A Contemporary Clinicopathologic Analysis of Primary Urothelial Carcinoma of the Urethra Without Concurrent Renal Pelvic, Ureteral, or Bladder Carcinoma.

Primary urothelial carcinoma (UCa) of the urethra is relatively uncommon, and the underlying pathogenesis has not been well characterized, especially in the absence of concurrent UCa at other sites. A search for cases of primary UCa of the urethra was conducted. Patients with concurrent UCa of the renal pelvis, ureter, or bladder at the time of diagnosis of the primary tumor were excluded. Clinicopathologic and follow-up data were obtained. A total of 35 cases from 30 patients (27 male and 3 female) were included in the study. The mean patient age at the initial diagnosis was 71 years (range: 41-90 years). Cases were composed of high-grade UCa (26 of 35 = 74%), low-grade UCa (4 of 35 = 11%), and UCa in situ (5 of 35 = 14%). Invasion was present in 14 of 26 (54%) cases of high-grade UCa. Interestingly, 23 of 30 (77%) patients had a previous history of UCa including 7 (30%) cases with divergent differentiation or variant histology. Follow-up data were available in 23 patients with a mean duration of 26.7 months (range: 0.6-87 months). Eleven patients (31%) died of metastatic UCa. This is one of the largest studies to date of primary UCa of the urethra without concurrent UCa of the renal pelvis, ureter, or bladder. Previous history of UCa of the bladder, especially with divergent differentiation or variant histology is conceivably a key risk factor for developing subsequent primary UCa of the urethra. These findings are important for the development of surveillance protocols and therapeutic strategies.

Primary tumor surgery improves survival in non-metastatic primary urethral carcinoma patients: a large population-based investigation.

BACKGROUND: Primary urethral carcinoma (PUC) is a rare genitourinary malignancy with a relatively poor prognosis. The aim of this study was to examine the impact of surgery on survival of patients diagnosed with PUC. METHODS: A total of 1544 PUC patients diagnosed between 2004 and 2016 were identified based on the SEER database. The Kaplan-Meier estimate and the Fine and Gray competing risks analysis were performed to assess overall survival (OS) and cancer-specific mortality (CSM). The multivariate Cox regression model and competing risks regression model were used to identify independent risk factors of OS and cancer-specific survival (CSS). RESULTS: The 5-yr OS was significantly better in patients who received either local therapy (39.8%) or radical surgery (44.7%) compared to patients receiving no surgery of the primary site (21.5%) (p < 0.001). Both local therapy and radical surgery were each independently associated with decreased CSM, with predicted 5-yr cumulative incidence of 45.4 and 43.3%, respectively, compared to 64.7% for patients receiving no surgery of the primary site (p < 0.001). Multivariate analyses demonstrated that primary site surgery was independently associated with better OS (local therapy, p = 0.037; radical surgery, p < 0.001) and decreased CSM (p = 0.003). Similar results were noted regardless of age, sex, T stage, N stage, and AJCC prognostic groups based on subgroup analysis. However, patients with M1 disease who underwent primary site surgery did not exhibit any survival benefit. CONCLUSION: Surgery for the primary tumor conferred a survival advantage in non-metastatic PUC patients.

Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy.

The expression status of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and the infiltration of CD8+ T cells in tumor tissues are considered to be related to immunotherapy efficacy and patient prognosis. The purpose of this study is to clarify the prognostic value of the PD-L1/PD-1/CD8 axis, and to develop and validate a comprehensive scoring system based on multiple immune variables to predict cancer survival of upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). The immunohistochemical method was used to detect the expression of PD-L1, PD-1, and CD8 in cancer tissues of UTUC patients after RNU. Then, an immunoscore was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model in the training cohort (n = 120), and it was verified in the validation cohort (n = 54). We found that infiltration of PD-L1+ immune cells (ICs), stromal PD-1+ tumor-infiltrating lymphocytes (TILs), and intratumoral CD8+ TILs was associated with poor overall survival (OS). The immunoscore based on the three immune variables further divided the patients into low- and high-risk groups, and there was a significant difference in the survival rate. A nomogram was constructed by combining tumor-node-metastasis (TNM) stage and immunoscore, and the area under the curve of the receiver-operating characteristic (ROC) (0.78) for predicting 5-year mortality was better than that of the TNM stage (0.70) and immunoscore (0.76). Our results show that the PD-L1/PD-1/CD8 axis-based classifier have potential clinical application to predict cancer survival of UTUC patients after RNU.

