RESUMEN
Clear cell urothelial carcinoma is a rare variant of urothelial carcinoma. It's recognition and accurate diagnosis are essential in deciding appropriate treatment protocols considering the prognosis of this variant. A 57-year-old male presented with a history of hematuria and lower urinary tract symptoms for 6 months. Microscopically, the tumor was arranged in sheets and had a nested pattern. The tumor was composed of round to polygonal cells with abundant clear cytoplasm (>90% clear cell differentiation), resembling a conventional clear renal cell carcinoma. On special stain, the tumor was positive for periodic acid-Schiff (PAS) and negative for periodic acid-Schiff with diastase (PAS-D) and mucicarmine stain. The urothelial origin of clear cells was confirmed by positivity for GATA Binding protein 3(GATA3) and High Molecular Weight Cytokeratin (HMWCK) immunohistochemistry and negativity for NK3 homeobox 1(NKX3.1), Prostate specific antigen (PSA) and Paired box gene 8 (PAX8) immunohistochemistry.
Asunto(s)
Carcinoma de Células Renales , Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Persona de Mediana Edad , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/patología , Vejiga Urinaria/patología , Ácido Peryódico , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/patologíaRESUMEN
Background: Bioinformatic analysis has revealed that OXR1 is significantly downregulated in muscle-invasive bladder cancer. Patients & methods: The expression of OXR1 in patients with urothelial carcinoma was evaluated by immunohistochemistry, including 340 cases with urothelial carcinoma in the upper urinary tract and 295 in the urinary bladder. Results: Low expression of OXR1 was significantly correlated with adverse pathological parameters including high primary tumor (pT) stage, high node stage, high histological grade, high mitotic activity and increased vascular or perineural invasion (all p < 0.05). Low expression of OXR1 independently predicted worse metastasis-free survival (p = 0.033) in urothelial carcinoma of the upper urinary tract and worse disease-specific survival (p = 0.022) and metastasis-free survival (p < 0.001) in urothelial carcinoma of the urinary bladder. Conclusion: Low expression of OXR1 is an adverse prognostic factor in urothelial carcinoma.
Asunto(s)
Carcinoma de Células Transicionales/mortalidad , Proteínas Mitocondriales/análisis , Neoplasias Urológicas/mortalidad , Adulto , Anciano , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias Urológicas/química , Neoplasias Urológicas/patologíaRESUMEN
BACKGROUND: CD276 is an immune checkpoint molecule. Elevated CD276 expression by urothelial carcinoma is associated with poor prognosis, but little is known about its expression across different tumor stages. We therefore investigated CD276 expression in bladder cancer (BC) cells and in tissue samples of BC stages from pT2 to pT4. METHODS: CD276 expression was explored in 4 urothelial cancer cell lines and 4 primary normal urothelial cell populations by quantitative RT-PCR, Western blot and flow cytometry. CD276 was investigated in bladder tumors from 98 patients by immunohistochemistry using a score (0-300) incorporating both, staining intensity and area of CD276 staining. Normal appearing urothelium in the bladder of the same patients served as controls. RESULTS: The urothelial carcinoma cell lines expressed significantly higher levels of CD276 on transcript (p < 0.006), total protein levels (p < 0.005), and on the cell surface (p < 0.02) when compared to normal urothelial cells. In pT2-T4 tumor tissue samples, CD276 was overexpressed (median score 185) when compared to corresponding healthy tissues from the same patients (median score 50; p < 0.001). No significant differences in CD276 expression were recorded in late, locally advanced ≥ pT3a tumors (median score 185) versus organ-confined < pT3a tumors (median score 190), but it was significantly lower in the normal urothelial tissue associated with ≥ pT3a tumors (median score 40) versus < pT3a tumors (median score 80; p < 0.05). CONCLUSION: CD276 expression is significantly elevated in urothelial carcinoma cells in all stages but varies between individuals considerably. Reduced CD276 expression in normal urothelial cells may imply that these cells would be protected from CD276-mediated immuno therapies.
