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Caveolin-1 Expression in Upper Tract Urothelial Carcinoma
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Urothelial Cancer
Caveolin-1 Expression in Upper Tract Urothelial Carcinoma David D’Andrea a, Marco Moschini a,b, Beat Foerster a,c, Mohammad Abufaraj a, Vitaly Margulis d, Jose Karam e, Yair Lotan d, Jay Raman f, Romain Mathieu g, Morgan Roupreˆt h, Pierre I. Karakiewicz i, Alberto Briganti b, Andrea Haitel j, Sharhrokh F. Shariat a,d,k,* a
Department of Urology, Medical University of Vienna, Vienna, Austria;
b
Urological Research Institute, San Raffaele Scientific Institute, Vita-Salute San
Raffaele University, Milan, Italy; c Department of Urology, Kantonsspital Winterthur, Winterthur, Switzerland; d Department of Urology, University of Texas Southwestern, Dallas, TX, USA; e Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; f Division of Urology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA; g Department of Urology, Rennes University Hospital, Rennes, France; h Department of Urology, Pitié-Salpétrière Hospital, APHP, University Paris VI, Paris, France; i Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada; j Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; k Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
Article info
Abstract
Article history: Accepted June 13, 2017
Background: Improvement in postoperative risk stratification of upper tract urothelial carcinoma (UTUC) is required to better predict outcomes and counsel patients on adjuvant treatment. Objective: To validate the association between caveolin-1 and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for UTUC. Design, setting, and participants: Caveolin-1 expression was evaluated via immunochemistry on a tissue microarray from 621 patients. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positive. The median follow-up in this retrospective study was 35 mo (interquartile range 16–65). Intervention: Radical nephroureterectomy. Outcome measurements and statistical analysis: Univariate and multivariable Cox proportional hazards regression models were used to assess the association between caveolin-1 expression and recurrence and cancer-specific mortality (CSM). Results and limitations: Caveolin-1 was overexpressed in 150 patients (24%). Overexpression was associated with higher pathological stage (p < 0.001) and grade (p < 0.001). In univariate analyses, overexpression of caveolin-1 was significantly associated with lower recurrence (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2–2.6; p = 0.004) and CSM (HR 1.8, 95% CI 1.2–2.7; p = 0.005); however, multivariable analyses did not prove its independent association with outcomes. The study is limited by its retrospective nature. Conclusions: Despite overexpression in a quarter of UTUC patients, caveolin-1 was not independently associated with oncological outcomes. Its use could be evaluated to improve clinical staging of biopsy specimens and to help in clinical decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Patient summary: Development of a panel of prognostic and predictive markers is mandatory for patient consultations in the era of personalized medicine. We evaluated the role of caveolin-1 in a large series of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) and found that it was not independently associated with oncological outcomes. Nevertheless, it was associated with adverse pathological features. Considering caveolin-1 in UTUC biopsy specimens could help in improving clinical staging and decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Caveolin-1 Biomarker Nephroureterectomy Outcome Upper tract urothelial carcinoma
* Corresponding author. Department of Urology, Comprehensive Cancer Center, Medical University Vienna, General Hospital, Währinger Gürtel 18–20, A 1090 Vienna, Austria. Tel: +43 1 4040026150; Fax: +43 1 4040023320. E-mail address: [email protected] (S.F. Shariat). http://dx.doi.org/10.1016/j.euf.2017.06.011 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: D’Andrea D, et al. Caveolin-1 Expression in Upper Tract Urothelial Carcinoma. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.06.011
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1.
Introduction
Upper tract urothelial carcinoma (UTUC) represents 5% of all urothelial cancers [1]. It exhibits aggressive behavior, with almost 60% of cases being invasive at diagnosis [2]. Standard treatment for high-risk UTUC is radical nephroureterectomy (RNU) with ipsilateral bladder cuff removal, with or without lymphadenectomy. Radical surgery alone for locally advanced UTUC is unlikely to effect a long-term durable cure [2]. Therefore, efforts have focused on improving the accuracy of existing postoperative prognostication in patients after RNU to identify those who might benefit from adjuvant therapies [3]. Pathological T stage, lymph node metastasis, tumor grade, and lymphovascular invasion (LVI) are the key components for postoperative prediction of prognosis after RNU; nevertheless, the accuracy of these models remains suboptimal [4–10]. Biomarkers may help in deciphering the biological and clinical behavior of tumors, thereby incrementally improving outcome prediction in addition to ushering the age of targeted therapy based on precision medicine [11–13]. Caveolins are a family of integral membrane proteins and are the main components of the caveole, the vesicular invaginations of the plasma membrane [14]. As an intracellular scaffolding protein, caveolin-1 is involved in regulation of several biological processes including endocytosis, transcytosis, vesicular transport, and signaling pathways. Caveolins are also involved in carcinogenesis, but depending on the type of tumor, they can either inhibit [15] or promote [16] cancer growth and metastasis. In UTUC, caveolin-1 has been linked to carcinogenesis [17] and progression [18], but studies to date are limited by case numbers and the homogeneity of study populations, precluding more definitive recommendations. Integration of caveolin-1 in a postoperative prediction model could help not only in prognostication but also in postoperative monitoring and refinement of adjuvant systemic therapies. Therefore, we sought to investigate the role of caveolin-1 expression in a large multi-institutional cohort of patients treated with RNU for UTUC. We hypothesized that caveolin-1 overexpression is independently associated with recurrence-free and cancer-specific survival following RNU for UTUC.
2.2.
Radical nephroureterectomy
Preoperative staging of patients was carried out using computed tomography (CT) or magnetic resonance (MR) urography. Concomitant bladder cancer was excluded on cystoscopy. RNU was performed at the discretion of the treating urologist according to the standard criteria for RNU (extrafascial dissection of the kidney with the entire length of the ureter and adjacent segment of the bladder cuff). However, the surgical procedure, including lymph node dissection and distal ureter management, was not standardized.
2.3.
Pathological evaluation
All specimens were processed according to standard pathological procedures in agreement to the 2009 TNM classification. Tumor grade was assigned according to the 2004 World Health Organization system. Tumor architecture was defined as papillary or sessile according to the predominant feature of the index lesion [7]. LVI was defined as the presence of tumor cells within an endothelium-lined space without underlying muscular walls [19]. The histological variant was defined as papillary with morphological variant features such as micropapillary, plasmacytoid, small cell carcinoma/neuroendocrine, or lymphoepithelial types [10,20].
2.4.