Primary Squamous Cell Carcinoma of the Male Proximal Urethra: Outcomes from a Single Centre.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the male proximal urethra is an aggressive and rare urogenital malignancy. OBJECTIVE: To review the surgical management and outcomes for male proximal urethral SCCs within a single centre and to suggest an algorithm for the surgical management of these rare tumours. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of patients undergoing surgery for male proximal urethral SCC within a single tertiary academic centre managing rare genital tumours. Ten patients with a histological diagnosis of proximal urethral SCC were identified from an institutional database over a period of 10 yr with a median follow-up of 22.5 mo (standard deviation±25.77 mo). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathological staging, surgical treatment, and neoadjuvant and adjuvant treatment were recorded. Complications according to the Clavien-Dindo classification and overall survival rates were recorded. Kaplan-Meier curves were used for overall survival. RESULTS AND LIMITATIONS: A total of 10 patients were identified of whom eight underwent panurethrectomy and radical prostatectomy. Radical inguinal lymphadenectomy was performed in five patients, which confirmed bilateral metastatic disease. Perioperative complications were reported in six patients (Clavien I and II). Within 6 mo of surgery, 90% of patients developed distant metastatic disease. Nine patients died of urethra cancer during the follow-up. One patient is still on follow-up. The median overall follow-up was 13.92 mo (range: 5-91 mo). At 5 yr, cancer-specific/overall survival was 10%. A limitation of this study is the retrospective design, which is unavoidable for such a rare disease. CONCLUSIONS: Radical surgery allows local disease control, but despite neo/adjuvant treatment, proximal urethral SCC is associated with poor survival outcomes and progression to distant metastatic disease within 6 mo. PATIENT SUMMARY: Proximal urethral squamous cell carcinoma is a rare cancer in men which is often detected late. Patients often present with problems such as voiding, urethral bleeding, or a palpable mass. Aggressive surgery allows local control, but despite this the overall survival is poor. Adjuvant and neoadjuvant radiochemotherapy can improve survival. Multicentric randomised trials are needed to identify the correct treatment modality.

Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies.

BACKGROUND: The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. MATERIALS AND METHODS: We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. RESULTS: Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. CONCLUSION: Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

The effect of centralization of care on overall survival in primary urethral cancer.

PURPOSE: Centralization of care to high-volume centers improves outcomes across urologic malignancies, but there exists a paucity of data for low-incidence cancers. Given the rarity of primary urethral cancer (UC) and the need for complex multidisciplinary treatment, we sought to evaluate differences in practice patterns and clinical outcomes across types of treating facilities. MATERIALS AND METHODS: We identified all patients diagnosed with UC from 2004 to 2016 in the National Cancer Database. The Kaplan-Meier method was used to evaluate overall survival (OS) and multivariable Cox regression analysis was used to investigate independent predictors of OS. The chi-square test was used to analyze differences in practice patterns. RESULTS: We identified 6,445 patients with UC. Median overall survival was 40.5 months (interquartile range 38.4-42.6). There was a significant difference in OS based upon facility type, and this difference remained significant on subgroup analysis for squamous cell carcinoma and urothelial carcinoma. Academic centers had superior OS on pairwise comparisons (all P< 0.05) and were associated with decreased risk of death, hazard ratio 0.858 (95% confidence interval 0.749-0.983). Academic centers had a significantly greater frequency of neoadjuvant/adjuvant chemotherapy and radiation (P < 0.001). Academic centers performed radical surgery in 34.1% of patients compared to 14.5% in community programs (P < 0.001), and regional lymphadenectomy in 31.6% of patients compared to 13.2% in community programs (P < 0.001). CONCLUSION: There exist significant differences in survival for patients with UC based upon treating facility. Variations in practice patterns including multimodal treatment, radical surgery, and regional lymphadenectomy may contribute to the observed differences in clinical outcomes.

