Site of metastatic recurrence impacts prognosis in patients with high-grade upper tract urothelial carcinoma

PurposeMetastatic recurrence occurs in over 25% of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. While metastatic recurrence suggests poor prognosis, the impact of the specific site of recurrence on prognosis is not well documented.Materials and methodsWe retrospectively analyzed 188 patients who underwent radical nephroureterectomy for high-grade, node-negative upper tract urothelial carcinoma at our institution from 2003 to 2018 without receiving neoadjuvant or adjuvant chemotherapy. Competing-risks survival analysis was performed to evaluate the cumulative incidence and predictors of metastatic recurrence. The Kaplan-Meier method and log-rank test were used to estimate and compare recurrence site-specific survival probabilities following metastatic recurrence. Cox regression analyses were performed to assess site-specific prognoses.ResultsOf the 188 patients, 47 (25%) developed metastatic recurrence over a median follow-up of 30 months (interquartile range: 10.5–58.5 months). The 1- and 2-year cumulative incidences of metastatic recurrence were 13.6% and 23.6%, respectively. On multivariable analysis, lymphovascular invasion was significantly predictive of metastatic recurrence (subhazard ratio: 2.6, P = 0.01). Of the 47 patients who developed recurrence, 38 (80.9%) died over a median follow-up of 10 months (interquartile range: 5–20 months). Metastatic recurrence was most common in the lungs (n= 13, 28%) and at multiple sites (n= 14, 30%). Median time to recurrence was shorter for recurrences at multiple sites (6.5 months) and those in the liver (13 months) and bone (18 months) compared to other sites. Patients who recurred in the liver (hazard ratio: 6.3, P = 0.007), bone (hazard ratio: 4.9, P = 0.02), and multiple sites (hazard ratio: 4.6, P = 0.01) had significantly worse prognosis compared to those who recurred in lymph nodes. Statistical significance persisted after adjusting for treatment with salvage therapy.ConclusionsA significant proportion of high-grade upper tract urothelial carcinoma patients recur systemically after radical nephroureterectomy. Lymphovascular invasion is a predictor of metastatic recurrence and may inform decisions regarding perioperative chemotherapy. Hepatic and osseous recurrences have relatively quicker onset and less favorable prognosis compared to other sites. These findings may benefit future efforts to develop recurrence site-specific treatment plans and highlight the necessity of subsequent endeavors to explore the genetic associations of recurrence in upper tract urothelial carcinoma.     

Clinicopathological characteristics and prognosis of metastatic collecting duct carcinoma

ObjectiveTo investigate the clinicopathological characteristics, response to different treatment regimens, and prognostic factors of metastatic collecting duct carcinoma (CDC).Patients and MethodsInformation of patients with metastatic CDC was retrieved from a database including clinical and survival data. Survival outcomes were analyzed with the Kaplan-Meier method, and prognostic factors were identified with the Cox proportional hazard model.ResultsFifty patients with metastatic CDC were included in this study. Most patients had an advanced T stage (58% T3-4) and high WHO/ISUP grade (86% G3-4). Twenty-nine patients (58%) developed metastases from an early stage, 42% had distant metastases at diagnosis, and 28% received cytoreductive nephrectomy. In the first-line setting, the objective response rate was 27.0%, and the median progression-free survival was 6.4 months (95%CI 4.9–7.9) for 37 patients who received chemotherapy combined with sorafenib. One PR was seen in 4 patients who received anti-PD-1 antibody plus axitinib. The median overall survival for the whole population was 12.6 months (95%CI 7.8–17.4). In univariate analyses, advanced T stage, East Cooperative Oncology Group Performance Score ≥1, anemia, elevated lactate dehydrogenase, and no response to first-line treatment was associated with poor prognosis (P < 0.05). In multivariate analyses, advanced T stage and anemia were independently associated with a poorer prognosis. The Memorial Sloan-Kettering Cancer Center (MSKCC) model (P = 0.002) predicted the prognosis of metastatic CDC patients more accurately than the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model (P = 0.063).ConclusionT Stage and anemia were independent prognostic factors for metastatic CDC. MSKCC was more accurate than the IMDC model to predict the outcome. Chemotherapy plus sorafenib demonstrated substantial efficacy in the first-line setting. Anti-PD-1 plus axitinib showed a preliminary antitumor effect and is worthy of further exploration.     