Asunto(s)
Antígenos B7/genética , Carcinoma de Células Transicionales/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígenos B7/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
PURPOSE: We evaluated the prognostic value of 10 putative tumor markers by immunohistochemistry in a large multi-institutional cohort of patients with locally advanced urothelial cancer of the bladder (UCB) with the aim to validate their clinical value and to harmonize protocols for their evaluation. MATERIALS AND METHODS: Primary tumor specimens from 576 patients with pathologic (p)T3 UCB were collected from 24 institutions in North America and Europe. Three replicate 0.6-mm core diameter samples were collected for the construction of a tissue microarray (TMA). Immunohistochemistry (IHC) for 10 previously described tumor markers was performed and scored at 3 laboratories independently according to a standardized protocol. Associations between marker positivity and freedom from recurrence (FFR) or overall survival (OS) were analyzed separately for each individual laboratory using Cox regression analysis. RESULTS: The overall agreement of the IHC scoring among laboratories was poor. Correlation among the 3 laboratories varied across the 10 markers. There was generally a lack of association between the individual markers and FFR or OS. The number of altered cell cycle regulators (p53, Rb, and p21) was associated with increased risk of cancer recurrence (P < 0.032). There was no clear pattern in the relationship between the percentage of markers altered in an 8-marker panel and FFR or OS. CONCLUSIONS: This large international TMA of locally advanced (pT3) UCB suggests that altered expression of p53, Rb, and p21 is associated with worse outcome. However this study also highlights limitations in the reproducibility of IHC even in the most expert hands.
Asunto(s)
Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/mortalidad , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Cooperación Internacional , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
PURPOSE: The present systematic review aimed to identify prognostic values of tissue-based biomarkers in patients treated with neoadjuvant systemic therapy (NAST), including chemotherapy (NAC) and checkpoint inhibitors (NAI) for urothelial carcinoma of the bladder (UCB). MATERIAL AND METHODS: The PubMed, Web of Science, and Scopus databases were searched in August 2020 according to the PRISMA statement. Studies were deemed eligible if they compared oncologic or pathologic outcomes in patients treated with NAST for UCB with and without detected pretreatment tissue-based biomarkers. RESULTS: Overall, 44 studies met our eligibility criteria. Twenty-three studies used immunohistochemistry (IHC), 19 - gene expression analysis, three - quantitative polymerase chain reaction (QT PCR), and two - next-generation sequencing (NGS). According to the currently available literature, predictive IHC-assessed biomarkers, such as receptor tyrosine kinases and DNA repair pathway alterations, do not seem to convincingly improve our prediction of pathologic response and oncologic outcomes after NAC. Luminal and basal tumor subtypes based on gene expression analysis showed better NAC response, while claudin-low and luminal-infiltrated tumor subtypes did not. In terms of NAI, PD-L1 seems to maintain value as a predictive biomarker, while the utility of both tumor mutational burden and molecular subtypes remains controversial. Specific genomic alterations in DNA repair genes have been shown to provide significant predictive value in patient treated with NAC. QT PCR quantification of specific genes selected through microarray analysis seems to classify cases regarding their NAC response. CONCLUSION: We believe that the present systematic review may offer a robust framework that will enable the testing and validation of predictive biomarkers in future prospective clinical trials. NGS has expanded the discovery of molecular markers that are reflective of the mechanisms of the NAST response.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Humanos , Terapia Neoadyuvante , PronósticoRESUMEN
PURPOSE: While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. METHODS: We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. RESULTS: Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. CONCLUSIONS: PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients' clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.
Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/diagnóstico , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/diagnóstico , Carcinoma de Células Transicionales/terapia , Humanos , Neoplasias de la Vejiga Urinaria/terapiaAsunto(s)
Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano , Biopsia , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/cirugía , Femenino , Factor de Transcripción GATA3/análisis , Humanos , Proteínas de la Membrana/análisis , Segunda Cirugía , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/cirugía , Urotelio/patologíaRESUMEN
BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) of the urinary bladder is a variant of urothelial carcinoma that carries a poor prognosis. The epithelial-mesenchymal transition (EMT) has been demonstrated to contribute to tumor progression. As the cause of the increased aggressiveness of PUC is unknown, we investigated PUC and EMT-related marker expression. METHODS: A total of 633 bladder carcinoma cases diagnosed from 2006 to 2015 at the Nippon Medical School Hospital were analyzed. Twelve patients were found to have plasmacytoid histology and diagnosed with PUC. Slides were evaluated for percentage of plasmacytoid variant, and stained for E-cadherin, N-cadherin, Vimentin, Fibronectin and Snail expression. RESULTS: The incidence of PUC was 1.9% (12/633). The median patient age at diagnosis was 71 years (range, 60-80 years) and the male-female ratio was 11:1. All but three patients had stage T2b or higher. The median overall survival was 10 months. In 10/12 cases, Snail and N-cadherin were positive. Vimentin was positive in 9/12 cases. Fibronectin was positive in 8/12 cases. While E-cadherin was negative in 10/12 cases. Nine cases showed > 10% plasmacytoid component. Eight of the nine patients (88.9%) with > 10% plasmacytoid component died. CONCLUSIONS: The results indicate that PUC may induce EMT and may be associated with high invasion.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Transición Epitelial-Mesenquimal , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Vejiga Urinaria/químicaRESUMEN
OBJECTIVES: Real-time monitoring of disease status would be beneficial for timely decision making in the treatment of urothelial cancer (UC), and may accelerate the evaluation of clinical trials. Use of cell free tumor DNA (cftDNA) as a biomarker in liquid biopsy is minimally invasive and its successful use has been reported in various cancer types, including UC. The objective of this study was to evaluate the use of digital droplet PCR (ddPCR)-based assays to monitor UC after treatment. METHOD AND MATERIALS: Blood, urine and matching formalin fixed, paraffin embedded diagnostic specimens were collected from 20 patients diagnosed with stage T1 (nâ¯=â¯2) and T2/T3 (nâ¯=â¯18) disease. SNaPshot assays, Sanger sequencing and whole exome sequencing were used to identify tumor-specific mutations, and somatic mutation status was confirmed using patient-matched DNAs extracted from buffy coats and peripheral blood mononucleocytes. The ddPCR assays of the tumor-specific mutations were used to detect the fractional abundance of cftDNA in plasma and urine. RESULTS: SNaPshot and Sanger sequencing identified point mutations in 70% of the patients that were assayable by ddPCR. Cases of remission and relapse monitored by assays for PIK3CA E542K and TP53 Y163C mutations in plasma and urine concurred with clinical observations up to 48 months from the start of chemotherapy. A new ddPCR assay for the telomerase reverse transcriptase (TERT) promoter (-124) mutation was developed. The TERT assay was able to detect mutations in cases below the limit of detection by SNaPshot. Whole exome sequencing identified a novel mutation, CNTNAP4 G727*. A ddPCR assay designed to detect this mutation was able to distinguish mutant from wild-type alleles. CONCLUSIONS: The study demonstrated that ddPCR assays could be used to detect cftDNA in liquid biopsy monitoring of the post-therapy disease status in patients with UC. Overall, 70% of the patients in our study harbored mutations that were assayable by ddPCR.
Asunto(s)
Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , ADN Tumoral Circulante/análisis , Reacción en Cadena de la Polimerasa/métodos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/metabolismo , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/orina , Estudios de Factibilidad , Femenino , Humanos , Biopsia Líquida , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
The high occurrence of bladder cancer and its tendency to recur in combination with a lifelong surveillance make the treatment of superficial bladder cancer one of the most expensive and time-consuming. Moreover, carcinoma in situ often leads to muscle invasion with an unfavorable prognosis. Currently, invasive methods including cystoscopy and cytology remain a gold standard. The aim of this study was to explore urine-based biomarkers to find the one with the best specificity and sensitivity, which would allow optimizing the treatment plan. In this review, we sum up the current knowledge about Cytokeratin fragments (CYFRA 21.1), Excision Repair Cross-Complementation 1 (ERCC1), Tumour Protein p53 (Tp53), Fibroblast Growth Factor Receptor 3 (FGFR3), Tumor-Associated Trypsin Inhibitor (TATI) and their potential applications in clinical practice.
