Prognostic impact of histological discordance between transurethral resection and radical cystectomy.

OBJECTIVE: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. PATIENTS AND METHODS: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. RESULTS: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). CONCLUSION: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS.

Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy.

PURPOSE: To evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes. MATERIALS AND METHODS: A total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Among 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55-3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35-5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27-3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology. CONCLUSIONS: Variant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively.

Variant histology is associated with more non-urothelial tract recurrence but less intravesical recurrence for upper tract urothelial carcinoma after radical nephroureterectomy.

PURPOSE: To investigate the prognostic impact of variant histology (VH) on oncological outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU). PATIENTS AND METHODS: A total of 1239 patients with clinically localized UTUC who underwent RNU at a single institution between January 2005 and June 2020 were included. The VH was reviewed by a uro-pathologist at our institution. The Cox regression model was used to perform multivariate analysis, including VH and other established prognostic factors for post-RNU oncological outcomes (intravesical recurrence [IVR], non-urothelial recurrence, and cancer-specific death). RESULTS: Of the 1239 patients with UTUC, 384 patients (31%) were found to have VH. Advanced tumor stage, lymph node metastasis, high tumor grade, lymphovascular invasion, open surgery, and renal pelvis had a significantly larger proportion of UTUC with VH compared to pure UTUC (all p < 0.05). VH was an independent prognostic factor associated with less IVR identified by multivariate analysis, more non-urothelial recurrence, and more cancer-specific mortality. CONCLUSION: Patients with VH account for 31% with UTUC treated with RNU in this cohort. VH was an independent prognostic factor associated with more non-urothelial recurrence and cancer-specific mortality but less IVR.

The prognostic significance of histologic variant on survival outcomes in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitor therapy.

BACKGROUND: While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. METHOD: We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. RESULT: A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). CONCLUSION: The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy.

OBJECTIVES: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). MATERIALS AND METHODS: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as 'organ-confined' (≤pT2N0), 'locally advanced' (pT3-4N0) and 'node-positive' (pTanyN1-3). RESULTS: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. CONCLUSIONS: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

Variant histology of pediatric nodular lymphocyte-predominant Hodgkin lymphoma with IgD and CD30 expression.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), recently known as nodular lymphocyte-predominant B-cell lymphoma (NLPBL), accounts for 5%-10% of Hodgkin lymphoma (HL). Different morphologic patterns of NLPBL are identified and categorized as typical patterns (type A and B) and variant histologic patterns (types C, D, E, and F). PATIENTS AND METHOD: We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. RESULTS: Forty-six (53%) of the patients exhibited a typical histologic pattern, whereas the remaining (47%) exhibited variant histologic pattern. Variant histology is associated with unfavorable clinical characteristics, such as advanced stages, B-symptoms, and extranodal involvements, particularly bone marrow and bone infiltration, with p-values of .06, .05, and 0.01%, respectively. Additionally, 39% of patients with variant histology experienced disease progression or relapse, compared to only 15.2% of patients with typical patterns (p = .009). Types C and D are related to decreased event-free survival (EFS), as shown by a p-value of .05. The 5-year EFS for patients with variant histology was 94.4% for the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (RCHOP) versus 33.3% for the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). IgD expression in lymphocyte-predominant (LP) cells was detected in 44 (50%) patients, while CD30 expression in LP cells was found in 39 (44%) patients. CONCLUSION: Variant histology of NLPBL was associated with advanced disease stages and a poor prognosis, while expression of IgD and CD30 in LP cells was not. The poor outcome of variant histology improved with the RCHOP regimen.

Temporal trends, tumor characteristics and stage-specific survival in penile non-squamous cell carcinoma vs. squamous cell carcinoma.