Endoscopic management of upper tract urothelial carcinoma in patients with a history of bladder urothelial carcinoma

PURPOSE: Endoscopic management of renal pelvis and ureteral urothelial carcinoma is gaining acceptance as a conservative treatment modality. Patients with a history of bladder urothelial carcinoma are at high risk for upper tract recurrence. We evaluate the role of endoscopic management of upper tract urothelial carcinoma in patients with a history of primary bladder urothelial carcinoma. MATERIALS AND METHODS: We retrospectively reviewed 90 patients with a history of primary bladder urothelial carcinoma who underwent endoscopic treatment of localized upper tract urothelial carcinoma between 1983 and 2004. RESULTS: Median patient age at diagnosis was 73 years (range 50 to 90). A total of 13 (14.4%) patients previously underwent cystectomy. With a median followup of 4.3 years (range 0.1 to 17), 105 upper tract urothelial carcinoma recurrences developed in 55 patients at a mean of 0.6 years (range 22 days to 5.9 years). Of these recurrences 76 were amenable to endoscopic management while 29 required nephroureterectomy. In 38 patients there were 91 bladder recurrences. At last followup 48 patients died, 17 of urothelial carcinoma at a median of 3.4 years (range 1 to 10). Cancer specific survival at 5 years for this cohort was 71.2%. Risk of death from urothelial carcinoma was significantly associated with stage (RR 3.23) and grade (RR 4.05) of upper tract urothelial carcinoma, imperative indication (RR 4.30), and treatment of bladder urothelial carcinoma with cystectomy (RR 3.34). CONCLUSIONS: Endoscopic management of upper tract urothelial carcinoma in patients with primary bladder urothelial carcinoma demonstrates a significant local recurrence rate. Furthermore, 5-year cancer specific survival is low. These patients represent a high risk cohort requiring strict ureteroscopic followup after endoscopic management is instituted.     

Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma

Objectives

Studies indicate overexpression of osteopontin (OPN) promotes carcinogenesis, progression and metastasis of multiple human malignancies. However, the function of OPN in urothelial carcinoma (UC) of the upper urinary tract has not been investigated. This study evaluates the clinical significance of OPN expression in upper urinary tract UC.

Materials and methods

One hundred and ten cases (median age = 64, range = 24–84 years) of renal pelvic or ureter UC were retrospectively reviewed in this study. OPN expression were evaluated by immunohistochemistry staining on paraffin-embedded section of the tumor and scored by two qualified pathologists.

Results

High OPN expression was found in 54 (49.1%) of the cancer specimens. OPN expression was not significantly correlated with tumor T stage (P = 0.761), N stage (P = 0.339) or grade (P = 0.349). However, OPN expression was differently expressed by gender (P = 0.012) and cancer location (P = 0.026). OPN expression did not correlate with bladder recurrence-free (P = 0.661) or extra-bladder recurrence-free (P = 0.787) survival, but high OPN expression was a significant predictor for cancer-specific survival (P = 0.014).

Conclusion

Our findings indicated that higher OPN expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of OPN in the carcinogenesis of upper urinary tract UC.     

Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis

OBJECTIVE

To describe the lymphatic vessel density and to determine the functional and prognostic significance of tumoral lymphatic vessels in upper tract urothelial carcinoma (UTUC).

PATIENTS AND METHODS

The study included 65 patients who had a radical nephroureterectomy (RNU) for UTUC between 1997 and 2004. All pathological slides were re‐evaluated by one reference pathologist and clinical data were reviewed. Lymphatic endothelial cells (LECs) were stained immunohistochemically using D2‐40. The lymphatic vessel density (LVD) was described in representative intratumoral (ITLVD), peritumoral (PTLVD) and non‐tumoral (NTLVD) areas. Random samples were selected for double‐immunostaining with D2‐40 and CD‐34 (to distinguish blood and lymphatic vessels) and the proliferation marker Ki‐67 to detect lymphangiogenesis. The primary outcome measures were disease‐specific survival (DSS) and disease recurrence (urothelial and/or distant).

