RESUMEN
Whereas targeted and shotgun sequencing approaches are both powerful in allowing the study of tissue-associated microbiota, the human: microorganism abundance ratios in tissues of interest will ultimately determine the most suitable sequencing approach. In addition, it is possible that the knowledge of the relative abundance of bacteria and fungi during a treatment course or in pathological conditions can be relevant in many medical conditions. Here, we present a qPCR-targeted approach to determine the absolute and relative amounts of bacteria and fungi and demonstrate their relative DNA abundance in nine different human tissue types for a total of 87 samples. In these tissues, fungi genomes are more abundant in stool and skin samples but have much lower levels in other tissues. Bacteria genomes prevail in stool, skin, oral swabs, saliva, and gastric fluids. These findings were confirmed by shotgun sequencing for stool and gastric fluids. This approach may contribute to a more comprehensive view of the human microbiota in targeted studies for assessing the abundance levels of microorganisms during disease treatment/progression and to indicate the most informative methods for studying microbial composition (shotgun versus targeted sequencing) for various samples types.
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Bacterias , Metagenómica , Bacterias/genética , ADN de Hongos , Hongos/genética , Humanos , Metagenómica/métodos , Análisis de Secuencia de ADNRESUMEN
Rhabdomyosarcoma affects mainly pediatric patients and is currently classified into 4 categories: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. Epithelioid rhabdomyosarcoma is a recently described variant of rhabdomyosarcoma in which primary cutaneous presentation is infrequent. In this brief report, we describe a rare case of epithelioid rhabdomyosarcoma in an 81-year-old man, presenting as a skin lesion in the neck, which increased in size in 1 month. After imaging evaluation, a solid cervical mass was discovered. A biopsy was performed, and the diagnosis of epithelioid rhabdomyosarcoma was rendered. The patient died due to rapid progression of the tumor. To make an accurate diagnosis and ensure appropriate patient management, it is necessary to be aware of this variant and use proper immunohistochemical stains when facing an epithelioid malignancy, expanding the differential diagnosis of epithelioid neoplasms.
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Rabdomiosarcoma/patología , Neoplasias Cutáneas/patología , Anciano de 80 o más Años , Resultado Fatal , Humanos , MasculinoRESUMEN
The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased PBRM1 mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-ß, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC.
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Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Proteínas de Unión al ADN , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patologíaRESUMEN
Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a crucial role in cell proliferation, growth, differentiation, and apoptosis. IGF1R overexpression has been observed in several cancers, including invasive bladder carcinomas, as a potential prognostic factor. Given known biologic differences between upper and lower urinary tract urothelial carcinoma, we assessed the expression status and prognostic significance of IGF1R in upper tract urothelial carcinoma (UTUC). Two tissue microarrays (TMAs) were built from 99 Japanese patients with non-metastatic UTUC submitted to radical nephroureterectomy between 1997 and 2011. TMAs were constructed with triplicate tumor and paired benign urothelium. Membranous IGF1R staining was evaluated using immunohistochemistry. Two scoring methods were applied (Her2-score and H-score). The highest score was assigned to each tumor. IGF1R positivity was defined as Her2-score ≥ 1+. Association with clinicopathologic parameters and outcome was assessed using hazard ratios (HR) with 95% confidence intervals (CI) and adjusted P values. We found positive IGF1R expression in 70% of UTUC. Outcomes were as follows: tumor recurrence, 33%; tumor progression, 59%; overall mortality, 33%; and cancer-specific mortality, 30%. IGF1R was not associated with any clinicopathologic features. In addition, IGF1R expression was not associated with tumor recurrence (HR = 0.54, CI = 0.25-1.1, P = 0.11), tumor progression (HR = 1.6, CI = 0.8-3.1, P = 0.19), overall mortality (HR = 1.5, CI = 0.68-3.4, P = 0.31), or cancer-specific mortality (HR = 1.6, CI = 0.68-3.8, P = 0.27). Positive IGF1R expression was found in more than two thirds of UTUC. This finding provides a rationale to investigate IGF1R as a potential therapeutic target in UTUC. In contrast to bladder cancer, IGF1R expression in UTUC did not correlate with outcome, further pointing to biologic differences between UTUC and bladder cancer.
