-1.02)
.3
1.02 (1.01-1.03)
Multivariable OM P .006
HR (CI 95%)
P
1.02 (1.01-1.04)
<.001
Year of surgery
0.98 (0.95-1.00)
.08
0.97 (0.95-0.99)
.004
0.98 (0.96-0.99)
.02
Gender (Ref: female)
1.01 (0.72-1.42)
.9
1.10 (0.80-1.52)
.5
1.12 (0.84-1.49)
.4
0
Ref
Ref
Ref
Ref
Ref
Ref
1
1.48 (1.10-1.99)
.009
1.54 (1.16-2.04)
.003
1.54 (1.19-1.99)
.001
2
1.44 (1.04-2.00)
.03
1.58 (1.16-2.14)
.003
1.81 (1.38-2.37)
<.001
CCI
Mixed variant vs. urothelial
1.21 (0.87-1.68)
.3
0.92 (0.66-1.29)
.6
0.97 (0.72-1.30)
.8
Pure variant vs. urothelial
2.04 (1.49-2.81)
<.001
1.48 (1.09-2.00)
.01
1.40 (1.06-1.85)
.02
Pathologic stage pT0-T2 pT3
-
Ref
Ref
Ref
Ref
Ref
<.001
2.60 (1.92-3.52)
<.001
1.94 (1.50-2.52)
<.001 <.001
2.34 (1.59-3.46)
<.001
3.22 (2.25-4.60)
<.001
2.46 (1.81-3.35)
LVI
1.43 (1.09-1.88)
.009
1.22 (0.94-1.57)
.1
1.25 (1.00-1.58)
.06
Concomitant CIS
1.21 (0.90-1.63)
.2
1.05 (0.77-1.42)
.8
0.87 (0.66-1.15)
.3
pT4
4
Ref 2.18 (1.60-2.99)
PSTSM
1.86 (1.19-2.91)
.006
1.63 (1.09-2.45)
.02
1.61 (1.10-2.34)
.01
No. of positive nodes
1.03 (1.02-1.05)
<.001
1.05 (1.03-1.06)
<.001
1.04 (1.03-1.06)
<.001
No. of removed nodes
0.98 (0.97-0.99)
.007
0.98 (0.97-0.99)
.002
0.98 (0.97-1.00)
.007
Neoadjuvant chemotherapy
1.02 (0.47-2.20)
.9
0.98 (0.45-2.09)
.9
0.85 (0.42-1.73)
.6
Adjuvant chemotherapy
1.52 (1.15-2.00)
.003
0.90 (0.68-1.19)
.5
0.83 (0.64-1.08)
.2
Abbreviations: CCI ¼ Charlson comorbidity index; CI ¼ confidence interval; CIS ¼ carcinoma-in-situ; CSM ¼ cancer-specific mortality; HR ¼ hazard ratio; LVI ¼ lymphovascular invasion; OM ¼ overall mortality; PSTSM ¼ positive soft tissue surgical margin.
Clinical Genitourinary Cancer Month 2016
Marco Moschini et al exist in the literature on this topic. Xylinas et al2 were unable to assess any differences in survival outcomes considering histologic variants in multivariable analyses using a multicenter database composed of 1984 patients treated with RC between 2000 and 2008 at 5 centers. This was in contrast with the findings of Monn et al,1 who found that plasmacytoid and micropapillary differentiations were associated with decreased survival after RC by multivariable analyses. Other types of histologic variants were associated with worse pathologic features compared to urothelial carcinoma at the time of RC,16-20 although when all the parameters were accounted for in a multivariable model, the effect of the presence of histologic variants on survival disappeared. This can be related to the absence of a detailed pathologic description, which should include the concomitant presence of urothelial component and possibly the percentage of histologic variant in the specimen. From a biological point of view, the presence of a histologic variant may represent the phenotype of a different mutational landscape. Therefore, the concomitant presence of several mutational patterns may affect survival.14 The importance of our study in relation to previous reports consists of several aspects. First, our investigation represents the largest single-center available cohort assessing incidence of histologic variants at the time of oncologic outcomes in BCa patients treated with RC. Moreover, all the patients included in our study were treated at a single tertiary-care referral center. Therefore, the nature of our investigation takes advantage of experienced surgeons and dedicated uropathologists. Second, we found that only the presence of the pure histologic variant is related to a detrimental effect on survival, while the presence of mixed variant had no difference. These findings highlight the importance of reporting this parameter when assessing the pathologic specimen. Our findings highlight the necessity of further treatment for patients diagnosed with these adverse pathologic features in order to increase survival. Finally, we observed that year of surgery is a strong predictor of CSM and OM. These findings can be explained by our previous report assessing changes in BCa reported as an effect of stage migration.21 Our study has several limitations. First, our study, a retrospective chart review, was not prospective or randomized, and our findings should be interpreted in this context. However, such retrospective studies are usually the precursor for more extensive prospective investigations. Second, we could not evaluate the percentage of variant histology that was not reported in pathologic specimens. However, no evidence exists about the possible implication of survival prediction of this parameter.5,19 Third, our findings should be evaluated in the context of a high-volume tertiary-care referral center, and the rate of histologic variants in our series could therefore be higher than those in noninstitutional center, where they may be underestimated.15
Conclusion Approximately one third of patients were found to have a variant histology at RC specimen (mixed or pure). Differences in adverse pathologic features were found considering pure urothelial cancer or variants. Pure variants were found to be strongly associated with worse survival outcome by multivariable analyses, while this effect disappeared when considering mixed variants. Uropathologists should assess whether histologic variants are pure or mixed with urothelial carcinoma.
Clinical Practice Points The presence of histologic variants is a common finding after
RC, accounting for approximately 30% of patients. More commonly, it is associated with the concomitant presence
of urothelial carcinoma. At multivariable analysis, only pure histologic variants were
associated with worse survival after RC.
Acknowledgment Supported by a EUSP Scholarship, European Association of Urology (to M.M.).
Disclosure The authors have stated that they have no conflict of interest.
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