RESULTS

The median (interquartile range) PTLVD was 4.0 (3.0–6.3), and significantly higher than that for ITLVD, of 0.3 (0–1.7) (P < 0.001), and NTLVD, of 3 (2.0–3.7) (P < 0.001). Both a higher ITLVD and PTLVD, the presence of lymphovascular invasion (LVI) (each P < 0.001) and a high tumour grade (P = 0.004) were associated with reduced DSS on univariate analysis. A higher PTLVD (P = 0.028) and the presence of LVI (P = 0.020) independently predicted reduced DSS on multivariate analysis. IT and PT lymphatic vessels showed proliferating LECs in all analysed samples.

CONCLUSION

Lymphangiogenesis is present in UTUC, as shown by a significantly increased PTLVD and proliferating LECs. Our findings suggest functional relevance of PT lymphatic vessels during lymphatic tumour spread. PTLVD is a potential novel prognostic factor for DSS in UTUC, and further prospective studies will be needed to determine the effect of its routine evaluation on clinical outcomes of this malignancy.     

Primary upper tract urothelial carcinoma with thyroid-like features

Abstract:   We present a unique case of primary urothelial carcinoma with both histological and immunohistochemical features similar to thyroid papillary carcinoma. Following surgical resection of the primary tumor and localized metastatic lymphadenectomy, the patient was treated with a course of adjuvant chemotherapy. No evidence of primary thyroid carcinoma was noted. The patient was without recurrence after a 6 month follow-up.     

Impact of the primary tumor location on secondary sites and overall mortality in patients with metastatic upper tract urothelial carcinoma

BackgroundTo date it is unknown whether renal vs. ureteral urothelial carcinoma affects the type and the distribution of metastatic sites, and whether survival differs according to renal vs. ureteral location in metastatic patients.MethodsTwo datasets were used, namely Surveillance, Epidemiology and End Results (SEER) and National Inpatients Sample (NIS). Multivariable logistic regression models tested whether renal pelvis vs. ureteral location predicts site-specific metastases. Kaplan-Meier plots and multivariable Cox regression models (CRMs) tested overall mortality (OM) according to renal pelvis vs. ureteral location.ResultsIn SEER (2010–2016), 623 (71.1%) metastatic renal pelvis urothelial carcinoma (RPUC) vs. 253 (28.9%) ureteral urothelial carcinoma (UUC) patients were identified. Patients with RPUC more frequently harbored lung (46.1% vs. 35.2%, P < 0.01; Odds ratio [OR]: 1.57, P < 0.01), but less frequently liver metastases (27.9% vs. 36.4%, P = 0.02; OR:0.66, P = 0.01). In RPUC, lung, liver, bone, and brain metastases independently predicted higher OM. Only liver metastases independently predicted higher OM in UUC. In NIS (2005–2015), 818 (61.0%) RPUC vs. 522 (39.0%) UUC patients were identified. Patients with RPUC more frequently harbored lung (34.0% vs. 17.2%, P < 0.001; OR:2.36, P < 0.001), as well as brain (4.4% vs. 1.9%, P = 0.02; OR:2.00, P = 0.049) metastases, but less frequently harbored retroperitoneal and/or peritoneal (12.3% vs. 21.8%, P < 0.001; OR:0.51, P < 0.001), urinary tract (9.3% vs. 14.0%, P = 0.01; OR:0.65, P = 0.01) and multiple metastatic sites (62.6% vs. 70.7%, P < 0.01; OR:0.69, P < 0.01).ConclusionsIn both databases lung metastases were more frequent in RPUC and abdominal metastases were more frequent in UUC. Moreover, liver metastases independently predicted worse survival, regardless of primary site.     

The comparison of oncologic outcomes between metastatic upper tract urothelial carcinoma and urothelial carcinoma of the bladder after cisplatin-based chemotherapy