PURPOSE: To compare Cancer-specific mortality (CSM) in patients with Squamous cell carcinoma (SCC) vs. non-SCC penile cancer, since survival outcomes may differ between histological subtypes. METHODS: Within the Surveillance, Epidemiology and End Results database (2004-2016), penile cancer patients of all stages were identified. Temporal trend analyses, cumulative incidence and Kaplan-Meier plots, multivariable Cox regression and Fine and Gray competing-risks regression analyses tested for CSM differences between non-SCC vs. SCC penile cancer patients. RESULTS: Of 4,120 eligible penile cancer patients, 123 (3%) harbored non-SCC vs. 4,027 (97%) SCC. Of all non-SCC patients, 51 (41%) harbored melanomas, 42 (34%) basal cell carcinomas, 10 (8%) adenocarcinomas, eight (6.5%) skin appendage malignancies, six (5%) epithelial cell neoplasms, two (1.5%) neuroendocrine tumors, two (1.5%) lymphomas, two (1.5%) sarcomas. Stage at presentation differed between non-SCC vs. SCC. In temporal trend analyses, non-SCC diagnoses neither decreased nor increased over time (p > 0.05). After stratification according to localized, locally advanced, and metastatic stage, no CSM differences were observed between non-SCC vs. SCC, with 5-year survival rates of 11 vs 11% (p = 0.9) for localized, 33 vs. 37% (p = 0.4) for locally advanced, and 1-year survival rates of 37 vs. 53% (p = 0.9) for metastatic penile cancer, respectively. After propensity score matching for patient and tumor characteristics and additional multivariable adjustment, no CSM differences between non-SCC vs. SCC were observed. CONCLUSION: Non-SCC penile cancer is rare. Although exceptions exist, on average, non-SCC penile cancer has comparable CSM as SCC penile cancer patients, after stratification for localized, locally invasive, and metastatic disease.

Accuracy and prognostic value of radiological lymph node features in variant histologies of bladder cancer.

PURPOSE: To provide first evidence of lymph node (LN) staging using CT scan and its prognostic value in variant histologies of bladder cancer. This knowledge may optimize patient management with variant histologies based on CT morphological findings. METHODS: Preoperative CT scans of patients with variant histologies who underwent RC between 2004 and 2019 were reanalyzed by two independent radiologists in a blinded review process. Specificity, sensitivity, and accuracy for LN staging as well as LN characteristics were evaluated. Correlation with survival was investigated by Kaplan-Meier method, log-rank test and multivariate analysis. RESULTS: 1361 patients with primary tumor of the bladder underwent RC, of which 163 (12%) patients revealed variant histologies. 65 (47.8%) patients have shown an urothelial variant (UV) and 71 (52.2%) a non-urothelial variant (NUV). LN metastases were found in 18 (27.7%) patients with UV and 21 (29.6%) patients with NUV. The accuracy to detect LN metastasis for all variant histologies was 62% with a sensitivity of 46% and a specificity of 70%. Subgroups of UV and NUV revealed an accuracy of 67% and 57%. An increased number of regional LN (HR 2.8; 1.34-6.18) and the loss of fatty hilum (HR 0.36, 0.17-0.76) were prognostic parameters. In multivariate analysis, a fatty hilum (HR 0.313, 0.104-0.945) and the presence of lymph node metastases (HR 2.866, 1.140-7.207) were prognostic. CONCLUSION: This first study on CT morphological behavior of variant histologies revealed an accuracy of UV and NUV comparable to UC with low specificity for all variant histologies. CT scan prior RC should be interpreted in regard to histological subtypes.

Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies.

BACKGROUND: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616). METHODS: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related. CONCLUSIONS: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing. LAY SUMMARY: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.

Non-Muscle Invasive Bladder Cancer with Variant Histology: Biological Features and Clinical Implications.