The effect of race/ethnicity on histological subtype distribution, stage at presentation and cancer specific survival in urethral cancer.

OBJECTIVE: To test the effect of race/ethnicity on histological subtype, stage at presentation, and cancer specific mortality (CSM) in urethral cancer patients. MATERIAL AND METHODS: Stratified analyses (Surveillance, Epidemiology and End Results [2004-2016]) tested the effect of race/ethnicity on histology and stage. Cumulative incidence-plots and multivariable competing-risks regression models (CRR), addressed CSM, after matching for TNM-stage, histology, age, and gender. RESULTS: Of 1,904 urethral cancer patients, 71% were Caucasian, 16% African American, 7% Hispanic and 5% other. African Americans were younger (66 years) than Caucasians (73 years) and Hispanics (74 years). In African Americans, adenocarcinoma (25%) and squamous cell carcinoma (SCC; 29%) were more frequent than in Caucasians (12% and 23%) or Hispanics (15% and 20%). African Americans with adenocarcinoma exhibited higher stage than other adenocarcinoma patients. In CRR, African Americans (35%) and Hispanics (29%) exhibited highest and second highest 3-year CSM, even after matching. After further multivariable adjustment of matched CRRs, CSM was higher in Hispanics (HR: 1.93, P= 0.03) and in African Americans (Hazard ratio 1.35, P= 0.07), relative to Caucasians. CONCLUSION: Race/ethnicity impacts important differences on urethral cancer patients. African American race/ethnicity predisposes to higher rate of SCC and adenocarcinoma. Moreover, African Americans are younger and present with higher stage at diagnoses. Finally, even after most detailed matching for stage, age, gender, and adjustment for treatment and systemic therapy and socioeconomic status, African Americans and Hispanics exhibit higher CSM than Caucasians.

Primary Female Urethral Carcinoma: Proposed Staging Modifications Based on Assessment of Female Urethral Histology and Analysis of a Large Series of Female Urethral Carcinomas.

Primary female urethral carcinoma is rare. Limited clinicopathologic information has hindered development of staging criteria in this disease. We analyzed 29 primary female urethral carcinoma resections from 3 academic medical centers to characterize histopathologic features, clinical outcomes, and applicability of current and a novel modified staging criteria. We complemented this analysis with review of fully embedded female autopsy urethras to detail anterior and posterior urethral wall histology. Primary female urethral carcinoma subtypes included urothelial carcinoma in situ (3/29, 10%), adenocarcinoma in situ (1/29; 3%), invasive urothelial carcinoma (13/29, 45%), clear cell carcinoma (5/29, 17%), adenocarcinoma not otherwise specified (4/29, 14%) and squamous cell carcinoma (3/29, 10%). Only 6/29 cases (21%) were originally assigned a stage at diagnosis. Using histologic landmarks specific to the female urethra, we modified existing eighth edition American Joint Committee on Cancer urethral staging to a histology-based female urethral carcinoma staging (UCS) system. UCS stages were defined as pTa/pTisUCS (noninvasive carcinoma), pT1UCS (subepithelial tissue invasion), pT2UCS (periurethral muscle invasion), pT3UCS (vaginal adventitia or surrounding fibrovascular tissue), and pT4UCS (anterior wall fibroadipose tissue or posterior vaginal wall). UCS staging was applicable to all cases and showed stepwise changes in disease recurrence with increasing stage and was statistically significant for disease-specific and overall survival in contrast to the American Joint Committee on Cancer staging system. This study of one of the largest cohort of primary female urethral carcinomas provides a modified histology-based staging system specific to female urethral anatomy that provides outcomes-related information, which may be further validated by larger multi-institutional studies.