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Biomarcadores de Tumor/análisis , Carcinoma/química , Neoplasias Renales/química , Receptores de Somatomedina/análisis , Neoplasias Ureterales/química , Urotelio/química , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Japón , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Receptor IGF Tipo 1 , Estudios Retrospectivos , Análisis de Matrices Tisulares , Resultado del Tratamiento , Neoplasias Ureterales/mortalidad , Neoplasias Ureterales/patología , Neoplasias Ureterales/cirugía , Urotelio/patologíaRESUMEN
PURPOSE: To evaluate the prognostic impact of the protein expression of both PBRM1 and BAP1 in metastatic tissue of patients with metastatic clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all 124 consecutive cases of metastatic ccRCC, who underwent metastasectomy or biopsy of metastatic tumor tissue between 2007 and 2016 were selected from the medical records of our institution. Additionally, 38 paired cases with tissue from the primary tumor involving radical or partial nephrectomy for ccRCC were also selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. RESULTS: PBRM1 nuclear staining of the 124-immunostained metastases of ccRCC specimens showed that 98 (79.0%) had negative expression and 26 (21.0%) positive expression of PBRM1. Regarding BAP1 expression, we observed that 77 (62.1%) specimens were negative and 47 (37.9%) showed positive nuclear staining. When we compared the expression of both markers on primary tumor and tumor metastasis, we found disagreement in half of the cases. Five-year overall survival rates in patients with positive expression and negative expression of BAP1 were 53.2% and 35.1%, respectively (Pâ¯=â¯0.004). Five-year progression-free survival rates in patients with positive expression and negative expression of BAP1 were 14.9% and 3.9%, respectively (Pâ¯=â¯0.003). Conversely, PBRM1 expression did not significantly influence either overall survival or progression-free survival rates. In multivariate analysis, negative expression of BAP1 tumors also presented higher risks of death (hazard ratio (HR)â¯=â¯1.913, Pâ¯=â¯0.041) and disease progression (HRâ¯=â¯1.656, Pâ¯=â¯0.021). CONCLUSION: The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Proteínas Supresoras de Tumor/deficiencia , Ubiquitina Tiolesterasa/deficiencia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Supervivencia sin Progresión , Factores de Riesgo , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/biosíntesis , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.
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Aneuploidia , Carcinoma de Células Transicionales/diagnóstico , Detección Precoz del Cáncer/métodos , Mutación , Neoplasias de la Vejiga Urinaria/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/orina , Niño , Preescolar , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Telomerasa/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/orina , Adulto JovenRESUMEN
PURPOSE: To evaluate the prognostic impact of immunohistochemical expression of BAP1 and PBRM1 in patients with early stage (pT1-pT2N0M0) clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: A total of 441 consecutive patients treated surgically for stages I and II (TNM-AJCC 2010) ccRCC between 1990 and 2016 were selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. Sixty-two patients had frozen tumoral tissue available in the tumor bank of our institution for quantitative real-time reverse transcriptase polymerase chain reaction analysis. RESULTS: Of the 441-immunostained ccRCC specimens, 91 (20.6%) and 107 (24.3%) showed negative-expression of PBRM1 and BAP1, respectively. Fifty-eight (13.2%) showed negative-expression of both markers (PBRM1-/BAP-). There was an association between both markers expression pattern and classical parameters, such as pT stage (P<0.001), tumor size (P<0.001), and tumor grade (P<0.001). Both independent PBRM1 and BAP1 negative-expression were associated with lower rates of disease-specific survival and recurrence-free survival. When patients were grouped into presence of positive expression of one or both markers vs. PBRM1-/BAP1- patients, disease-specific survival and rates were 95.3% vs. 77.6%, respectively (P<0.001). PBRM1-/BAP1-group presented a higher risk of cancer specific death (hazard ratio = 2.722, P = 0.007) and disease recurrence (hazard ratio = 2.467, P = 0.004) in multivariate analysis. CONCLUSION: Patients with early stage tumors that present concomitant loss of both PBRM1 and BAP1 demonstrated worse survival rates and represent a relevant risk group for tumor recurrence and death.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Nefrectomía/mortalidad , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/cirugía , Proteínas de Unión al ADN , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