Immunhistochemistry
Immunostaining was performed on tissue microarrays using a Dako autostainer (Dako, Carpinteria, CA, USA) in a single laboratory using previously reported staining protocols [16]. We used bright-field microscopy imaging coupled with advanced color detection software (automated cellular imaging system, Clarient, CA, USA) for staining detection and classification. Three cores per patient were analyzed. The mean for triplicate cores was used for data analysis. A review of the slides was performed by two independent blinded pathologists. In the case of discrepancies between the two reviewers, a consensus judgment was reached via discussion. Caveolin-1 was considered overexpressed when more than 50% of the cells were stained positive. This 50% cutoff was defined according to a previous study that demonstrated that 50% cytoplasmic reactivity is the best discriminator for disease recurrence [21].
2.5.
Follow-up
Owing to the retrospective nature of the study, there was no standardized follow-up. Patients received clinical and radiological follow-up on the basis of final pathology, guidelines at that time, and physician discretion. In general, patients underwent physical examination, cytology, cystoscopy, laboratory testing, and upper tract imaging, including
2.
Patients and methods
CT/MR urography every 3 mo within the first year, semiannually from the second to the fifth year, and then annually. Chest imaging was performed semiannually. Disease recurrence was defined as tumor relapse in the
2.1.
Patient selection
operative field, regional lymph nodes, and/or distant metastasis. Occurrence of urothelial cancer in the bladder (UCB) or in the contralateral
This study was approved by an institutional review board, with all
upper urinary tract was considered as a novel primary tumor. Cause of
participating sites providing the necessary institutional data-sharing
death was attributed from review of patient charts or death records [22].
agreements before study initiation. A computerized databank was generated for data transfer. After combining the data sets from the different
2.6.
Statistical analysis
centers, reports were generated for each variable, identifying missing or inconsistent data. Incongruities were solved before freezing the final
Descriptive statistics for categorical variables focused on frequencies and
database. We identified 753 patients treated with RNU for unilateral
proportions. The mean, median, and interquartile range (IQR) were
UTUC between 1990 and 2008. Patients who had received perioperative
reported for continuous variables. The Mann-Whitney U test and x2 test
systemic therapy with or without radiation therapy (n = 105) or with
were used to compare the statistical significance of differences in
prior muscle-invasive bladder cancer (n = 27) were excluded to minimize
medians and proportions, respectively. The association of caveolin-1
confounding variables, leaving 621 patients for final analyses.
with recurrence and cancer-specific mortality (CSM) was assessed using
Please cite this article in press as: D’Andrea D, et al. Caveolin-1 Expression in Upper Tract Urothelial Carcinoma. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.06.011
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the Kaplan-Meier method; survival was compared between patients using the log-rank test. Univariate and multivariable Cox proportional hazard models addressed time to recurrence and CSM after RNU. Confounders were included in multivariable analyses on the basis of clinical evidence or if they changed the association of caveolin-1 with outcomes by at least 10% in bivariable analysis [23]. Statistical significance was considered at p < 0.05 and all tests were two-sided. Statistical analyses were performed using STATA v.14.1 (StataCorp LP, College Station, TX, USA).
3.
Results
Patient characteristics according to caveolin-1 expression status are listed in Table 1. Median age at surgery was 70 yr (IQR 62–76); the majority of patients (n = 321; 51.7%) had concomitant bladder cuff removal at RNU. The approach most commonly used was open RNU (n = 486; 78.3%). Lymphadenectomy was performed in 248 patients (39.9%), with a median of five nodes (IQR 2–8) removed. Interestingly, no lymph nodes were found in the harvested specimen for 146 patients. Caveolin-1 overexpression was associated with higher pathological tumor stage and grade
(both p < 0.001). Other pathological and clinical factors were well balanced between the two groups. During median follow-up of 35 mo (IQR 16–65), 113 patients (18.2%) experienced disease recurrence and 102 (16.4%) died of UTUC. The 5-yr recurrence and CSM were 66.7% vs 80.4% and 66% vs 81% for caveolin-1 overexpressing vs. non-overexpressing patients. On univariate analyses, caveolin-1 overexpression was significantly associated with recurrence and CSM (both p < 0.01; Fig. 1). On multivariable analyses adjusted for the effects of lymph node metastasis, pathological stage, pathological grade, LVI, and multifocal tumors, caveolin-1 overexpression was no longer independently associated with recurrence or CSM (Tables 2 and 3). We further conducted subgroups analyses based on tumor stage, grade, LVI, tumor focality, variant histology, and lymph node status. No association of caveolin-1 with recurrence or CSM could be observed in any of these subgroups. We also considered the subpopulation treated with RNU without lymphadenectomy, and no independent association of caveolin-1 with recurrence or CSM was found (Supplementary Table 1).
Table 1 – Descriptive characteristics for 621 patients undergoing RNU for upper tract urothelial carcinoma according to immunohistochemical expression of caveolin-1. Overall
Patients (n) Median age, yr (IQR) Gender, n (%) Male Female pT stage at RNU, n (%) pTa, pTis pT1 pT2 pT3 pT4 Grade at RNU, n (%) Low grade High grade Lymph node stage, n (%) N0 N+ Nx Lymphovascular invasion, n (%) Tumor architecture, n (%) Papillary Sessile Concomitant carcinoma in situ, n (%) Necrosis, n (%) Multifocal, n (%) Histological differentiation, n (%) Pure urothelial Other varianta Glandular or squamous Location, n (%) Pelvicalyceal Ureter Both Previous bladder cancer, n (%)
Caveolin-1 expression
p value
<50%
50%
621 70 (62–76)
471 70 (62–76)
150 70 (63–77)
340 (54.8) 281 (45.2)
256 (54.3) 215 (45.7)
84 (56) 66 (44)
124 (20) 200 (32.2) 112 (18) 155 (25) 30 (4.8)
113 (24) 149 (31.6) 80 (17) 111 (23.6) 18 (3.8)
11 (7.33) 51 (34) 32 (21.33) 44 (29.33) 12 (8)
176 (28.3) 445 (71.7)
149 (31.6) 322 (68.4)
27 (18) 123 (82)
216 (34.8) 15 (2.4) 390 (62.8) 106 (17.1)
161 (34.2) 10 (2.1) 300 (63.7) 74 (15.7)
55 (36.7) 5 (3.3) 90 (60) 32 (21.3)
524 (84.4) 97 (15.6) 99 (15.9) 74 (11.9) 126 (20.3)
402 (85.4) 69 (14.6) 75 (15.9) 53 (11.2) 91 (19.3)
122 (81.3) 28 (18.7) 24 (16) 21 (14) 35 (23.3)
551 (88.7) 68 (11) 2 (0.3)
418 (88.8) 51 (10.8) 2 (0.4)
133 (88.7) 17 (11.3) 0
454 (73.1) 159 (25.6) 8 (1.3) 196 (31.6)
347 (73.7) 118 (25) 6 (1.3) 145 (74)
107 (71.33) 41 (27.33) 2 (1.33) 51 (26)
0.4 0.7
<0.001
0.001
0.6
0.1 0.2
0.9 0.4 0.3 0.7
0.8
0.5
RNU = radical nephroureterectomy; IQR = interquartile range. Other variants included micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
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Fig. 1 – Univariate analyses for (A) recurrence and (B) cancer-specific mortality among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma stratified by caveolin-1 expression. HR = hazard ratio; CI = confidence interval.