Urethral involvement is associated with higher mortality and local recurrence in vulvar melanoma: a single institutional experience.

Vulvar malignant melanoma (VMM), although uncommon, comprises 5-10% of all vulvar malignancies. Local control is notoriously poor in VMM with recurrence rates of 30-50% compared with approximately 3% in cutaneous melanomas. We studied clinicopathologic features of 37 women with VMM, after reviewing three decades of clinical follow-up data in our institutional databases. Most patients were Caucasian (n = 35) with an average age at diagnosis of 60.6 years (range 23-83). The most common subtype was mucosal lentiginous melanoma (n = 25). We compared Kaplan-Meier survival curves of 31 patients defined by clinical and microscopic attributes using exact log-rank tests. Younger patients at diagnosis (23-64 years), those with thin melanomas (≤1 mm), and those with Clark's level II or III tumors had better 5-year survival rates than older patients (65-83 years) and those with thick melanomas (>1 mm) and those with Clark's level IV or V (P ≤ 0.05), respectively, by exact log-rank test. Local recurrence of melanoma occurred in 15 patients. Nine patients (24%) had eventual urethral involvement by malignant melanoma, and this feature was associated with significantly shorter survival (P = 0.036). Patients with urethral involvement had shorter median time to death and worse 5-year survival rates. Given that spread to the urethra is common in VMM and urethral recurrence is also associated with mortality, pathology excision specimens should be carefully reviewed with attention to urethral involvement as a potentially important prognostic factor.

Risk factors and oncological outcomes of urethral recurrence in male patients with muscle invasive bladder cancer after radical cystectomy combined with urinary diversion: a propensity score-matched case control study.

BACKGROUND: Radical cystectomy (RC) is the primary treatment strategy for muscle invasive bladder cancer (MIBC). However, it carries a high risk of urethral recurrence (UR) in male patients. The risk factors and oncological outcomes of UR remain unclear. We aimed to identify the risk factors and oncological outcomes of UR in male patients with MIBC after RC combined with urinary diversion. METHODS: After propensity score matching, we evaluated 137 male patients with MIBC who underwent RC combined with urinary diversion at our center between January 1, 2007 and December 31, 2015. Patient demographics, comorbidity, and perioperative data were recorded. Univariate and multivariate Cox proportional hazards regression were used to estimate the hazard ratio and 95% confidence intervals. Cancer-specific survival (CSS) and overall survival (OS) were measured using the Kaplan-Meier curve with log-rank test. P < 0.05 was considered statistically significant. RESULTS: Of the 310 patients, 30 (9.7%) patients underwent UR. In the matched group, the independent risk factors of UR were history of TURB (HR = 3.069, P = 0.018), tumor stage (T3 vs. T2, HR = 3.997, P = 0.014; T4 vs. T2, HR = 2.962, P = 0.015), and tumor multifocality (HR = 2.854, P = 0.011). The CSS and OS of patients with UR were equivalent to the patients without UR (P = 0.295, P = 0.616). CONCLUSION: This propensity score-matched case-control study showed that UR is not rare in male patients with MIBC after RC combined with urinary diversion. We identified three independent risk factors of UR: history of TURB, tumor stage, and tumor mutifocality. The oncological outcomes were equivalent between patients with and without UR. These findings could help improve treatment strategies and follow-up schedules.

Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site.

Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.

Nomograms for predicting long-term overall survival and cancer-specific survival in patients with primary urethral carcinoma: a population-based study.

