Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy

doi:10.1016/j.urolonc.2015.02.010

Urologic Oncology: Seminars and Original Investigations

Volume 33, Issue 5, May 2015, Pages 204.e9-204.e16

https://doi.org/10.1016/j.urolonc.2015.02.010 Get rights and content

Abstract

Objective

To evaluate the prognostic effect of concomitant variant histology (CVH) on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy.

Materials and methods

Data on 417 patients with UTUC treated with radical nephroureterectomy without preoperative adjuvant therapy were retrospectively reviewed with a focus on CVH. Clinicopathological features and prognostic factors were compared between patients with pure UTUC and patients with UTUC with CVH. The primary end points were cancer-specific survival (CSS), disease recurrence-free survival (DFS), and overall survival (OS).

Results

UTUC with CVH was present in 90 (21.6%) of 417 patients. At a median follow-up of 26 months, 153 (36.7%) had died of UTUC, 161 (38.6%) had experienced a relapse, and 176 (42.2%) had died of other causes. UTUC with CVH was significantly associated with advanced tumor stage, high tumor grade, tumor diameter, lymphovascular invasion, lymph node metastasis, positive surgical margins, and tumor architecture compared with pure UTUC (all P<0.01). The estimated 5-year CSS, DFS, and OS rates were 64.9%, 61.1%, and 62.1%, respectively, in the pure UTUC group, compared with 36.3%, 34.3%, and 26.5%, respectively, in the UTUC with CVH group (P<0.001). Multivariate analysis demonstrated that CVH was an independent predictor of CSS (hazard ratio [HR] = 1.594; 95% CI: 1.125–2.259; P = 0.009), DFS (HR = 1.549; 95% CI: 1.077–2.152; P = 0.017), and OS (HR = 1.685; 95% CI: 1.212–2.343; P = 0.002).

Conclusions

Approximately one-fifth of the specimens of patients with UTUC were observed to exhibit CVH. CVH was an independent prognostic factor for CSS, DFS, and OS in patients with UTUC on both univariate and multivariate analyses. Genitourinary pathologists should look for potential CVH components in UTUC specimens and report this in routine pathological practice. The presence of CVH should identify patients as candidates for consultation regarding early adjuvant therapy and intensive surveillance protocols.

Introduction

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare but potentially fatal disease, accounting for approximately 5% of all urothelial carcinomas (UCs) including renal pelvicalyceal and ureteric UC. The incidence of UTUC is approximately 2 cases per 100,000 person-years, which has increased slightly over the past 3 decades [1]. Pure UC accounts for most of the UTUCs; however, UTUC with concomitant variant histology (CVH) owing to aberrant histological differentiation is a phenomenon that is well recognized by pathologists [2], [3], [4] and is similar to UC of the bladder [5]. Because of the rarity of UTUC, few studies have examined the influence of CVH on the prognosis of patients with UTUC treated with radical nephroureterectomy (RNU); the studies that have attempted to assess this have resulted in indefinite conclusions because of small sample sizes and methods of analyses [3], [6].

Recently, a multi-institutional study on CVH conducted by Rink et al. [7] showed that CVH in UTUC was associated with adverse outcomes in cancer-specific survival (CSS) and disease recurrence-free survival (DFS) following RNU on univariate analysis; however, the association was not statistically significant on multivariate analysis. Similar results were reported in another multi-institutional study conducted by Sakano et al. [8]. However, in a subgroup analysis, Sakano et al. [8] found that CVH was an independent predictor of DFS in patients with non–organ-confined disease (pT3/4) on multivariate analysis (P = 0.0095). Thus, the effect of CVH on the prognosis of patients with UTUC following RNU needs to be further investigated. The aim of this study was to evaluate the prognostic effect of variant histological components on the outcomes in patients with UTUC treated with RNU in a single large tertiary referral center in western China.