4.
Discussion
In our large retrospective study, we investigated the role of caveolin-1 overexpression in predicting recurrence and CSM in patients treated with RNU for clinically nonmetastatic UTUC. Overexpression of caveolin-1 was found in 24% of the patients. Overall, 37.3% and 27.6% of patients with caveolin-1 overexpression had locally advanced and high-grade tumors, respectively. As reported in a previous study [24], this could further indicate that the expression
of caveolin-1 is a late event in the biology of UTUC progression. Surprisingly, caveolin-1 was not associated with higher rates of lymph node metastasis. This could be explained by a nonstandardized lymphadenectomy approach. Indeed, no template was used, and no lymph nodes were found at all in a significant proportion of specimens harvested. Overall, this reflects the immaturity of the technique and points to the need for better definition of the template to improve staging and, eventually, disease control.
Table 2 – Univariate and multivariable analyses assessing the association between predictor variables and recurrence among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Univariate analysis HR (95% CI) Age Gender (reference female) Laparoscopic surgery (reference open) Lymphadenectomy (reference not performed) Lymph node stage (reference N0) N+ Nx Stage (reference pTa/pTis) pT1 pT2 pT3 pT4 Grade (reference low) Lymphovascular invasion (reference absent) Concomitant carcinoma in situ (reference absent) Sessile architecture (reference papillary) Necrosis (reference absent) Tumor focality (reference unifocal) Differentiation (reference urothelial) Other varianta Glandular or squamous Location (reference pelvicalyceal) Ureter Both Caveolin-1 expression (reference underexpression)
Multivariable analysis p value
HR (95% CI)
p value
1.02 (0.99–1.03) 1.002 (0.7–1.4) 0.7 (0.4–1.2) 1.3 (0.9–1.9)
0.06 0.9 0.2 0.1
– – – –
4.9 (2.4–10) 1 (0.7–1.5)
<0.001 0.9
1.9 (0.8–4.3) 1.3 (0.8–2)
0.1 0.2
4.2 (0.9–18) 14 (3.3–59) 24 (5.9–100) 156 (36–672) 2.7 (1.6–4.6) 3.8 (2.6–5.6) 1.9 (1.2–2.9) 3.2 (2.1–4.8) 1.8 (1.05–2.9) 2.2 (1.5–3.3)
0.06 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 <0.001 0.03 <0.001
3.6 (0.8–16) 11.5 (2.6–49) 20 (4.7–83) 81 (17–378) 1.3 (0.7–2.4) 1.1 (0.7–1.8) – – – 1.7 (1.1–2.7)
0.09 0.001 <0.001 <0.001 0.3 0.5
1.1 (0.6–2.1) 4.9 (0.7–35)
0.6 0.7
– –
0.8 (0.5–1.3) 0.8 (0.1–5.8) 1.7 (1.2–2.6)
0.5 0.8 0.005
– – 1.2 (0.8–1.8)
0.01
0.3
HR = hazard ratio; CI = confidence interval. Other variants include micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
Please cite this article in press as: D’Andrea D, et al. Caveolin-1 Expression in Upper Tract Urothelial Carcinoma. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.06.011
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Table 3 – Univariate and multivariable analyses assessing the association between predictor variables and cancer-specific mortality among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Univariate HR (95% CI) Age Gender (reference female) Laparoscopic surgery (reference open) Lymphadenectomy (reference not performed) Lymph node stage (reference N0) N+ Nx Stage (reference pTa/pTis) pT1 pT2 pT3 pT4 Grade (reference low) Lymphovascular invasion (reference absent) Concomitant carcinoma in situ (reference absent) Sessile architecture (reference papillary) Necrosis (reference absent) Tumor focality (reference unifocal) Differentiation (reference urothelial) Other varianta Glandular or squamous Location (reference pelvicalyceal) Ureter Both Caveolin-1 expression (reference under-expression)
Multivariable p value
HR (95% CI)
p value
1.02 (1.003–1.04) 0.9 (0.6–1.4) 0.8 (0.4–1.4) 1.2 (0.8–1.8)
0.02 0.714 0.399 0.347
– – – –
6 (2.9–12) 1.1 (0.7–1.7)
<0.001 0.6
2 (0.8–4.9) 1.6 (0.99–2.5)
0.1 0.05
3.5 (0.8–15) 11 (2.7–49) 21 (5.2–88) 183 (42–789) 2.8 (1.5–4.9) 4.4 (2.9–6.6) 1.7 (1.09–2.8) 3.5 (2.3–5.2) 1.9 (1.1–3.2) 2.3 (1.6–3.5)
0.1 0.001 <0.001 <0.001 0.001 <0.001 0.019 <0.001 0.026 <0.001
3.1 (0.7–14) 9.8 (2.2–43) 18 (4.3–77) 88 (18–420) 1.4 (0.7–2.6) 1.2 (0.7–1.9) – – – 1.9 (1.2–3)
0.1 0.002 <0.001 <0.001 0.3 0.4
1.3 (0.7–2.4) 5.7 (0.9–41)
0.4 0.08
– –
0.9 (0.6–1.5) 0.9 (0.1–6.7) 1.8 (1.2–2.7)
0.8 0.9 0.006
– – 1.1 (0.7–1.7)
0.008
0.5
HR = hazard ratio; CI = confidence interval. Other variants include micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
The role of caveolin-1 in oncogenesis is still controversial. In a recent study by Mathieu et al. [16] caveolin-1 overexpression was significantly associated with adverse pathological features after radical prostatectomy and independently predicted biochemical recurrence. Ther are only limited data on caveolin-1 and UTUC, so comparisons are mainly only possible with UCB, despite their potentially different biology [25]. Rajjayabun et al [26] reported that caveolin-1 overexpression was associated with tumor stage and grade in UCB, but not with clinical outcomes. Our study confirms these findings. Moreover, in their series, caveolin-1 positivity was found in only 10% of cases. In our series, caveolin-1 was overexpressed in approximately 24% of cases, in line with the findings of Fong et al [24], probably reflecting the high aggressiveness of UTUC [27]. Cho et al [18] reported that approximately 25% of pT2 and almost none of non–muscle-invasive UTUC cases showed positive immunostaining for caveolin-1. Moreover, caveolin-1 was an independent prognostic factor for CSM. This series is limited by its small population (n = 98). It has been reported that UTUC is associated with worse prognosis if the histopathological report shows variant histology [28]. In our series, caveolin-1 expression had no association with variant histology; its incidence was fairly low, but was still in line with level generally reported in the literature [10,28,29]. Even if no independent association with recurrence and CSM could be proven, our study suggests that caveolin-1 plays a role in the carcinogenesis of advanced UTUC. The relevance and, more importantly, the clinical value of these findings remain to be proven.