Our group and others have previously demonstrated the presence of TERT promoter mutations (TERT-mut) in 60-80% of urothelial carcinomas and some of their histologic variants. Five other genes have been frequently implicated in bladder cancer: FGRF3, TP53, PIK3CA, HRAS, and CDKN2A. In the current study, we sought to determine the prevalence of mutations in TERT and these five other genes in de novo papillary urothelial neoplasms of low malignant potential (PUNLMP) of the urinary bladder. A retrospective search of our archives for PUNLMP was performed and 30 de novo cases were identified and included in the study. We found mutations in TERT (TERT-mut) and FGFR3 (FGFR3-mut) to be the most common alterations in the cohort (63 and 60%, respectively). The majority of the TERT-mut-positive tumors (84%) had a g.1295228C > T alteration with the remaining tumors demonstrating g.1295250C > T. Approximately one fourth of tumors had TP53 mutations. These findings support the potential utility of a uniform genetic mutation panel to detect bladder cancers of various subtypes.
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Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
ETS family gene fusions are common in prostate cancer and molecularly define a tumor subset. ERG is the most commonly rearranged, leading to its overexpression, followed by ETV1, ETV4, and ETV5, and these alterations are generally mutually exclusive. We validated the Decipher prostate cancer assay to detect ETS alterations in a Clinical Laboratory Improvement Amendments-accredited laboratory. Benchmarking against ERG immunohistochemistry and ETV1/4/5 RNA in situ hybridization, we examined the accuracy, precision, and reproducibility of gene expression ETS models using formalin-fixed, paraffin-embedded samples. The m-ERG model achieved an area under curve of 95%, with 93% sensitivity and 98% specificity to predict ERG immunohistochemistry status. The m-ETV1, -ETV4, and -ETV5 models achieved areas under curve of 98%, 88%, and 99%, respectively. The models had 100% robustness for ETS status, and scores were highly correlated across sample replicates. Models predicted 41.5% of a prospective radical prostatectomy cohort (n = 4036) to be ERG+, 6.3% ETV1+, 1% ETV4+, and 0.4% ETV5+. Of prostate tumor biopsy samples (n = 509), 41.2% were ERG+, 8.6% ETV1+, 0.4% ETV4+, and none ETV5+. Higher Decipher risk status tumors were more likely to be ETS+ (ERG or ETV1/4/5) in the radical prostatectomy and the biopsy cohorts (P < 0.05). These results support the utility of microarray-based ETS status prediction models for molecular classification of prostate tumors.
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Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Proteínas E1A de Adenovirus/genética , Proteínas de Unión al ADN/genética , Humanos , Inmunohistoquímica , Masculino , Estudios Prospectivos , Prostatectomía , Neoplasias de la Próstata/cirugía , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Factores de Transcripción/genéticaRESUMEN
Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic diseases require a multidisciplinary treatment approach. However, mortality and morbidity remain high, and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune-checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays. Tissue microarrays were stained with immunohistochemistry for PD-L1, FOXP3, CD8, and Ki-67. PD-L1 was investigated using rabbit monoclonal anti-PD-L1 antibody (Cell Signaling, Boston, MA; E1L3N, 1:100). Overall, 21 (40%) of 53 penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. Forty-four percent (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion, or tumor grade. FOXP3 expression in tumoral immune cells was found in 26 (49%) of 53 cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P = .0086). The ratio of CD8/FOXP3 was greater than 1 in 62% of cases in tumor-infiltrating immune cells and 34% of cases in stromal immune cells. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC.