Asunto(s)
Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Proteínas de Unión al ADN/análisis , Endonucleasas/análisis , Queratina-19/análisis , Proteínas de Neoplasias/análisis , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/análisis , Inhibidor de Tripsina Pancreática de Kazal/análisis , Proteína p53 Supresora de Tumor/análisis , Neoplasias de la Vejiga Urinaria/química , Carcinoma de Células Transicionales/diagnóstico , Humanos , Pronóstico , Neoplasias de la Vejiga Urinaria/diagnósticoRESUMEN
In accordance with US Food and Drug Administration recommendations, tumor PD-L1 expression should be assessed in all patients with platinum-ineligible metastatic urothelial carcinoma (mUC), and patients with low PD-L1 expression should not receive single-agent immune checkpoint inhibition treatment. By contrast, PD-L1 should not be tested in metastatic renal cell carcinoma and platinum-refractory mUC.
Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Neoplasias Urogenitales/química , Carcinoma de Células Transicionales/patología , Humanos , Estadificación de Neoplasias , Neoplasias Urogenitales/patologíaRESUMEN
OBJECTIVES: Micropapillary urothelial carcinoma of the urinary bladder (MPUC) is a rare variant of urothelial carcinoma which has aggressive clinical characteristics. The objective is to investigate the molecular subtypes of MPUC and the impact to the clinical outcome and determine whether MPUC represents a variant of adenocarcinoma. MATERIALS AND METHODS: We evaluated surrogate immunohistochemical markers of luminal, basal, and p53-like subtypes and correlated with prognosis and the expression of markers related to bladder adenocarcinoma and glandular differentiation in 56 cases of MPUC (10 cases of transurethral resection and 46 cases of radical cystectomy). Biomarker expression in co-existing conventional urothelial carcinoma was also analyzed. Cox regression analysis was performed to study the impact of molecular subtype on the clinical outcome. RESULTS: Thirty-four cases (61%) met criteria for the luminal subtype. Twenty-two cases (39%) displayed a p53-like subtype. In contrast, 40/56 (71%) cases of coexisting conventional urothelial carcinoma were classified as luminal subtype and 16/56 (29%) cases were designated as p53-like subtype. There was no significant survival difference between luminal subtype and p53-like subtype. CDX2, villin, and cadherin 17 were negative in all cases. MUC1 was strongly and diffusely expressed in the stroma-facing surface of MPUC tumor cells in all the cases. CONCLUSIONS: Our findings suggest that MPUC possesses characteristics of luminal and p53-like subtypes, and does not harbor phenotypic features of the basal subtype. There is no significant difference in the prognosis between luminal and p53-like subtype MPUC. MPUC is not a variant of adenocarcinoma and does not represent a form of glandular differentiation, in contrast to other organ sites.
Asunto(s)
Adenocarcinoma/clasificación , Biomarcadores de Tumor/análisis , Carcinoma Papilar/clasificación , Carcinoma de Células Transicionales/clasificación , Proteína p53 Supresora de Tumor/análisis , Neoplasias de la Vejiga Urinaria/clasificación , Adenocarcinoma/química , Anciano , Anciano de 80 o más Años , Algoritmos , Carcinoma Papilar/química , Carcinoma Papilar/mortalidad , Carcinoma Papilar/cirugía , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/cirugía , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Background: Response to neoadjuvant cisplatin treatment in bladder cancer has been linked to expression of Bcl-2 protein by cancer cells. The objective of this study was to test Bcl-2 as a predictive marker of neoadjuvant cisplatin chemotherapy response in a patient cohort from randomized cystectomy trials. Methods: Tumor samples were taken from 247 patients with T2-T4 bladder cancer enrolled in two randomized trials comparing cystectomy with or without neoadjuvant chemotherapy. Tissue microarrays from pre-intervention transurethral resection specimens were assessed for Bcl-2 protein status by immunohistochemistry. Extension of staining above 10% was regarded as positive. Downstaging and survival ratios in relation to Bcl-2 immunoreactivity and neoadjuvant chemotherapy utilization were calculated using the log rank test and multivariate Cox proportional hazards regression analyses. Results: Bcl-2 expression was positive in 38% and negative in 62% of the 236 evaluable patients. Bcl-2 negative patients receiving neoadjuvant chemotherapy had a significant increase in survival (p = 0.009), while Bcl-2 positive patients showed no difference (p = 0.4). However, the interaction variable between neoadjuvant chemotherapy and biomarker status was not significant (p = 0.38). When the prognostic value was assessed in the no-chemotherapy group, 5-year overall survival times were significantly better among Bcl-2 positive patients than among Bcl-2 negative patients (42 months vs 33 months, p = 0.04), but again Bcl-2 status did not remain independent when other factors were adjusted. Also, in a multivariate analysis with all patients, Bcl-2 was not significant. Conclusions: Bcl-2 status is not an independent predictor of neoadjuvant cisplatin chemotherapy response and is not prognostic in muscle-invasive bladder cancer.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante , Cistectomía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
PURPOSE: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies. METHODS: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of <â1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05. RESULTS: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS. CONCLUSIONS: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.