BACKGROUND: The most common bladder cancer (BC) histotype is pure urothelial carcinoma (UC), which may undergo divergent differentiation in some cases. Variant histology (VH) presents along variable morphologies, either single or combined between them or with pure UC. From a clinical standpoint, the vast majority of BC is diagnosed at non-invasive or minimally invasive stages, namely as non-muscle invasive BC (NMIBC). There is a wide range of therapeutic options for patients with NMIBC, according to their clinical and pathological features. However, current risk stratification models do not show optimal effectiveness. Evidence from the literature suggests that VH has peculiar biological features, and may be associated with poorer survival outcomes compared to pure UC. SUMMARY: In order to describe the biological features and prognostic/predictive role of VH in NMIBC, and to discuss current treatment options, we performed a systematic literature search through multiple databases (PubMed/Medline, Google Scholar) for relevant articles according to the following terms, single and/or in combination: "non-muscle invasive bladder cancer," "variant histology," "micropapillary variant," "glandular differentiation," "squamous differentiation," "nested variant," "plasmacytoid variant," and "sarcomatoid variant." We extracted 99 studies including original articles, reviews, and systematic reviews, and subsequently analyzed data from 16 studies reporting on the outcome of NMIBC with VH. We found that the relative rarity of these forms as well as the heterogeneity in study populations and therapeutic protocols results in conflicting findings overall. Key Messages: The presence of VH should be taken into account when counseling a patient with NMIBC, since it may upgrade the disease to high-risk tumor and thus warrant a more aggressive treatment.

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes.

OBJECTIVES: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line). RESULTS: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively). CONCLUSION: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.

Prognostic value of pretreatment inflammatory markers in variant histologies of the bladder: is inflammation linked to survival after radical cystectomy?

PURPOSE: To investigate differences in standard preoperative inflammatory markers in patients with urothelial carcinoma (UC) and variant histologies undergoing radical cystectomy (RC) and determine its impact on survival. METHODS: Patients undergoing RC at an academic high-volume center were retrospectively analyzed. Preoperatively taken CRP, leukocytes, hemoglobin (Hb), and thrombocytes were analyzed as routine inflammatory biomarkers. Log-rank tests and Kruskal-Wallis analysis were used to calculate for differences in survival and in blood levels of biomarkers. RESULTS: 886 patients with complete follow-up and UC or variant histology underwent RC at our institution between 2004 and 2019. Although variant histology presents with significantly higher t stage than UC, cancer-specific survival (CSS) of UC (1-year-CSS: 93%) is not significantly different to variant histology of UC with squamous differentiation (UCSD, 1-year-CSS: 81%), squamous cell carcinoma (SCC, 1-year-CSS: 82%), and adenocarcinoma (AC, 1-year-CSS: 81%). In UC, alterations in all biomarkers except leukocytes beyond routine cut-off values were associated with poor survival (p < 0.01), whereas Hb beyond cut-off values are associated with poor prognosis in SCC (p < 0.05). CRP levels are significantly elevated in UCSD and SCC at time of surgery compared to UC (p < 0.05). CONCLUSION: Inflammatory biomarkers reveal distinctive patterns across UC and variant histologies of bladder cancer. As inflammation might play an important role in cancer progression, further research is warranted to understand those molecular mechanisms and their potential therapeutic impact in variant histology of bladder cancer.

Bladder cancer in patients younger than 40 years: outcomes from the National Cancer Database.

PURPOSE: To evaluate the clinical, pathological, and survival outcomes of bladder cancer in patients aged 18-40 years. METHODS: We identified 362,091 bladder cancer patients from the National Cancer Database between 2004-2013 and compared patients aged 18-40 years to those > 40 years of age with univariate analysis using Chi-square tests. A subset analysis was performed on patients who underwent cystectomy. Multivariable Cox regression was used for overall survival analysis. RESULTS: Our final analysis included 314,177 patients with 3314 (1.1%) patients aged 18-40 years. Patients aged 18-40 years had a lower male-to-female ratio (2.4 versus 3.0), a greater proportion of low-grade tumors (72.7% versus 48.3%, p < 0.001), non-muscle invasive tumors (90.3% versus 81.2%, p < 0.001), and variant histology (4.0% versus 3.3%, p < 0.001). Similar trends were observed at cystectomy including lower male-to-female ratio in the 18-40 years group (1.7 versus 3.1), a greater proportion of variant histology (25.0% versus 10.0%, p < 0.001); and 53.3% of those younger patients with variant histology were women. Patients aged 18-40 years who underwent cystectomy had a higher proportion of locally advanced disease (pT4 19.2% versus 14.6%, p = 0.004). Multivariable analyses in both cohorts demonstrated that variant histology was a predictor of worse overall survival. CONCLUSION: The majority of patients aged 18-40 years with bladder cancer present with low-grade, non-muscle-invasive disease associated with better survival. However, a subset of younger patients with a higher proportion of women presents with aggressive bladder cancer which may be partly explained by a higher prevalence of variant histology.