Moreover, it is unlikely that a single biomarker would be a perfect outcome predictor for an oncological pathology [11]. Indeed, caveolin-1 should be considered as part of a larger panel of prognostic and predictive markers, like those already developed for UCB [13,30]. Adjuvant chemotherapy for high risk features is probably underutilized at present [20]; the use of caveolin-1 might aid in the decision process [31]. Some limitations must be considered for our study, mainly in relation to its retrospective nature. RNU was performed using different techniques by different surgeons, which could have potentially influenced outcomes. There was no consistent reporting on resection margins by all centers, so this variable could not be included in the analyses. Adjuvant systemic therapy could have influenced survival outcomes. Even if UCB occurrence after RNU was not considered recurrence but a primary tumor in a different organ, our study lacks such data. Indeed, new UCB could have influenced outcomes. We used the arbitrary cutoff of 50% for caveolin-1 expression on the basis of previous reports [21]. In general, immunohistochemical staining is subject to variations related to reaction and interpretation bias. We tried to reduce this bias via review of the staining by two independent pathologists. Moreover, specimens were not reviewed via central pathology. Finally, patients had short median follow-up and the study period was relatively long, leading to possible biases related to changes in operative and pathological techniques over time, as well as in indication and systemic therapy protocols.
Please cite this article in press as: D’Andrea D, et al. Caveolin-1 Expression in Upper Tract Urothelial Carcinoma. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.06.011
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5.
Conclusions
[5] Otto W, Shariat SF, Fritsche H-M, et al. Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and
Caveolin-1 was overexpressed in 25% of patients with UTUC and was associated with adverse tumor features. Nevertheless, it could not independently predict recurrence or CSM. Validation and qualification of this marker in appropriate target cohorts are needed to assess its value in enhancing a biomarker panel for UTUC prognostication for clinical decision-making, particularly if a kidney-sparing approach or neoadjuvant systemic therapy is considered.
survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J Urol 2011;29:487–94. http://dx.doi.org/10. 1007/s00345-011-0645-8. [6] Shariat SF, Favaretto RL, Gupta A, et al. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol 2011;29:481–6. http://dx.doi.org/10.1007/s00345-010-0594-7. [7] Remzi M, Haitel A, Margulis V, et al. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 2009;103: 307–11. http://dx.doi.org/10.1111/j.1464-410X.2008.08003.x. [8] Novara G, Matsumoto K, Kassouf W, et al. Prognostic role of
Author contributions: Sharhrokh F. Shariat had full access to all the data
lymphovascular invasion in patients with urothelial carcinoma of
in the study and takes responsibility for the integrity of the data and the
the upper urinary tract: an international validation study. Eur Urol
accuracy of the data analysis. Study concept and design: Shariat. Acquisition of data: Margulis, Karam, Lotan, Raman, Mathieu, Rouprêt,
2010;57:1064–71. http://dx.doi.org/10.1016/j.eururo.2009.12.029. [9] Shariat SF, Godoy G, Lotan Y, et al. Advanced patient age is associated with inferior cancer-specific survival after radical nephro-
Karakiewicz, Briganti, Haitel, Shariat.
ureterectomy. BJU Int 2010;105:1672–7. http://dx.doi.org/10.1111/
Analysis and interpretation of data: Foerster, Abufaraj, Margulis, Karam,
j.1464-410X.2009.09072.x.
Lotan, Raman, Mathieu, Rouprêt, Karakiewicz, Briganti, Haitel, Shariat.
[10] Rink M, Robinson BD, Green DA, et al. Impact of histological variants
Drafting of the manuscript: D’Andrea, Moschini.
on clinical outcomes of patients with upper urinary tract urothelial
Critical revision of the manuscript for important intellectual content:
carcinoma. J Urol 2012;188:398–404. http://dx.doi.org/10.1016/j.
Foerster, Abufaraj, Margulis, Karam, Lotan, Raman, Mathieu, Rouprêt, Karakiewicz, Briganti, Haitel, Shariat. Statistical analysis: D’Andrea, Moschini. Obtaining funding: None. Administrative, technical, or material support: None.
juro.2012.04.009. [11] Bensalah K, Montorsi F, Shariat SF. Challenges of cancer biomarker profiling. Eur Urol 2007;52:1601–9. http://dx.doi.org/10.1016/j. eururo.2007.09.036. [12] Soria F, Moschini M, Haitel A, et al. HER2 overexpression is associ-
Supervision: None.
ated with worse outcomes in patients with upper tract urothelial
Other: None.
carcinoma (UTUC). World J Urol 2017;35:251. http://dx.doi.org/10. 1007/s00345-016-1871-x.
Financial disclosures: Sharhrokh F. Shariat certifies that all conflicts of
[13] Shariat SF, Chade DC, Karakiewicz PI, et al. Combination of multiple
interest, including specific financial interests and relationships and
molecular markers can improve prognostication in patients with
affiliations relevant to the subject matter or materials discussed in the
locally advanced and lymph node positive bladder cancer. J Urol
manuscript (eg, employment/affiliation, grants or funding, consultan-
2010;183:68–75. http://dx.doi.org/10.1016/j.juro.2009.08.115.
cies, honoraria, stock ownership or options, expert testimony, royalties,
[14] Williams TM, Lisanti MP. The caveolin proteins. Genome Biol
or patents filed, received, or pending), are the following: None.
2004;5:214. http://dx.doi.org/10.1186/gb-2004-5-3-214. [15] Deb M, Sengupta D, Kar S, et al. Elucidation of caveolin 1 both as a
Funding/Support and role of the sponsor: None.
tumor suppressor and metastasis promoter in light of epigenetic modulators. Tumor Biol 2014;35:12031–47. http://dx.doi.org/10. 1007/s13277-014-2502-z.
Appendix A. Supplementary data
[16] Mathieu R, Klatte T, Lucca I, et al. Prognostic value of caveolin-1 in patients treated with radical prostatectomy: a multicentric validation study. BJU Int 2016;118:243–9. http://dx.doi.org/10.1111/bju.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. euf.2017.06.011.