BACKGROUND: Our aim was to identify the independent prognostic factors in patients with primary urethral carcinoma (PUC) and to predict their overall survival (OS) and cancer-specific survival (CSS) at 3, 5, and 8 years. METHODS: Patients with PUC identified in the Surveillance, Epidemiology, and End Results (SEER) database were divided into training and validation cohorts. Nomograms were constructed based on the results of Cox regression analysis. The predictive performance of each nomogram was evaluated using the consistency index (C-index), the area under the receiver operating characteristics curve (AUC), and calibration plots. Decision-curve analysis (DCA) was used to test the clinical value of the predictive models. RESULTS: Our study screened 822 patients with PUC. Multivariate analysis showed that the age at diagnosis, race, histology, American Joint Committee on Cancer (AJCC) stage, and surgery status were independent prognostic factors for CSS and age at diagnosis, race, histology, AJCC stage, surgery status, and chemotherapy for OS (all P < 0.05). We used these prognostic factors to construct nomograms. The C-indexes for OS and CSS were 0.713 and 0.741 in training cohorts and 0.714 and 0.738 in validation cohorts, respectively. The AUC and calibration plots demonstrated the good performance of both nomograms. The DCA indicated the presence of clinical net benefits in both the training and validation cohorts. CONCLUSION: We developed and validated nomograms for predicting OS and CSS in patients with PUC, which can help clinicians make treatment decisions.

Optimizing the Role of Surgery and Radiation Therapy in Urethral Cancer Based on Histology and Disease Extent.

PURPOSE: Urethral cancer is rare, with limited data guiding treatment. A national hospital-based registry was used to evaluate the role of local therapy in these patients. METHODS AND MATERIALS: We performed a retrospective cohort study of patients who, between 2004 and 20013, received a diagnosis of T0-4N0-2 M0 urethral cancer. Local therapy was radiation therapy (RT), surgery (S), or S and RT (S+RT). The Cox proportional hazards model was used to assess the impact of therapy type on overall survival (primary endpoint). Subgroup analysis by extent of disease (early stage [T0-2 N0] vs locally advanced [T3+ or N+]) and histology was performed. RESULTS: In our study, 2614 patients had a median follow-up of 28 months. Three-year overall survival was 54%. In 501 patients with locally advanced disease, S+RT was associated with improved survival versus S alone (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.42-0.80). There was no difference for patients with squamous cell carcinoma by treatment type, but patients with adenocarcinoma (RT vs S: HR 0.20; 95% CI, 0.07-0.60) or transitional cell carcinoma (S+RT vs S: HR 0.45, 95% CI, 0.26-0.77) had improved OS with RT as part of treatment. In 1705 early-stage patients, there was no association with survival when comparing S+RT versus S. CONCLUSIONS: For patients with locally advanced disease and transitional cell carcinoma undergoing S, the addition of RT is associated with improved overall survival and should be considered. An RT-based approach may be preferred for adenocarcinoma, but there was no clear association with survival by therapy type for squamous cell carcinoma. This study is hypothesis generating; prospective trials are necessary.

Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling.

We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 (P = 0.015)/phospho-NF-κB/p65 (P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade (P = 0.015)/muscle-invasive (P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression (P < 0.001) and cancer-specific mortality (P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR.

Treatment and Outcomes of Primary Urethra Cancer.