Adjuvant chemotherapy is ineffective in patients with bladder cancer and variant histology treated with radical cystectomy with curative intent.

OBJECTIVES: Adjuvant chemotherapy (ACT) is recommended for non-organ-confined bladder cancer (BCa) after radical cystectomy (RC) and pelvic lymph node dissection (PLND), but there are sparse data regarding its specific efficacy in patients with histological variants. The aim of our study was to evaluate the role of ACT on survival outcomes in patients with variant histology in a large multicenter cohort. MATERIALS AND METHODS: We retrospectively evaluated data of 3963 patients with BCa treated with RC and bilateral PLND with curative intent at several institutions between 1999 and 2018. The histological type was classified into six groups: pure urothelial carcinoma (PUC) or squamous, sarcomatoid, micropapillary, glandular and neuroendocrine differentiation. Multivariable competing risk analysis was applied to assess the role of ACT on recurrence and cancer-specific mortality (CSM) in each histological subtype. RESULTS: Of the 3963 patients included in the study, 23% had variant histology at RC specimen and 723 (18%) patients received ACT. ACT was found to be significantly associated with reduced risk of recurrence (sub-hazard ratio [SHR]: 0.55, confidence interval [CI] 0.42-0.71, p < 0.001) and CSM (SHR: 0.58, CI 0.44-0.78, p < 0.001) in the PUC only, while no histological subtype received a significant benefit on survival outcomes (all p > 0.05) from administration of ACT. The limitation of the study includes the retrospective design, the lack of a central pathology review and the number of ACT cycles. CONCLUSION: In our study, the administration of ACT was associated with improved survival outcomes in PUC only. No histological subtype found a benefit in overall recurrence and CSM from ACT.

Sarcomatoid variant urothelial carcinoma of the bladder: a systematic review and meta-analysis of the clinicopathological features and survival outcomes.

BACKGROUND: A systematic review and meta-analysis was performed to compare the clinicopathological features and survival outcomes between sarcomatoid variant (SV)-urothelial carcinoma of the bladder (UCB) and conventional UCB (C-UCB). METHODS: A comprehensive search of PubMed, Embase, and Cochrane Library was performed. Endpoints included clinicopathological features and survival outcomes (overall survival [OS], cancer-specific survival [CSS], and progression-free survival [PFS]). The survival benefits of neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) for SV-UCB also have been studied. RESULTS: A total of 8 observational studies were included. Patients with SV-UCB had a higher rate of ≥ stage pT3 (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.64-2.59; p < 0.001) and a lower rate of concomitant carcinoma in situ (OR, 0.25; 95% CI, 0.09-0.72; p = 0.010). The other clinicopathological variables were similar between SV-UCB and C-UCB. With unadjusted data, patients with SV-UCB had a significant inferior OS (HR, 1.24; 95% CI, 1.07-1.44; p = 0.004) and CSS (HR, 2.08; 95% CI, 1.63-2.66; p < 0.001). However, after adjusted, SV-UCB had worse OS (HR, 1.41; 95% CI, 0.95-2.08; p = 0.090) and CSS (HR, 1.54; 95% CI, 0.95-2.52; p = 0.080) approaching the borderline of significance. For SV-UCB, NAC (HR, 0.73; 95% CI, 0.51-1.05; p = 0.090) and AC (HR, 0.88; 95% CI, 0.66-1.17; p = 0.370) seemed to have no benefit on OS. CONCLUSIONS: Compared to C-UCB, SV-UCB was associated with more advanced disease and more inferior OS and CSS. NAC and AC had no survival benefit for SV-UCB.