Section snippets

Patient selection

The present retrospective study was approved by the Institutional Review Board of West China Hospital, Sichuan University. Medical records of 514 consecutive patients with UTUC treated in the authors׳ center were reviewed between 2002 and 2012. We excluded 73 patients from the study because of loss to follow-up (n = 58) and the diagnosis of pure nonurothelial upper tract cancer (n = 15). In addition, 9 patients with a history of radical cystectomy for muscle-invasive bladder cancer and 8

Results

The median age of the entire cohort at surgery was 67 years (range: 26–86 y). UTUC with CVH was present in 90 (21.6%) of 417 patients. The histological distribution of both the groups is shown in Table 1. Specifically, squamous cell differentiation was the most common divergent histological type (n = 48 [11.5%]), followed by glandular differentiation (n = 15 [3.6%]). Multiple CVH differentiations were observed in 13 (3.1%) patients.

Associations between variant histological components and

Discussion

To the best of our knowledge, the present analysis is by far the largest single-institutional study to address the effect of CVH on clinical outcomes in patients with UTUC treated with RNU. In this study, we confirmed that the presence of CVH in patients with UTUC was associated with biologically and clinically aggressive features. CVH was an independent risk factor for CSS, DFS, and OS on both univariate and multivariate analyses among patients with UTUC following RNU in this cohort.

We found

Conclusion

Approximately, one-fifth of UTUC specimens exhibited CVH after RNU. UTUC with CVH was correlated with adverse clinicopathological features and was an independent predictor of CSS, DFS, and OS on both univariate and multivariate analysis in this study population from the western part of China. Additional studies are needed to confirm these findings in different patient populations. Surgical pathologists should be conscious of potentially different forms of multidirectional differentiation in

References (30)

D. Perez-Montiel et al.
Upper urinary tract carcinomas: histological types and unusual morphological variants
Diagn Histopathol
(2008)
D. Perez-Montiel et al.
High-grade urothelial carcinoma of the renal pelvis: clinicopathologic study of 108 cases with emphasis on unusual morphologic variants
Mod Pathol
(2006)
G.Q. Xiao et al.
Renal pelvic urothelial carcinoma with divergent morphology
Ann Diagn Pathol
(2010)
A. Lopez-Beltran et al.
Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications
Hum Pathol
(2006)
S. Holmang et al.
Squamous cell carcinoma of the renal pelvis and ureter: incidence, symptoms, treatment and outcome
J Urol
(2007)
M. Rink et al.
Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma
J Urol
(2012)
P.N. Espiritu et al.
Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection
Urol Oncol
(2014)
G. Novara et al.
Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract: an international validation study
Eur Urol
(2010)
H. Isbarn et al.
Location of the primary tumor is not an independent predictor of cancer specific mortality in patients with upper urinary tract urothelial carcinoma
J Urol
(2009)
V. Fradet et al.
Risk factors for bladder cancer recurrence after nephroureterectomy for upper tract urothelial tumors: results from the Canadian Upper Tract Collaboration
Urol Oncol
(2014)

R.B. Shah et al.

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)

L.W. Martin et al.

Sarcomatoid carcinoma of the lung: a predictor of poor prognosis

Ann Thorac Surg

(2007)

F. Sellner et al.

Well or poorly differentiated nonfunctioning neuroendocrine carcinoma of the pancreas: a single institution experience with 17 cases

Eur J Surg Oncol

(2008)

P.H. Chung et al.

Degree of hydronephrosis predicts adverse pathological features and worse oncologic outcomes in patients with high-grade urothelial carcinoma of the upper urinary tract

Urol Oncol

(2014)

G. Lughezzani et al.

Gender-related differences in patients with stage I to III upper tract urothelial carcinoma: results from the Surveillance, Epidemiology, and End Results database

Urology

(2010)

Cited by (26)