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Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Escamosas/inmunología , Factores de Transcripción Forkhead/análisis , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias del Pene/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Baltimore , Biopsia , Linfocitos T CD8-positivos/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias del Pene/mortalidad , Neoplasias del Pene/patología , Neoplasias del Pene/terapia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Células del Estroma/inmunología , Células del Estroma/patología , Análisis de Matrices Tisulares , Microambiente TumoralRESUMEN
AIMS: GATA3 has been reported as a specific urothelial marker among organs in the pelvic region, and has been classified as highly sensitive and specific for urothelial and breast carcinomas. Our aim was to verify GATA3 expression in extramammary Paget disease, and to determine whether it can be use to differentiate primary vulvar Paget disease from pagetoid urothelial intraepithelial neoplasia (PUIN). We also analysed HER2 protein expression and HER2 gene amplification and their roles as prognostic factors in extramammary Paget disease. METHODS AND RESULTS: We analysed GATA3 and HER2 expression in 11 primary vulvar Paget disease cases and two PUIN cases. All cases showed nuclear expression of GATA3. Of 13 cases, five were equivocal for HER2 expression (score 2+) and one was positive (3+). Fluorescence in-situ hybridization results showed amplification in two of these six cases. Both HER2-amplified cases were invasive. CONCLUSION: GATA3 was positive in all extramammary Paget disease cases tested (13 cases), and it has no value for differentiating between primary and secondary vulvar Paget disease from the urological tract. HER2 amplification might confer an aggressive and invasive pattern in primary vulvar Paget disease, as both amplified cases showed an invasive pattern.
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Biomarcadores de Tumor/análisis , Carcinoma in Situ/diagnóstico , Factor de Transcripción GATA3/biosíntesis , Enfermedad de Paget Extramamaria/diagnóstico , Neoplasias Urológicas/diagnóstico , Neoplasias de la Vulva/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Errores Diagnósticos , Femenino , Factor de Transcripción GATA3/análisis , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Enfermedad de Paget Extramamaria/metabolismo , Enfermedad de Paget Extramamaria/patología , Receptor ErbB-2/análisis , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patología , Neoplasias de la Vulva/metabolismo , Neoplasias de la Vulva/patologíaRESUMEN
OBJECTIVE: Ulceration is common in bladder tumors, but its prognostic role, although intuitive, is not established. We aim to explore the presence of gross ulceration and its relationship with other morphological and biological features classically associated with extravesical disease, in patients submitted to radical cystectomy. METHODS: Tumor size and morphology were noted on 101 cystectomy patients (2000-2010). Papillary, exophytic, and vegetant tumors were grouped as "papillary" and solid/nodular, ulcerated and infiltrative as "nonpapillary." Ulceration was noted grossly in every case as a binary parameter, regardless of morphology. Immunohistochemistry was performed for hypoxia (hypoxia-inducible factor-1α and vascular endothelial growth factor), and cell cycle proteins (pRb, p53, and cyclin D1). RESULTS: Mean age was 66.7 year, male:female ratio was 2:1, 20 patients received bacillus Calmette-Guerin and 10 neoadjuvant chemotherapy. Upstaging rate was 56.4%. Ulcerated lesions presented mostly as nonpapillary and nonorgan confined (nOC), whereas nonulcerated tumors were often papillary and organ confined (OC). Tumor size was smaller in nonpapillary tumors (P = 0.002), but did not associate with altered hypoxia or cell cycle expressions. pRb and cyclin D1 loss and p53 overexpression were more frequent in ulcerated and non-OC tumors as did the phenotype vascular endothelial growth factor-negative/hypoxia-inducible factor-1α-low (P<0.001). On a multivariate model, ulceration was an independent predictor of non-OC and extravesical disease. CONCLUSION: Patients with ulcerated tumors were often staged with extravesical disease, independent of other morphologic and biological features known to affect prognosis. Prospective studies are needed to confirm the predictive value of tumor ulceration at cystoscopy, which could improve patient stratification for neoadjuvant chemotherapy.