Differences in survival and impact of adjuvant chemotherapy in patients with variant histology of tumors of the renal pelvis.

BACKGROUND: The impact of variant histologies on overall survival (OS), as well as their influence on the response to neoadjuvant and adjuvant chemotherapy (AC) is well studied in patients diagnosed with bladder cancer. However, little is known about tumors with variant histologies of the upper urinary tract. The objective of this study was to assess the survival of the predominant variant histologies of tumors of the renal pelvis (RPT) after surgical intervention, and to examine the influence of AC on the OS of the different variant histologies. METHODS: We identified 21,318 patients with RPT undergoing surgical intervention using the National Cancer Database for the period 2004-2015. We employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to variant histology. Separate multivariable Cox regression models were used to assess the specific effect of AC on OS of the histological subgroups. RESULTS: The majority of patients were diagnosed with pure urothelial carcinoma (PUC) (96.1%). Overall, 826 patients were diagnosed with variant histologies (adenocarcinoma N = 298, squamous cell carcinoma N = 291, sarcomatoid N = 137, others N = 100). Compared to PUC, adenocarcinomas showed longer OS (HR 0.76, 95% confidence interval (CI) 0.62-0.94, p = 0.01), while sarcomatoid tumors had shorter OS (HR 1.59, 95% CI 1.12-2.26, p = 0.011). A subgroup analysis of patients undergoing AC showed a survival benefit in patients with PUC (HR 0.81, 95% CI 0.73-0.9, p < 0.001). CONCLUSION: We found that variant histologies of upper urinary tract carcinomas exhibit different survival rates and that AC was only associated with an OS benefit in patients with PUC.

Impact of adjuvant chemotherapy in patients with adverse features and variant histology at radical cystectomy for muscle-invasive carcinoma of the bladder: Does histologic subtype matter?

BACKGROUND: The use of adjuvant chemotherapy (AC) in pure urothelial carcinoma of the bladder is established. Regarding variant histology, there is a gap in knowledge concerning the optimal treatment after radical cystectomy (RC). The objective of this study was to assess the effect of AC on overall survival (OS) in patients who had pure urothelial carcinoma, urothelial carcinoma with concomitant variant histology, or another pure variant histology. METHODS: Within the National Cancer Data Base, 15,397 patients who underwent RC for nonmetastatic, localized carcinoma of the bladder and had positive lymph nodes (T2N+) or locally advanced stage (≥T3N0/N+) were identified, excluding those who had previously received neoadjuvant chemotherapy. Multivariable Cox regression models were used to examine the specific effect of AC on OS stratified by each distinct histologic subtype, including pure urothelial carcinoma, micropapillary or sarcomatoid differentiation, squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors. To account for immortal time bias, Cox regression analyses and Kaplan-Meier analyses were conducted with a landmark at 3 months. RESULTS: In multivariable landmark analyses, AC compared with initial observation was associated with an OS benefit for patients who had pure urothelial carcinoma (hazard ratio, 0.87; 95% confidence interval, 0.82-0.91), whereas no differences were observed with regard to those who had variant histology. CONCLUSIONS: Multivariable Cox regression landmark analysis revealed a survival benefit from AC for patients with a pure urothelial carcinoma. However, a survival benefit of AC for patients who had urothelial carcinoma with concomitant variant histology or other pure variant histology was not demonstrated.

The expanding morphological and genetic spectrum of MYOD1-mutant spindle cell/sclerosing rhabdomyosarcomas: a clinicopathological and molecular comparison of mutated and non-mutated cases.