ObjectiveTo compare the oncologic outcomes and prognostic factors between metastatic upper tract urothelial carcinoma (UTUC) and UC of the bladder (UCB) after cisplatin-based chemotherapy.Materials and methodsWe retrospectively reviewed patients with metastatic UTUC and UCB after methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or gemcitabine/cisplatin chemotherapy between 1997 and 2014 at Kaohsiung Chang Gung Memorial Hospital. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Univariate and multivariate analyses with Cox proportional hazard models were also performed to assess the effect of prognostic factors.ResultsTotally, 203 patients were enrolled into our study, including 120 patients with UTUC and 83 patients with UCB. For patients with UTUC, the median PFS was 7.3 months vs. 4.0 months (P<0.001), and the median OS was 17.0 months vs. 10.5 months (P<0.001) for MVAC and gemcitabine/cisplatin, respectively. For patients with UCB, the median PFS (P = 0.35) and OS (P = 0.06) of the 2 groups were insignificant. In multivariate analyses, number of metastatic sites was the identical prognostic factor for OS between UTUC (hazard ratio [HR] = 2.74; 95% CI: 1.63–4.62; P<0.001) and UCB (HR = 3.12; 95% CI: 1.52–6.39; P = 0.002). Presence of liver metastasis (HR = 1.84; 95% CI: 1.05–2.23; P = 0.03) and MVAC chemotherapy (HR = 0.54; 95% CI: 0.35–0.83; P<0.001) were significantly correlated to survival only for UTUC, not for UCB.ConclusionOur study suggests discordant oncologic outcomes and prognostic factors between metastatic UTUC and UCB after cisplatin-based chemotherapy. A prospective study is warranted to validate our results.     

Temporal stage and grade migration in surgically treated patients with upper tract urothelial carcinoma

Study Type – Therapy (individual cohort)
Level of Evidence 2b

OBJECTIVE

To examine the temporal trends in stage and grade at presentation, as well as cancer‐specific mortality (CSM) rates, in surgically treated patients with upper tract urothelial carcinoma (UTUC), as few population‐based studies addressed contemporary cancer‐control outcomes in patients with UTUC.

PATIENTS AND METHODS

Within the Surveillance, Epidemiology and End Results (SEER) database, we identified 4915 patients diagnosed with UTUC between 1983 and 2004, who had either a nephroureterectomy (NU) or a segmental ureterectomy (SU). Patients were divided into four groups according to the year‐of‐surgery quartiles. The chi‐square test and the chi‐square trend test were used for comparison of proportions and trends over time. Kaplan‐Meier plots were used to graphically depict CSM rates. Multivariable Cox regression models were used to test the effect of the year‐of‐surgery quartiles on CSM. Covariates consisted of SEER stage, tumour grade, age, race, primary tumour site, type of surgery, and SEER registries.

RESULTS

Of 4915 assessable patients, 1316, 1328, 1146 and 1125 were, respectively, treated in 1983–1988, 1989–94, 1995–99 and 2000–2004. Of those, 4430 had a NU and 485 had a SU. The rates of non‐localized stage and of grade III‐IV disease at surgery increased, respectively, from 49.8% to 69.5% (P < 0.001) and 45.7 to 70.2% (P < 0.001) during the study period. CSM rates at 4 years after surgery reflected the temporal stage and grade differences, and increased from 18.2 to 23.9% (P = 0.03) between 1983–1988 and 2000–2004. In multivariable analyses, when stage and grade were taken into account, most contemporary patients showed more favourable CSM rates than their historic counterparts (hazard ratio 0.7, P = 0.02).

CONCLUSIONS

We report a stage and grade migration at NU or SU towards more aggressive disease among surgically treated patients between 1983 and 2004. Despite this observation, the CSM rates of contemporary patients have not worsened, which validates the role of NU and SU as effective treatments for UTUC.     

Molecular aspects of upper tract urothelial carcinoma

ObjectivesPrimary upper tract urothelial carcinoma (UTUC) is a relatively rare tumor with up to 60% of cases being muscle invasive at presentation. In this article we review the molecular biology of UTUC, an understanding of which may help to address some of the dilemmas surrounding the diagnosis and treatment of this disease and ultimately lead to the introduction of personalized treatment plans.MethodsThe literature search on the molecular aspects of UTUC was performed using the National Library of Medicine database.ResultsUTUC and urothelial carcinomas of the bladder share many common biological pathways. UTUC are more commonly associated with conditions such as Balkan Endemic Nephropathy and Hereditary Non Polyposis Colon Cancer (HNPCC), the molecular basis of which is now being understood. A large number of potential biomarkers have been studied to help identify robust prognostic markers in UTUC.ConclusionAdvances in our understanding of the biology of UTUC is may in the future help to identify novel druggable targets, clinically applicable biomarkers and guide treatment of the rare but lethal condition.     