13224. [17] Chang W-S, Lin S-S, Li F-J, et al. Significant association of caveolin-1 (CAV1) genotypes with upper urothelial tract cancer. Anticancer Res 2013;33:4907–12. [18] Cho DS, Yim H, Cho KS, et al. Impact of caveolin-1 expression on the
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Urothelial Cancer
Caveolin-1 Expression in Upper Tract Urothelial Carcinoma David D’Andrea a, Marco Moschini a,b, Beat Foerster a,c, Mohammad Abufaraj a, Vitaly Margulis d, Jose Karam e, Yair Lotan d, Jay Raman f, Romain Mathieu g, Morgan Roupreˆt h, Pierre I. Karakiewicz i, Alberto Briganti b, Andrea Haitel j, Sharhrokh F. Shariat a,d,k,* a
Department of Urology, Medical University of Vienna, Vienna, Austria;
b
Urological Research Institute, San Raffaele Scientific Institute, Vita-Salute San
Raffaele University, Milan, Italy; c Department of Urology, Kantonsspital Winterthur, Winterthur, Switzerland; d Department of Urology, University of Texas Southwestern, Dallas, TX, USA; e Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; f Division of Urology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA; g Department of Urology, Rennes University Hospital, Rennes, France; h Department of Urology, Pitié-Salpétrière Hospital, APHP, University Paris VI, Paris, France; i Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada; j Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; k Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
Article info
Abstract
Article history: Accepted June 13, 2017
Background: Improvement in postoperative risk stratification of upper tract urothelial carcinoma (UTUC) is required to better predict outcomes and counsel patients on adjuvant treatment. Objective: To validate the association between caveolin-1 and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for UTUC. Design, setting, and participants: Caveolin-1 expression was evaluated via immunochemistry on a tissue microarray from 621 patients. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positive. The median follow-up in this retrospective study was 35 mo (interquartile range 16–65). Intervention: Radical nephroureterectomy. Outcome measurements and statistical analysis: Univariate and multivariable Cox proportional hazards regression models were used to assess the association between caveolin-1 expression and recurrence and cancer-specific mortality (CSM). Results and limitations: Caveolin-1 was overexpressed in 150 patients (24%). Overexpression was associated with higher pathological stage (p < 0.001) and grade (p < 0.001). In univariate analyses, overexpression of caveolin-1 was significantly associated with lower recurrence (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2–2.6; p = 0.004) and CSM (HR 1.8, 95% CI 1.2–2.7; p = 0.005); however, multivariable analyses did not prove its independent association with outcomes. The study is limited by its retrospective nature. Conclusions: Despite overexpression in a quarter of UTUC patients, caveolin-1 was not independently associated with oncological outcomes. Its use could be evaluated to improve clinical staging of biopsy specimens and to help in clinical decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Patient summary: Development of a panel of prognostic and predictive markers is mandatory for patient consultations in the era of personalized medicine. We evaluated the role of caveolin-1 in a large series of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) and found that it was not independently associated with oncological outcomes. Nevertheless, it was associated with adverse pathological features. Considering caveolin-1 in UTUC biopsy specimens could help in improving clinical staging and decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Caveolin-1 Biomarker Nephroureterectomy Outcome Upper tract urothelial carcinoma
* Corresponding author. Department of Urology, Comprehensive Cancer Center, Medical University Vienna, General Hospital, Währinger Gürtel 18–20, A 1090 Vienna, Austria. Tel: +43 1 4040026150; Fax: +43 1 4040023320. E-mail address: [email protected] (S.F. Shariat). http://dx.doi.org/10.1016/j.euf.2017.06.011 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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1.
Introduction
Upper tract urothelial carcinoma (UTUC) represents 5% of all urothelial cancers [1]. It exhibits aggressive behavior, with almost 60% of cases being invasive at diagnosis [2]. Standard treatment for high-risk UTUC is radical nephroureterectomy (RNU) with ipsilateral bladder cuff removal, with or without lymphadenectomy. Radical surgery alone for locally advanced UTUC is unlikely to effect a long-term durable cure [2]. Therefore, efforts have focused on improving the accuracy of existing postoperative prognostication in patients after RNU to identify those who might benefit from adjuvant therapies [3]. Pathological T stage, lymph node metastasis, tumor grade, and lymphovascular invasion (LVI) are the key components for postoperative prediction of prognosis after RNU; nevertheless, the accuracy of these models remains suboptimal [4–10]. Biomarkers may help in deciphering the biological and clinical behavior of tumors, thereby incrementally improving outcome prediction in addition to ushering the age of targeted therapy based on precision medicine [11–13]. Caveolins are a family of integral membrane proteins and are the main components of the caveole, the vesicular invaginations of the plasma membrane [14]. As an intracellular scaffolding protein, caveolin-1 is involved in regulation of several biological processes including endocytosis, transcytosis, vesicular transport, and signaling pathways. Caveolins are also involved in carcinogenesis, but depending on the type of tumor, they can either inhibit [15] or promote [16] cancer growth and metastasis. In UTUC, caveolin-1 has been linked to carcinogenesis [17] and progression [18], but studies to date are limited by case numbers and the homogeneity of study populations, precluding more definitive recommendations. Integration of caveolin-1 in a postoperative prediction model could help not only in prognostication but also in postoperative monitoring and refinement of adjuvant systemic therapies. Therefore, we sought to investigate the role of caveolin-1 expression in a large multi-institutional cohort of patients treated with RNU for UTUC. We hypothesized that caveolin-1 overexpression is independently associated with recurrence-free and cancer-specific survival following RNU for UTUC.
2.2.
Radical nephroureterectomy
Preoperative staging of patients was carried out using computed tomography (CT) or magnetic resonance (MR) urography. Concomitant bladder cancer was excluded on cystoscopy. RNU was performed at the discretion of the treating urologist according to the standard criteria for RNU (extrafascial dissection of the kidney with the entire length of the ureter and adjacent segment of the bladder cuff). However, the surgical procedure, including lymph node dissection and distal ureter management, was not standardized.
2.3.
Pathological evaluation
All specimens were processed according to standard pathological procedures in agreement to the 2009 TNM classification. Tumor grade was assigned according to the 2004 World Health Organization system. Tumor architecture was defined as papillary or sessile according to the predominant feature of the index lesion [7]. LVI was defined as the presence of tumor cells within an endothelium-lined space without underlying muscular walls [19]. The histological variant was defined as papillary with morphological variant features such as micropapillary, plasmacytoid, small cell carcinoma/neuroendocrine, or lymphoepithelial types [10,20].
2.4.