Impact of Variant Histology on Oncological Outcomes in Upper Tract Urothelial Carcinoma: Results From the ROBUUST Collaborative Group
2023, Clinical Genitourinary Cancer
Oncologic implications of variant histology (VH) have been extensively studied in bladder cancer; however, further investigation is needed in upper tract urothelial carcinoma (UTUC). Our study aims to evaluate the impact of VH on oncological outcomes in UTUC patients treated with radical nephroureterectomy (RNU).
A retrospective analysis was performed on patients who underwent a robotic or laparoscopic RNU for UTUC using the ROBUUST database, a multi-institutional collaborative including 17 centers worldwide. Logistic regression was used to assess the effect of VH on urothelial recurrence (bladder, contralateral upper tract), metastasis, and survival following RNU.
A total of 687 patients were included in this study. Median (IQR) age was 71 (64-78) years and 470 (68%) had organ confined disease. VH was present in 70 (10.2%) patients. In a median follow-up of 16 months, the incidence of urothelial recurrence, metastasis, and mortality was 26.8%, 15.3%, and 11.8%, respectively. VH was associated with increased risk of metastasis (HR 4.3, P <.0001) and death (HR 2.0, P =.046). In multivariable analysis, VH was noted to be an independent risk factor for metastasis (HR 1.8, P =.03) but not for urothelial recurrence (HR 0.99, P =.97) or death (HR 1.4, P =.2).
Variant histology can be found in 10% of patients with UTUC and is an independent risk factor for metastasis following RNU. Overall survival rates and the risk of urothelial recurrence in the bladder or contralateral kidney are not affected by the presence of VH.
Histological variants and lymphovascular invasion in upper tract urothelial carcinoma can stratify prognosis after radical nephroureterectomy
2022, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
This result is consistent with that of a previous study [15,16], and similar observations have been reported for the bladder cancer [8,17]. Previous studies reported a broad range for the prevalence of HV in UTUC, ranging from 3.6% to 24.2% [15,18–21]. Recently, the importance of HV as a prognostic factor after RNU has been recognized.
Patients with histological variants (HV) of bladder cancer have more advanced disease and poorer survival rates than those with pure urothelial carcinoma (UC). Moreover, lymphovascular invasion (LVI) is an important biomarker after RNU in systematic reviews and meta-analyses. Thus, here we investigated the clinical and prognostic impact of HV and LVI in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).
Data from 223 UTUC patients treated with RNU without neoadjuvant chemotherapy were retrospectively evaluated. We analyzed differences in clinicopathological features and survival rates between patients with pure UC and those with HV. Conditional survival (CS) analysis was performed to obtain prognostic information over time.
A total of 32 patients (14.3%) had HV, with the most common variant being squamous differentiation, followed by glandular differentiation. UTUC with HV was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and LVI, compared to pure UC (all P < 0.01). Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were all significantly worse in the HV group compared to the pure UC group (all, P < 0.001). In multivariable analysis, HV and LVI were independent predictors of CSS and OS. We classified the patients into three groups using these two predictors: low-risk (neither HV nor LVI), intermediate-risk (either HV or LVI), and high-risk (both HV and LVI). Significant differences in PFS, CSS, and OS rates were found among the 3 groups. In CS analysis, the conditional PFS, CSS, and OS rates at 1, 2, 3, 4, and 5 years improved with increased duration of event-free survival. CS analysis revealed that most progression events occurred within 2 years after RNU, and patients with risk factors had worse PFS at all time points.
A risk model using HV and LVI can stratify PFS, CSS, and OS of patients treated with RNU. In addition, CS analysis revealed that HV and LVI were poor prognostic factors over time after RNU.
Upper Urinary Tract Tumors: Variant Histology Versus Urothelial Carcinoma
2021, Clinical Genitourinary Cancer
To evaluate stage at presentation and cancer-specific mortality (CSM) in upper urinary tract tumors according to histologic subtype.