AIMS: Spindle cell/sclerosing rhabdomyosarcomas (SC/SRMS) feature spindled and/or rounded rhabdomyosarcomatous cells within variably hyalinised stroma. Only 30-67% of SC/SRMSs harbour neomorphic MYOD1 p.L122R mutations, indicating heterogeneity in this RMS type. We compared MYOD1-mutant and non-mutant cases to characterise the histological and genetic spectrum of mutated SC/SRMS. METHODS AND RESULTS: Seventeen RMSs with spindled, sclerosing or hybrid histology were sequenced to identify MYOD1 and PIK3CA mutations and reappraised to assess histological features and myogenic immunophenotypes. Twelve SC/SRMSs harboured MYOD1 mutations, including homozygous p.L122R (n = 8), heterozygous p.L122R (n = 3) and heterozygous p.E118K (n = 1). MYOD1-mutant tumours affected nine females and three males aged 8-64 years (median = 22.5), had a median size of 4.2 cm (range = 2-22) and involved the head and neck (n = 7), extremities (n = 4) and mediastinum (n = 1). Fascicular/spindle histology was predominant in four cases, including one with heterologous lipoblasts in focally myxoid stroma. Four sclerosing cases mainly comprised rounded cells, including one with multinucleated tumour cells. Four cases were histologically hybrid. The only PIK3CA (p.H1047R) mutation was detected in a predominantly spindled MYOD1-p.L122R-mutated case, but not in its laser-microdissected lipoblast-containing area. All MYOD1-mutant cases exhibited diffuse MYOD1 expression but patchy myogenin reactivity. At final follow-up (median = 13.5 months), recurrences (n = 4), metastases (n = 2) or both (n = 1) occurred in seven MYOD1-mutant cases; one had died of disease. Five non-mutated cases were reclassified as spindle embryonal (n = 3), dense embryonal (n = 1) and unclassifiable (n = 1) RMSs. CONCLUSION: MYOD1-mutant RMSs are uncommonly mutated with PIK3CA and behave aggressively with an expanded morphological and genetic spectrum, including lipoblastic differentiation, multinucleated cells and the alternative p.E118K mutation.

Variants and new entities of bladder cancer.

Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.

The impact of non-urothelial variant histology on oncological outcomes following radical cystectomy.

OBJECTIVES: To determine if the presence of non-urothelial variant histology (NUVH) is associated with a poorer prognosis following radical cystectomy (RC) compared to pure urothelial carcinoma (PUC). PATIENTS AND METHODS: A prospectively maintained database of all patients undergoing RC at a high-volume regional tertiary bladder cancer service between January 2010 and January 2017 was retrospectively analysed looking for patients with NUVH. Multivariate Cox proportional hazards regression analysis was used to determine disease recurrence, overall survival and bladder cancer-specific survival, as well as lymph node positivity. Association of tumour stage was determined using chi-squared analysis. RESULTS: In total, 430 patients underwent RC of which 73 (17%) had NUVH and 357 (83%) had PUC. The median (range) follow-up was 45.0 (8.5-100.2) months. The presence of NUVH was associated with both increased overall (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.21-2.85) and bladder cancer-specific mortality (HR 1.81, 95% CI 1.91-3.01), as well as disease recurrence (HR 1.71, 95% CI 1.06-2.75) in multivariate analysis. Squamous cell variant was also associated with increased overall mortality (HR 1.91, 95% CI 1.16-3.13), cancer-specific mortality (HR 2.03, 95% CI 1.21-3.42) and disease recurrence (HR 2.08, 95% CI 1.23-3.52), although this was not seen in other variant subtypes. Lymph node positivity was not associated with NUVH in multivariate analysis (HR 1.28, 95% CI 0.59-2.75), but NUVH was associated with advanced tumour stage on chi-squared analysis (P < 0.001). CONCLUSION: Our results showed a risk of shorter survival in NUVH compared to PUC. This suggests NUVH as an independent predictor of worse outcomes. As a result, patients with NUVH should be counselled preoperatively that overall and disease-specific outcomes are worse postoperatively and about the possible need for adjuvant treatment.