Immunhistochemistry
Immunostaining was performed on tissue microarrays using a Dako autostainer (Dako, Carpinteria, CA, USA) in a single laboratory using previously reported staining protocols [16]. We used bright-field microscopy imaging coupled with advanced color detection software (automated cellular imaging system, Clarient, CA, USA) for staining detection and classification. Three cores per patient were analyzed. The mean for triplicate cores was used for data analysis. A review of the slides was performed by two independent blinded pathologists. In the case of discrepancies between the two reviewers, a consensus judgment was reached via discussion. Caveolin-1 was considered overexpressed when more than 50% of the cells were stained positive. This 50% cutoff was defined according to a previous study that demonstrated that 50% cytoplasmic reactivity is the best discriminator for disease recurrence [21].
2.5.
Follow-up
Owing to the retrospective nature of the study, there was no standardized follow-up. Patients received clinical and radiological follow-up on the basis of final pathology, guidelines at that time, and physician discretion. In general, patients underwent physical examination, cytology, cystoscopy, laboratory testing, and upper tract imaging, including
2.
Patients and methods
CT/MR urography every 3 mo within the first year, semiannually from the second to the fifth year, and then annually. Chest imaging was performed semiannually. Disease recurrence was defined as tumor relapse in the
2.1.
Patient selection
operative field, regional lymph nodes, and/or distant metastasis. Occurrence of urothelial cancer in the bladder (UCB) or in the contralateral
This study was approved by an institutional review board, with all
upper urinary tract was considered as a novel primary tumor. Cause of
participating sites providing the necessary institutional data-sharing
death was attributed from review of patient charts or death records [22].
agreements before study initiation. A computerized databank was generated for data transfer. After combining the data sets from the different
2.6.
Statistical analysis
centers, reports were generated for each variable, identifying missing or inconsistent data. Incongruities were solved before freezing the final
Descriptive statistics for categorical variables focused on frequencies and
database. We identified 753 patients treated with RNU for unilateral
proportions. The mean, median, and interquartile range (IQR) were
UTUC between 1990 and 2008. Patients who had received perioperative
reported for continuous variables. The Mann-Whitney U test and x2 test
systemic therapy with or without radiation therapy (n = 105) or with
were used to compare the statistical significance of differences in
prior muscle-invasive bladder cancer (n = 27) were excluded to minimize
medians and proportions, respectively. The association of caveolin-1
confounding variables, leaving 621 patients for final analyses.
with recurrence and cancer-specific mortality (CSM) was assessed using
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the Kaplan-Meier method; survival was compared between patients using the log-rank test. Univariate and multivariable Cox proportional hazard models addressed time to recurrence and CSM after RNU. Confounders were included in multivariable analyses on the basis of clinical evidence or if they changed the association of caveolin-1 with outcomes by at least 10% in bivariable analysis [23]. Statistical significance was considered at p < 0.05 and all tests were two-sided. Statistical analyses were performed using STATA v.14.1 (StataCorp LP, College Station, TX, USA).
3.
Results
Patient characteristics according to caveolin-1 expression status are listed in Table 1. Median age at surgery was 70 yr (IQR 62–76); the majority of patients (n = 321; 51.7%) had concomitant bladder cuff removal at RNU. The approach most commonly used was open RNU (n = 486; 78.3%). Lymphadenectomy was performed in 248 patients (39.9%), with a median of five nodes (IQR 2–8) removed. Interestingly, no lymph nodes were found in the harvested specimen for 146 patients. Caveolin-1 overexpression was associated with higher pathological tumor stage and grade
(both p < 0.001). Other pathological and clinical factors were well balanced between the two groups. During median follow-up of 35 mo (IQR 16–65), 113 patients (18.2%) experienced disease recurrence and 102 (16.4%) died of UTUC. The 5-yr recurrence and CSM were 66.7% vs 80.4% and 66% vs 81% for caveolin-1 overexpressing vs. non-overexpressing patients. On univariate analyses, caveolin-1 overexpression was significantly associated with recurrence and CSM (both p < 0.01; Fig. 1). On multivariable analyses adjusted for the effects of lymph node metastasis, pathological stage, pathological grade, LVI, and multifocal tumors, caveolin-1 overexpression was no longer independently associated with recurrence or CSM (Tables 2 and 3). We further conducted subgroups analyses based on tumor stage, grade, LVI, tumor focality, variant histology, and lymph node status. No association of caveolin-1 with recurrence or CSM could be observed in any of these subgroups. We also considered the subpopulation treated with RNU without lymphadenectomy, and no independent association of caveolin-1 with recurrence or CSM was found (Supplementary Table 1).
Table 1 – Descriptive characteristics for 621 patients undergoing RNU for upper tract urothelial carcinoma according to immunohistochemical expression of caveolin-1. Overall
Patients (n) Median age, yr (IQR) Gender, n (%) Male Female pT stage at RNU, n (%) pTa, pTis pT1 pT2 pT3 pT4 Grade at RNU, n (%) Low grade High grade Lymph node stage, n (%) N0 N+ Nx Lymphovascular invasion, n (%) Tumor architecture, n (%) Papillary Sessile Concomitant carcinoma in situ, n (%) Necrosis, n (%) Multifocal, n (%) Histological differentiation, n (%) Pure urothelial Other varianta Glandular or squamous Location, n (%) Pelvicalyceal Ureter Both Previous bladder cancer, n (%)
Caveolin-1 expression
p value
<50%
50%
621 70 (62–76)
471 70 (62–76)
150 70 (63–77)
340 (54.8) 281 (45.2)
256 (54.3) 215 (45.7)
84 (56) 66 (44)
124 (20) 200 (32.2) 112 (18) 155 (25) 30 (4.8)
113 (24) 149 (31.6) 80 (17) 111 (23.6) 18 (3.8)
11 (7.33) 51 (34) 32 (21.33) 44 (29.33) 12 (8)
176 (28.3) 445 (71.7)
149 (31.6) 322 (68.4)
27 (18) 123 (82)
216 (34.8) 15 (2.4) 390 (62.8) 106 (17.1)
161 (34.2) 10 (2.1) 300 (63.7) 74 (15.7)
55 (36.7) 5 (3.3) 90 (60) 32 (21.3)
524 (84.4) 97 (15.6) 99 (15.9) 74 (11.9) 126 (20.3)
402 (85.4) 69 (14.6) 75 (15.9) 53 (11.2) 91 (19.3)
122 (81.3) 28 (18.7) 24 (16) 21 (14) 35 (23.3)
551 (88.7) 68 (11) 2 (0.3)
418 (88.8) 51 (10.8) 2 (0.4)
133 (88.7) 17 (11.3) 0
454 (73.1) 159 (25.6) 8 (1.3) 196 (31.6)
347 (73.7) 118 (25) 6 (1.3) 145 (74)
107 (71.33) 41 (27.33) 2 (1.33) 51 (26)
0.4 0.7
<0.001
0.001
0.6
0.1 0.2
0.9 0.4 0.3 0.7
0.8
0.5
RNU = radical nephroureterectomy; IQR = interquartile range. Other variants included micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
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Fig. 1 – Univariate analyses for (A) recurrence and (B) cancer-specific mortality among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma stratified by caveolin-1 expression. HR = hazard ratio; CI = confidence interval.