Within the Surveillance, Epidemiology, and End Results registry (SEER, 2004-2016), we identified patients with upper urinary tract tumors with pure variant histology (UTVH) and pure upper urinary tract urothelial carcinoma (UTUC). Cumulative incidence plots, after propensity score matching for tumor and patient characteristics, addressed CSM. Subgroup analyses addressed efficacy of radical nephroureterectomy (RNU) in stage T1-2 and of chemotherapy in metastatic UTVH patients.
Of all 11,809 upper urinary tract tumor patients, 154 (1.3%) harbored squamous cell carcinoma (SCC), 86 (0.7%) adenocarcinoma, 39 (0.3%) neuroendocrine carcinoma, 38 (0.3%) other UTVH, and 11,492 (97.3%) UTUC. UTVH patients were more likely to exhibit metastatic stage disease at diagnosis than UTUC (odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P < .01). After detailed matching for performance status, only SCC showed significantly higher CSM than UTUC (multivariate HR = 1.71; P < .01). Subgroup analyses in stage T1-2 RNU patients showed, relative to UTUC patients, no CSM differences for SCC or adenocarcinoma patients. No significant survival benefit for chemotherapy administration was identified in patients with metastatic SCC or metastatic adenocarcinoma. This study is limited by its sample size and the missing centralized pathologic review.
Disease stage at diagnosis is more advanced in UTVH patients than UTUC. Across all stages, CSM is higher for SCC than for UTUC. However, in T1-2 stage disease, RNU results in similar survival in SCC or adenocarcinoma versus UTUC.
Clinicopathological characteristics, prognosis, and chemosensitivity in patients with metastatic upper tract urothelial carcinoma
2021, Urologic Oncology: Seminars and Original Investigations
To investigate the clinical characteristics, chemosensitivity, and outcome of metastatic upper tract urothelial carcinoma (UTUC).
Records of patients with metastatic UTUC since January 2005 were retrieved from a database that included clinical and survival data. Statistical analyses including survival and multivariate analyses of factors were respectively performed by the Kaplan-Meier method and Cox proportional hazard model.
A total of 250 consecutive UTUC cases were evaluated. There were 56 patients (22.4%) with initially diagnosed stage IV disease. The most common metastatic sites were lung (39.6%), distant lymph nodes (39.2%), bone (19.6%), liver (18.0%), and adrenal gland (7.2%), respectively, and the local recurrence rate was 10.4%. Two hundred thirteen patients received first-line chemotherapy. The overall response rate was only 28.7% and the median progression-free survival time was only 5.0 months. The overall survival time of the cohort was 18.0 months. Multivariate analyses showed that initially diagnosed stage IV disease, number of metastatic organs ≥3, no response to chemotherapy and cycles of chemotherapy ≤2 were adverse prognosticators for overall survival.
UTUC presented to be more prone to metastasize than locally recur and thought to have low chemosensitivity. Stage IV disease at initial diagnosis, number of metastatic organs, response and cycles of chemotherapy were independent prognosticators for metastatic UTUC.
Effects of Variant Histology on the Oncologic Outcomes of Patients With Upper Urinary Tract Carcinoma After Radical Nephroureterectomy: A Propensity Score–Matched Analysis
2019, Clinical Genitourinary Cancer
Citation Excerpt :
Although UTUC is histologically similar to bladder UC, to date only a very few reports focusing on UTUC with VH have been published.8,10-13 In this study, VH was present in 7.9% of UTUC specimens at a rate of 3.6% to 24.2%, which is relatively lower than those described in previous studies.8-13,20 Variance in the frequency of VH might be due to the different disease stages and clinical practices among pathologists at different institutions.
To determine the prognostic effect of upper tract urothelial carcinoma (UTUC) with variant histology (VH) after radical nephroureterectomy (RNU).
The data of 1173 patients who received RNU for UTUC without neoadjuvant chemotherapy in 11 institutions between 2002 and 2016 were retrospectively reviewed. A matched propensity score analysis was performed. Clinicopathologic variables, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were compared between patients with pure UTUC and patients with UTUC and VH. Univariate and multivariate Cox proportional regression models were used to determine the independent variables associated with oncologic outcomes.