Asunto(s)
Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/mortalidad , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Proteínas Supresoras de Tumor/biosíntesis , Ubiquitina Tiolesterasa/biosíntesis , Neoplasias Ureterales/metabolismo , Neoplasias Ureterales/mortalidad , Anciano , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/patología , Femenino , Humanos , Neoplasias Renales/química , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Proteínas Supresoras de Tumor/análisis , Ubiquitina Tiolesterasa/análisis , Neoplasias Ureterales/química , Neoplasias Ureterales/patologíaRESUMEN
Urothelial carcinoma (UC) is one of the most common cancers and survival rates are low in metastatic disease with currently established first-line platinum-based chemotherapies. Unlike in many other cancers, no clinically established molecular targeted therapies exist for the treatment of this malignancy. Here we present a case of complete tumor remission following third-line treatment with trastuzumab and gemcitabine in a patient with human epidermal growth factor receptor 2 (HER2)-positive UC after progression under cisplatin and vinflunine chemotherapies. This case shows the potential significance of anti-HER2 therapy in selected patients with molecularly characterized UC. Clinical trials so far show inconclusive outcomes of anti-HER2 therapies in UC, indicating further need for both basic research and clinical studies for the identification of resistance factors and improved patient selection.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Desoxicitidina/análogos & derivados , Trastuzumab/uso terapéutico , Carcinoma de Células Transicionales/química , Desoxicitidina/uso terapéutico , Humanos , Receptor ErbB-2/análisis , Inducción de Remisión , GemcitabinaRESUMEN
We report a case of lymphoepithelioma-like carcinoma of the urinary bladder in an elderly female patient. A 97-year old woman presented with hematuria, and an ultrasonographic urinary study showed a localized tumor in the trigone region of the urinary bladder. A transurethral resection revealed a mixed tumor formed by high-grade transitional carcinoma and lymphoepithelioma-like carcinoma that had infiltrated into the muscular propria. We describe the clinicopathological, morphological and immunohistochemical features of this tumor and briefly discuss its differential diagnosis and biological behavior.
Asunto(s)
Carcinoma de Células Transicionales/patología , Neoplasias de Células Escamosas/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/complicaciones , Diagnóstico Diferencial , Femenino , Hematuria/etiología , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/patología , Invasividad Neoplásica , Neoplasias de Células Escamosas/química , Neoplasias de Células Escamosas/complicaciones , Pronóstico , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/complicacionesRESUMEN
IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.