4.
Discussion
In our large retrospective study, we investigated the role of caveolin-1 overexpression in predicting recurrence and CSM in patients treated with RNU for clinically nonmetastatic UTUC. Overexpression of caveolin-1 was found in 24% of the patients. Overall, 37.3% and 27.6% of patients with caveolin-1 overexpression had locally advanced and high-grade tumors, respectively. As reported in a previous study [24], this could further indicate that the expression
of caveolin-1 is a late event in the biology of UTUC progression. Surprisingly, caveolin-1 was not associated with higher rates of lymph node metastasis. This could be explained by a nonstandardized lymphadenectomy approach. Indeed, no template was used, and no lymph nodes were found at all in a significant proportion of specimens harvested. Overall, this reflects the immaturity of the technique and points to the need for better definition of the template to improve staging and, eventually, disease control.
Table 2 – Univariate and multivariable analyses assessing the association between predictor variables and recurrence among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Univariate analysis HR (95% CI) Age Gender (reference female) Laparoscopic surgery (reference open) Lymphadenectomy (reference not performed) Lymph node stage (reference N0) N+ Nx Stage (reference pTa/pTis) pT1 pT2 pT3 pT4 Grade (reference low) Lymphovascular invasion (reference absent) Concomitant carcinoma in situ (reference absent) Sessile architecture (reference papillary) Necrosis (reference absent) Tumor focality (reference unifocal) Differentiation (reference urothelial) Other varianta Glandular or squamous Location (reference pelvicalyceal) Ureter Both Caveolin-1 expression (reference underexpression)
Multivariable analysis p value
HR (95% CI)
p value
1.02 (0.99–1.03) 1.002 (0.7–1.4) 0.7 (0.4–1.2) 1.3 (0.9–1.9)
0.06 0.9 0.2 0.1
– – – –
4.9 (2.4–10) 1 (0.7–1.5)
<0.001 0.9
1.9 (0.8–4.3) 1.3 (0.8–2)
0.1 0.2
4.2 (0.9–18) 14 (3.3–59) 24 (5.9–100) 156 (36–672) 2.7 (1.6–4.6) 3.8 (2.6–5.6) 1.9 (1.2–2.9) 3.2 (2.1–4.8) 1.8 (1.05–2.9) 2.2 (1.5–3.3)
0.06 <0.001 <0.001 <0.001 <0.001 <0.001 0.005 <0.001 0.03 <0.001
3.6 (0.8–16) 11.5 (2.6–49) 20 (4.7–83) 81 (17–378) 1.3 (0.7–2.4) 1.1 (0.7–1.8) – – – 1.7 (1.1–2.7)
0.09 0.001 <0.001 <0.001 0.3 0.5
1.1 (0.6–2.1) 4.9 (0.7–35)
0.6 0.7
– –
0.8 (0.5–1.3) 0.8 (0.1–5.8) 1.7 (1.2–2.6)
0.5 0.8 0.005
– – 1.2 (0.8–1.8)
0.01
0.3
HR = hazard ratio; CI = confidence interval. Other variants include micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
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Table 3 – Univariate and multivariable analyses assessing the association between predictor variables and cancer-specific mortality among 621 patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Univariate HR (95% CI) Age Gender (reference female) Laparoscopic surgery (reference open) Lymphadenectomy (reference not performed) Lymph node stage (reference N0) N+ Nx Stage (reference pTa/pTis) pT1 pT2 pT3 pT4 Grade (reference low) Lymphovascular invasion (reference absent) Concomitant carcinoma in situ (reference absent) Sessile architecture (reference papillary) Necrosis (reference absent) Tumor focality (reference unifocal) Differentiation (reference urothelial) Other varianta Glandular or squamous Location (reference pelvicalyceal) Ureter Both Caveolin-1 expression (reference under-expression)
Multivariable p value
HR (95% CI)
p value
1.02 (1.003–1.04) 0.9 (0.6–1.4) 0.8 (0.4–1.4) 1.2 (0.8–1.8)
0.02 0.714 0.399 0.347
– – – –
6 (2.9–12) 1.1 (0.7–1.7)
<0.001 0.6
2 (0.8–4.9) 1.6 (0.99–2.5)
0.1 0.05
3.5 (0.8–15) 11 (2.7–49) 21 (5.2–88) 183 (42–789) 2.8 (1.5–4.9) 4.4 (2.9–6.6) 1.7 (1.09–2.8) 3.5 (2.3–5.2) 1.9 (1.1–3.2) 2.3 (1.6–3.5)
0.1 0.001 <0.001 <0.001 0.001 <0.001 0.019 <0.001 0.026 <0.001
3.1 (0.7–14) 9.8 (2.2–43) 18 (4.3–77) 88 (18–420) 1.4 (0.7–2.6) 1.2 (0.7–1.9) – – – 1.9 (1.2–3)
0.1 0.002 <0.001 <0.001 0.3 0.4
1.3 (0.7–2.4) 5.7 (0.9–41)
0.4 0.08
– –
0.9 (0.6–1.5) 0.9 (0.1–6.7) 1.8 (1.2–2.7)
0.8 0.9 0.006
– – 1.1 (0.7–1.7)
0.008
0.5
HR = hazard ratio; CI = confidence interval. Other variants include micropapillary, plasmocytoid, sarcomatoid, and neuroendocrine types.
a
The role of caveolin-1 in oncogenesis is still controversial. In a recent study by Mathieu et al. [16] caveolin-1 overexpression was significantly associated with adverse pathological features after radical prostatectomy and independently predicted biochemical recurrence. Ther are only limited data on caveolin-1 and UTUC, so comparisons are mainly only possible with UCB, despite their potentially different biology [25]. Rajjayabun et al [26] reported that caveolin-1 overexpression was associated with tumor stage and grade in UCB, but not with clinical outcomes. Our study confirms these findings. Moreover, in their series, caveolin-1 positivity was found in only 10% of cases. In our series, caveolin-1 was overexpressed in approximately 24% of cases, in line with the findings of Fong et al [24], probably reflecting the high aggressiveness of UTUC [27]. Cho et al [18] reported that approximately 25% of pT2 and almost none of non–muscle-invasive UTUC cases showed positive immunostaining for caveolin-1. Moreover, caveolin-1 was an independent prognostic factor for CSM. This series is limited by its small population (n = 98). It has been reported that UTUC is associated with worse prognosis if the histopathological report shows variant histology [28]. In our series, caveolin-1 expression had no association with variant histology; its incidence was fairly low, but was still in line with level generally reported in the literature [10,28,29]. Even if no independent association with recurrence and CSM could be proven, our study suggests that caveolin-1 plays a role in the carcinogenesis of advanced UTUC. The relevance and, more importantly, the clinical value of these findings remain to be proven.