BACKGROUND: Urethral cancer is a rare malignancy, representing <1% of all malignancies. Optimal management, due to its rarity, presents as a treatment dilemma for physicians. There is a lack of consensus regarding treatment as large randomized trials cannot be performed; thus, optimal management decisions rely on study of retrospective cases. This is a review of our institutional experience with urethral cancer treated with various treatment modalities. METHODS: A retrospective chart review was performed on 31 patients treated for primary cancer of the urethra from 1958 to 2008. The patients were stratified by sex, histologic type, stage, date of diagnosis, type of treatment, and last follow-up. Early stage cases were designated as Tis-T2N0M0 and advanced cases were designated as T3-4, N+ or M+. Analysis was performed based on clinical stage, treatment modalities and outcomes. RESULTS: Fourteen early stage cases and 17 advanced stage cases of urethral cancer were analyzed. The majority of early stage cases occurred in men (M:F=8:6) and the majority of advanced stage cases occurred in women (M:F=5:12). The most common histology was squamous cell carcinoma for both early and advanced stage cases. Surgery was the preferred modality of treatment for early stage cases (surgery used in 13 cases vs. chemo/radiotherapy used in 1 case) while for advanced cases, radiation ±chemotherapy was commonly used. Overall survival for this series was 45% at mean follow-up of 7 years. Eight of the 14 cases of early stage cancer remained disease free at last follow-up. Comparatively, only 5 of 17 with advanced cancers had no apparent disease at last follow-up. All but one of those patients were treated with combined modality therapy. CONCLUSIONS: Patients with early stage urethral cancers do well with single modality therapy, whereas patients who present with advanced cancers may benefit from combined modality therapy. More extensive study is required to recommend a particular treatment protocol. However, in this rare malignancy, institutional experiences provide the best evidence currently due to the lack of multi-institutional trials.

The prognostic effect of salvage surgery and radiotherapy in patients with recurrent primary urethral carcinoma.

BACKGROUND: To evaluate the impact of salvage therapy (ST) on overall survival (OS) in recurrent primary urethral cancer (PUC). PATIENTS: A series of 139 patients (96 men, 43 women; median age = 66, interquartile range: 57-77) were diagnosed with PUC at 10 referral centers between 1993 and 2012. The modality of ST of recurrence (salvage surgery vs. radiotherapy) was recorded. Kaplan-Meier analysis with log-rank was used to estimate the impact of ST on OS (median follow-up = 21, interquartile range: 5-48). RESULTS: The 3-year OS for patients free of any recurrence (I), with solitary or concomitant urethral recurrence (II), and nonurethral recurrence (III) was 86.5%, 74.5%, and 48.2%, respectively (P = 0.002 for I vs. III and II vs. III; P = 0.55 for I vs. II). In the 80 patients with recurrences, the modality of primary treatment of recurrence was salvage surgery in 30 (37.5%), salvage radiotherapy (RT) in 8 (10.0%), and salvage surgery plus RT in 5 (6.3%) whereas 37 patients did not receive ST for recurrence (46.3%). In patients with recurrences, those who underwent salvage surgery or RT-based ST had similar 3-year OS (84.9%, 71.6%) compared to patients without recurrence (86.7%, P = 0.65), and exhibited superior 3-year OS compared to patients who did not undergo ST (38.0%, P<0.001 compared to surgery, P = 0.045 to RT-based ST, P = 0.29 for surgery vs. RT-based ST). CONCLUSIONS: In this study, patients who underwent ST for recurrent PUC demonstrated improved OS compared to those who did not receive ST and exhibited similar survival to those who never developed recurrence after primary treatment.

TERT promoter mutation status in sarcomatoid urothelial carcinomas of the upper urinary tract.

AIM: To determine TERT promoter mutation status as well as the expression of PAX8, GATA3, p63, p40, p53 and uroplakin III in 17 patients with the upper urinary tract sarcomatoid urothelial carcinoma. METHODS & RESULTS:  TERT C228T mutations were found in six of 17 cases (35%). p53 was expressed in 77% of these tumors. PAX8, GATA3, p40 and uroplakin III are less frequently expressed. Lymph node metastases were present in ten cases (59%). Eight patients (47%), including all three patients with TERT mutation, died of cancer within 2 years after surgery. CONCLUSION: Sarcomatoid carcinoma of the upper urinary tract is an aggressive tumor and the presence of TERT mutation may portend poor prognosis.

Outcomes and Prognostic Factors of Primary Urethral Cancer.