Asunto(s)
Neoplasias Abdominales/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Abdominales/química , Neoplasias Abdominales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno B7-H1/análisis , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/secundario , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Criterios de Evaluación de Respuesta en Tumores Sólidos , Retratamiento , Tasa de SupervivenciaRESUMEN
PURPOSE: To our knowledge the frequency and prognostic significance of PTEN protein expression in upper tract urothelial carcinoma have not yet been investigated in large studies. We analyzed PTEN protein status and its association with disease recurrence and survival outcomes in a large, multi-institutional upper tract urothelial carcinoma cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 611 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy between 1991 and 2008 at a total of 7 institutions. Median followup was 23 months. Tissue microarrays and immunohistochemical PTEN staining (monoclonal antibody) were performed. Univariable and multivariable Cox regression models were created to address the association of PTEN protein expression with disease recurrence, and cancer specific and overall mortality. RESULTS: PTEN staining was absent in 45 cases (7.4%). Patients with PTEN loss had significantly advanced pathological tumor stage and grade (p <0.001), and higher rates of lymph node metastasis (p <0.01) and lymphovascular invasion (p <0.001) compared to patients with PTEN expression. PTEN loss was associated with disease recurrence, and cancer specific and overall mortality on univariable Cox regression analyses. However, on multivariable Cox regression analyses adjusted for the effect of standard clinicopathological features PTEN loss was only associated with overall mortality (HR 1.69, 95% CI 1.09-2.61, p = 0.02). CONCLUSIONS: In patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma loss of PTEN protein expression is rare but associated with features of biologically aggressive disease such as higher grade and stage as well as lymph node metastasis. Loss of PTEN expression was associated with overall mortality. PTEN loss seemed to promote worse outcomes in this relatively small group of patients.
Asunto(s)
Carcinoma de Células Transicionales/cirugía , Neoplasias Renales/cirugía , Recurrencia Local de Neoplasia/epidemiología , Nefroureterectomía , Fosfohidrolasa PTEN/biosíntesis , Neoplasias Ureterales/cirugía , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/epidemiología , Femenino , Humanos , Neoplasias Renales/química , Neoplasias Renales/epidemiología , Masculino , Nefroureterectomía/métodos , Fosfohidrolasa PTEN/análisis , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias Ureterales/química , Neoplasias Ureterales/epidemiologíaRESUMEN
PURPOSE: Stage pT1 urothelial bladder cancer (UBC) is characterized as a challenging subentity of urothelial carcinoma with an unforeseeable clinical course. In addition to more or less established clinical and histopathological features, we evaluated the role of epithelial-mesenchymal transition (EMT) marker E-cadherin, shown to be of prognostic value in muscle-invasive disease, regarding the prognosis of stage pT1 high-grade (hg) UBC. METHODS: Tissue of 226 stage pT1 hg UBC patients from transurethral resection could be immunostained for E-cadherin. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses regarding progression-free (PFS) and cancer-specific survival (CSS) were performed. RESULTS: Aberrant expression of E-cadherin was recognized in 74% of patients. Kaplan-Meier analysis showed that aberrant E-cadherin expression was associated with worse 10-year PFS (62 vs. 90%, p = 0.045). In univariate analysis, aberrant E-cadherin staining, associated carcinoma in situ, grading 3 after WHO classification 1973 and infiltrative growth pattern at the invasion front were the statistically significant predictive factors for worse PFS, only infiltrative growth pattern for CSS. With regard to progression, grading 3 after WHO classification of 1973 (HR 6.49; CI 1.54-27.28, p = 0.011) and infiltrative tumor invasion pattern (HR 2.06; CI 1.10-3.86, p = 0.024) revealed as independent factors for PFS, and there was a trend also for E-cadherin expression (HR 0.45; CI 0.19-1.06; p = 0.068). Regarding CSS, infiltrative tumor growth pattern (HR 3.79; CI 1.67-8.60, p = 0.001) was the only statistically significantly independent predictive factor in multivariate Cox regression analysis. CONCLUSIONS: Beside invasion growth pattern and WHO grading 1973 that achieved to be independent prognostic factors, there was a trend for the parameter E-cadherin expression to be of predictive value for PFS in stage pT1 hg urothelial bladder carcinoma after organ-sparing approach. Further studies on genetic level are warranted to define the distinct role of EMT in early-invasive UBC.
Asunto(s)
Cadherinas/análisis , Carcinoma in Situ/química , Carcinoma in Situ/patología , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/patología , Anciano , Biomarcadores de Tumor/análisis , Carcinoma in Situ/cirugía , Carcinoma de Células Transicionales/cirugía , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Tratamientos Conservadores del Órgano , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.