Moreover, it is unlikely that a single biomarker would be a perfect outcome predictor for an oncological pathology [11]. Indeed, caveolin-1 should be considered as part of a larger panel of prognostic and predictive markers, like those already developed for UCB [13,30]. Adjuvant chemotherapy for high risk features is probably underutilized at present [20]; the use of caveolin-1 might aid in the decision process [31]. Some limitations must be considered for our study, mainly in relation to its retrospective nature. RNU was performed using different techniques by different surgeons, which could have potentially influenced outcomes. There was no consistent reporting on resection margins by all centers, so this variable could not be included in the analyses. Adjuvant systemic therapy could have influenced survival outcomes. Even if UCB occurrence after RNU was not considered recurrence but a primary tumor in a different organ, our study lacks such data. Indeed, new UCB could have influenced outcomes. We used the arbitrary cutoff of 50% for caveolin-1 expression on the basis of previous reports [21]. In general, immunohistochemical staining is subject to variations related to reaction and interpretation bias. We tried to reduce this bias via review of the staining by two independent pathologists. Moreover, specimens were not reviewed via central pathology. Finally, patients had short median follow-up and the study period was relatively long, leading to possible biases related to changes in operative and pathological techniques over time, as well as in indication and systemic therapy protocols.
Please cite this article in press as: D’Andrea D, et al. Caveolin-1 Expression in Upper Tract Urothelial Carcinoma. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.06.011
EUF-352; No. of Pages 7 6
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5.
Conclusions
[5] Otto W, Shariat SF, Fritsche H-M, et al. Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and
Caveolin-1 was overexpressed in 25% of patients with UTUC and was associated with adverse tumor features. Nevertheless, it could not independently predict recurrence or CSM. Validation and qualification of this marker in appropriate target cohorts are needed to assess its value in enhancing a biomarker panel for UTUC prognostication for clinical decision-making, particularly if a kidney-sparing approach or neoadjuvant systemic therapy is considered.
survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J Urol 2011;29:487–94. http://dx.doi.org/10. 1007/s00345-011-0645-8. [6] Shariat SF, Favaretto RL, Gupta A, et al. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol 2011;29:481–6. http://dx.doi.org/10.1007/s00345-010-0594-7. [7] Remzi M, Haitel A, Margulis V, et al. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 2009;103: 307–11. http://dx.doi.org/10.1111/j.1464-410X.2008.08003.x. [8] Novara G, Matsumoto K, Kassouf W, et al. Prognostic role of
Author contributions: Sharhrokh F. Shariat had full access to all the data
lymphovascular invasion in patients with urothelial carcinoma of
in the study and takes responsibility for the integrity of the data and the
the upper urinary tract: an international validation study. Eur Urol
accuracy of the data analysis. Study concept and design: Shariat. Acquisition of data: Margulis, Karam, Lotan, Raman, Mathieu, Rouprêt,
2010;57:1064–71. http://dx.doi.org/10.1016/j.eururo.2009.12.029. [9] Shariat SF, Godoy G, Lotan Y, et al. Advanced patient age is associated with inferior cancer-specific survival after radical nephro-
Karakiewicz, Briganti, Haitel, Shariat.
ureterectomy. BJU Int 2010;105:1672–7. http://dx.doi.org/10.1111/
Analysis and interpretation of data: Foerster, Abufaraj, Margulis, Karam,
j.1464-410X.2009.09072.x.
Lotan, Raman, Mathieu, Rouprêt, Karakiewicz, Briganti, Haitel, Shariat.
[10] Rink M, Robinson BD, Green DA, et al. Impact of histological variants
Drafting of the manuscript: D’Andrea, Moschini.
on clinical outcomes of patients with upper urinary tract urothelial
Critical revision of the manuscript for important intellectual content:
carcinoma. J Urol 2012;188:398–404. http://dx.doi.org/10.1016/j.
Foerster, Abufaraj, Margulis, Karam, Lotan, Raman, Mathieu, Rouprêt, Karakiewicz, Briganti, Haitel, Shariat. Statistical analysis: D’Andrea, Moschini. Obtaining funding: None. Administrative, technical, or material support: None.
juro.2012.04.009. [11] Bensalah K, Montorsi F, Shariat SF. Challenges of cancer biomarker profiling. Eur Urol 2007;52:1601–9. http://dx.doi.org/10.1016/j. eururo.2007.09.036. [12] Soria F, Moschini M, Haitel A, et al. HER2 overexpression is associ-
Supervision: None.
ated with worse outcomes in patients with upper tract urothelial
Other: None.
carcinoma (UTUC). World J Urol 2017;35:251. http://dx.doi.org/10. 1007/s00345-016-1871-x.
Financial disclosures: Sharhrokh F. Shariat certifies that all conflicts of
[13] Shariat SF, Chade DC, Karakiewicz PI, et al. Combination of multiple
interest, including specific financial interests and relationships and
molecular markers can improve prognostication in patients with
affiliations relevant to the subject matter or materials discussed in the
locally advanced and lymph node positive bladder cancer. J Urol
manuscript (eg, employment/affiliation, grants or funding, consultan-
2010;183:68–75. http://dx.doi.org/10.1016/j.juro.2009.08.115.
cies, honoraria, stock ownership or options, expert testimony, royalties,
[14] Williams TM, Lisanti MP. The caveolin proteins. Genome Biol
or patents filed, received, or pending), are the following: None.
2004;5:214. http://dx.doi.org/10.1186/gb-2004-5-3-214. [15] Deb M, Sengupta D, Kar S, et al. Elucidation of caveolin 1 both as a
Funding/Support and role of the sponsor: None.
tumor suppressor and metastasis promoter in light of epigenetic modulators. Tumor Biol 2014;35:12031–47. http://dx.doi.org/10. 1007/s13277-014-2502-z.
Appendix A. Supplementary data
[16] Mathieu R, Klatte T, Lucca I, et al. Prognostic value of caveolin-1 in patients treated with radical prostatectomy: a multicentric validation study. BJU Int 2016;118:243–9. http://dx.doi.org/10.1111/bju.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. euf.2017.06.011.
13224. [17] Chang W-S, Lin S-S, Li F-J, et al. Significant association of caveolin-1 (CAV1) genotypes with upper urothelial tract cancer. Anticancer Res 2013;33:4907–12. [18] Cho DS, Yim H, Cho KS, et al. Impact of caveolin-1 expression on the
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