Optimizing management of upper tract urothelial carcinoma

Upper tract urothelial cancer (UTUC) is a rare cancer of the urothelium, comprising only a fraction of cases as compared to urothelial tumors of the bladder. As a result, systemic treatment approaches in bladder cancer are often applied to patients with UTUC. Given the anatomical location of these tumors, the age, the comorbid conditions of these patients with UTUC, and the need for radical nephroureterectomy for treatment, most patients have substantial impairment of renal reserve. There is growing evidence for the benefit of perioperative chemotherapy in this disease. Patients with UTUC have high rates of microsatellite instability and fibroblast growth factor receptor 3 mutations as compared to their bladder counterparts presenting unique, important subsets in UTUC. Immune checkpoint inhibitors targeting the programmed death receptor 1 and ligand have provided a new second-line treatment option for patients with UTUC and appear particularly well suited for patients with microsatellite instability. More work in understanding the molecular gene signatures and its relationship to response to chemotherapy, immunotherapy, and targeted therapy is needed to continually optimize care for patients with all stages of disease. Advances in UTUC are possible, when one accounts for the unique clinical and biological features of this disease.     

Longitudinal change in renal function after nephroureterectomy in patients with upper tract urothelial carcinoma

AimsChronic kidney disease is a significant risk factor for several comorbidities and death. The longitudinal change in renal function after nephroureterectomy in patients with upper tract urothelial carcinomas and the risk of developing chronic kidney disease (CKD) was investigated.Materials and methodsThis retrospective study included 186 patients who underwent unilateral nephroureterectomy between 1997 and 2001. Creatinine data prior to and after the surgery were collected and the estimated Glomerular Filtration Rate (eGFR) were calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.ResultsThe cohort of 186 patients included 87 men and 99 women with a mean age of 67.2 years. Preoperative mean eGFR was 41.97 mL/minute/1.73 m². Eighty six percent of the patients' preoperative eGFR were <60 mL/minute/1.73 m². The mean eGFR was 35.85 mL/minute/1.73 m² at the end of the 5-year follow up. For the 26 patients with preoperative normal renal function, 17 patients (65.4%) had new chronic kidney diseases. Ten patients (5.4%) required hemodialysis at the end of the study.ConclusionIn this study, it was found that the average renal function of the patients with upper tract urothelial carcinoma is not as good as the general population. More than half of the normal renal function patients have new onset chronic kidney disease after surgery. For preventing further deterioration of renal function, the implication of partial nephrectomy or segmental ureterectomy for selected patients with localized urothelial carcinoma should be re-examined. Besides, neoadjuvant chemotherapy should be considered for those who are not good candidates for local treatment.     

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

ObjectiveTo 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 methodsData 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).ResultsUTUC 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).ConclusionsApproximately 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.     

Loss of uroplakin III expression is associated with a poor prognosis in patients with urothelial carcinoma of the upper urinary tract

OBJECTIVE: To investigate the association between the expression of uroplakin III (UPIII) and the prognosis of patients with urothelial carcinoma of the upper urinary tract, as uroplakins are urothelium-specific markers of terminal urothelial differentiation. PATIENTS AND METHODS: Clinicopathological and follow-up data from 71 patients who had undergone radical nephroureterectomy and lymph node dissection or sampling for urothelial carcinoma of the upper urinary tract were reviewed. The expression of UPIII was evaluated immunohistochemically in surgical specimens. Cancer-specific survival was calculated using Kaplan-Meier plots. Prognostic values of clinicopathological variables including UPIII expression status, tumour stage and grade were evaluated by univariate analyses, followed by multivariate analysis using the Cox proportional-hazard model. RESULTS: In all specimens there was intense UPIII immunoreactivity of umbrella cells of normal urothelium. In tumour samples, UPIII expression was positive in 75% of < or = pT1 tumours and 40% of > or = pT2 (P = 0.02), and in 65% of grade 1-2 tumours and 33% of grade 3 (P = 0.009). Of the 71 patients, 21 died from the disease during the median follow-up of 61 months. The cancer-specific survival of patients with negative UPIII expression was significantly worse than that of those with positive UPIII expression (5-year cancer-specific survival, 100% vs 46%, P < 0.001). Neither patient age at diagnosis, histological grade, sex, or multiplicity of the tumour had significant prognostic value. Multivariate analysis revealed that UPIII expression was the most powerful prognostic indicator (P < 0.001) followed by tumour stage (P = 0.04) and lymph node metastasis (P = 0.05). CONCLUSION: The present data suggest that UPIII expression is a powerful prognostic factor in patients with upper urinary tract urothelial carcinoma.