OBJECTIVE: To identify prognostic and treatment factors for primary urethral cancer using a nationwide database. MATERIALS AND METHODS: The National Cancer Database was queried for all cases of primary urethral cancer from 2004 to 2013. Patients with other cancer diagnoses, metastasis, or diagnosis on autopsy were excluded. Proportional hazards regression was used to identify independent predictors of overall survival in patients with primary urethral cancer. Because we hypothesized that predictors may covary by sex, we also performed regression analysis stratified by sex. RESULTS: We identified 1268 men and 869 women with primary urethral cancer. Women tended to have more advanced tumors and adenocarcinoma histology. Median survival for the entire cohort was 49 months (43-55), with 5- and 10-year survival rates of 46% and 31%, respectively. On multivariate analysis, age, race, stage, grade, and Charlson comorbidity index were independent predictors of overall survival. Histology was not a predictor of overall survival in the combined model; however, adenocarcinoma in women increased hazards of death, whereas it decreased hazards of death in men when compared with squamous cell carcinoma. CONCLUSION: Men and women with primary urethral cancer had significant differences in histology, grade, and nodal status. In addition to several expected disease-related factors, black race was associated with increased mortality for patients with primary urethral cancer.

Perioperative treatments for resected upper tract urothelial carcinoma: a network meta-analysis.

BACKGROUND: Perioperative treatments have been used to improve prognosis in patients with upper tract urothelial carcinoma (UTUC). However, optimal management remains unestablished. METHODS: We searched the Embase, Web of Science and Cochrane databases for studies published before June 20, 2015. All included studies were categorised into three groups on the basis of the outcome reported (overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS)). Relative hazard ratios (HRs) for death were calculated using random-effects Bayesian network meta-analysis methods. We also ranked the three different treatments in terms of three outcomes. RESULTS: A total of 31 trials with 8100 patients were included. Compared with the control, adjuvant chemotherapy (AC) could improve OS, DSS and RFS by 32% (HR 0.68, 95% CI 0.51-0.89), 29% (HR 0.71, 95% CI 0.54-0.89) and 51% (HR 0.49, 95% CI 0.23-0.85), respectively. We noted a marked prolongation of RFS in both intravesical chemotherapy (HR 0.32, 95% CI 0.09-0.69) as well as concurrent radiotherapy and intravesical chemotherapy (HR 0.32, 95% CI 0.03-0.97) than in the control. Neoadjuvant chemotherapy (NAC) showed a significant improvement in DSS relative to the control (HR 0.25, 95% CI 0.06-0.61) and a distinct advantage over AC (HR 0.36, 95% CI 0.08-0.90) or AR (HR 6.89, 95% CI 1.25-18.66). CONCLUSIONS: Our results showed that AC; intravesical chemotherapy; and concurrent radiotherapy and intravesical chemotherapy could improve the prognosis of UTUC patients. NAC was found to be more favourable for UTUC than AC in terms of DSS.

DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness.

Urothelial carcinoma (UC) is common cancer worldwide. The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. By data mining the datasets in Gene Expression Omnibus, specifically focus on the proteolysis pathway, and followed by a preliminary validation in a pilot batch of tumor samples, we identified that the upregulation of dipeptidyl peptidase 4 (DPP4) was most significantly associated with clinical aggressiveness of UCs. Quantitative RT-PCR confirmed upregulation of DPP4 mRNA in advanced stage UCs. The clinical significance of DPP4 expression was validated in our large cohort consists of 635 UCs from upper urinary tract and urinary bladder. Univariate and multivariate analyses show that DPP4 is an independent prognosticatory biomarker for disease-specific survival and metastasis-free survival. Comparing the DPP4 expression level of three urothelial cell lines with normal urothelial cells, J82 and RTCC-1 showed a significantly increased in transcript and protein expression. DPP4 knockdown as conducted by using short-hairpin RNA resulted in a significantly decreased cell viability, proliferation, migration, and invasion in J82 and RTCC-1 cells. These findings implicate that DPP4 plays a role in the aggressiveness of UCs, and can serve as a novel prognostic marker and therapeutic target.