UTUC with VH was observed in 93 patients (7.9%). After propensity score matching, UTUC with VH showed no difference in clinicopathologic features compared to pure UTUC; however, it was associated with shorter RFS, CSS, and OS (log rank, P = .011, P = .002, P = .006, respectively). Additionally, the multivariate analysis revealed that VH was independently associated with a poor RFS [hazard ratio (HR) = 1.92; 95% confidence interval (CI), 1.27-2.89; P = .002], CSS (HR = 4.47; 95% CI, 1.99-10.1; P = .001), and OS (HR = 3.00; 95% CI, 1.55-5.78; P = .001). However, the Kaplan-Meier method revealed that differences in RFS, CSS, and OS were not significant in patients who received adjuvant chemotherapy (log rank, P = .562, P = .060, P = .153, respectively).
UTUC with VH was independently associated with poor oncologic outcomes in patients with UTUC after RNU. Although patients with UTUC and VH had a poor prognosis compared to patients with pure UTUC, adjuvant chemotherapy would be helpful in improving the survival rates of these patients.
Programmed Death-ligand 1 Expression in Upper Tract Urothelial Carcinoma
2017, European Urology Focus
Citation Excerpt :
Previous studies of UTUC have estimated 5-yr recurrence-free, cancer-specific, and overall survival rates of 61%, 65%, and 62%, respectively [6]. Locally-advanced (American Joint Committee on Cancer stage pathologic T [pT]2 or higher) UTUC have particularly poor long-term survival; the 5-yr cancer-specific survival is <50% for pT2/pT3 tumors and <10% for pT4 tumors [7], and the presence of divergent histology (ie, squamous, sarcomatoid, etc.) is associated with worse clinical outcome [6]. From a clinical standpoint, UTUC can be stratified as low-risk (unifocal disease, size < 1 cm, low-grade cytology or biopsy, and no radiologic evidence of invasion) or high-risk (hydronephrosis, size > 1 cm, high-grade cytology or biopsy, multifocal disease, or previous radical cystectomy for bladder cancer) [3].
Urothelial carcinoma (UC) is the most common malignancy of the urinary tract. Upper tract (renal pelvis and ureter) urothelial carcinomas (UTUC) account for approximately 5% of UCs but a significant subset are invasive and associated with poor clinical outcomes.
To evaluate programmed death-ligand 1 (PD-L1) expression in UTUC.
UTUC cases from 1997–2016 were retrospectively identified from the surgical pathology database at a single large academic institution. The cohort included 149 cases: 27 low-grade and 24 high-grade pathologic T (pT)a, 29 pT1, 23 pT2, 38 pT3, and eight pT4. PD-L1 immunohistochemistry (IHC) was performed on representative whole tumor sections using anti-PD-L1 primary antibody clone 5H1.
PD-L1 expression was evaluated using a previously established cut-off for positivity (≥ 5% membranous staining). Association between PD-L1 IHC expression and clinicopathologic parameters was examined with Fisher's exact test; the effect of PD-L1 expression on cancer-specific mortality was assessed using the Cox proportional hazard model.
Approximately one-third (32.7%) of invasive primary UTUC and 23.5% of all primary UTUC (invasive and noninvasive tumors) demonstrated positive PD-L1 expression. Positive PD-L1 expression was associated with high histologic grade, high pathologic stage, and angiolymphatic invasion. Cancer-specific survival was not significantly associated with positive PD-L1 expression using a 5% cut-off. Study limitations include the retrospective nature and the fact that PD-L1 expression by IHC is an imperfect surrogate for response to therapy.
Positive PD-L1 expression in approximately one-third of primary invasive UTUC and association with high-risk clinicopathologic features provide a rational basis for further investigation of PD-L1-based immunotherapeutics in these patients.
Upper tract urothelial carcinoma is often associated with poor clinical outcome. While current treatment options for advanced upper tract urothelial carcinoma are limited, programmed death-ligand 1 positivity in approximately one-third of invasive tumors provides a rational basis for further investigation of programmed death-ligand 1-based immunotherapeutics in these patients.

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^☆: The study was supported by the National Natural Science Foundation of China and Technology through the Program of Ministry of Science and Technology of Sichuan Province.

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Original articleEffect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy☆

Abstract

Objective

Materials and methods

Results

Conclusions

Introduction

Section snippets

Patient selection

Results

Discussion

Conclusion

Diagn Histopathol

Mod Pathol

Ann Diagn Pathol

Hum Pathol

J Urol

J Urol

Urol Oncol

Eur Urol

J Urol

Urol Oncol

Urol Oncol

Ann Thorac Surg

Eur J Surg Oncol

Urol Oncol

Urology

Original article
Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy☆