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Carcinoma de Células Transicionales/secundario , Cistectomía , Úlcera/etiología , Neoplasias de la Vejiga Urinaria/patología , Anciano , Antineoplásicos/uso terapéutico , Vacuna BCG/uso terapéutico , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/complicaciones , Carcinoma de Células Transicionales/terapia , Ciclo Celular , Hipoxia de la Célula , Terapia Combinada , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Proteínas de Neoplasias/análisis , Carga Tumoral , Úlcera/patología , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/terapia , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
PURPOSE: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression. MATERIALS AND METHODS: Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG+, m-ETS+, m-SPINK1+ or Triple Negative (m-ERGâ/m-ETSâ/m-SPINK1â), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes. RESULTS: Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG+, m-ETS+, m-SPINK1+ and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1+ tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG+ group. Compared to the Triple Negative group, m-SPINK1+ showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG+, m-ETS+ and Triple Negative cases. m-SPINK1+ independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96-6.4) and biochemical recurrence (HR 3, 95% CI 1.1-8). CONCLUSIONS: SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.
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Prostatectomía , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/genética , Inhibidor de Tripsina Pancreática de Kazal/genética , Adulto , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Prostatectomía/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well.
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Biomarcadores de Tumor/genética , Carcinoma in Situ/genética , Hibridación Fluorescente in Situ , Neoplasias de Células Germinales y Embrionarias/genética , Seminoma/genética , Telómero/genética , Neoplasias Testiculares/genética , Proteínas Adaptadoras Transductoras de Señales/análisis , Adulto , Biomarcadores de Tumor/análisis , Carcinoma in Situ/química , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Proteínas Co-Represoras , ADN Helicasas/análisis , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Chaperonas Moleculares , Neoplasias de Células Germinales y Embrionarias/química , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/cirugía , Proteínas Nucleares/análisis , Factor 3 de Transcripción de Unión a Octámeros/análisis , Seminoma/química , Seminoma/patología , Seminoma/cirugía , Telómero/química , Homeostasis del Telómero , Acortamiento del Telómero , Neoplasias Testiculares/química , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Proteína Nuclear Ligada al Cromosoma X , Adulto JovenRESUMEN
Solitary fibrous tumor (SFT) diagnosis in prostate can be challenging on small biopsies. Prostatic stromal tumors of unknown malignant potential (STUMP) and SFT have overlapping features. NAB2-STAT6 gene fusions that were recently identified in various SFTs lead to nuclear translocalization of STAT6. Nuclear STAT6 immunostaining is now considered an adjunct for SFT diagnosis. We evaluated STAT6 and an emerging stemness marker, ALDH1, in the differential diagnosis of SFT versus prostatic stromal lesions. Sixteen STUMPs, 12 SFTs, and 4 prostatic stromal sarcomas (12 needle biopsies, 13 radical prostatectomies, 7 transurethral resections) were retrieved (1995-2015). Sections were stained with polyclonal STAT6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; S20, 1:100) and monoclonal ALDH1 antibody (BD Biosciences, San Jose, CA; clone 44, 1:250). In STAT6 cases, only unequivocal nuclear staining (with/without cytoplasmic staining) was considered positive. Cytoplasmic ALDH1 staining was counted positive. Ten of 11 evaluable SFTs demonstrated strong and diffuse nuclear STAT6 positivity; 4 of 16 STUMPs had nuclear staining that was weak (1/4) or focal (1/4). ALDH1 positivity was seen in 10 of 12 evaluable SFTs and 3 of 15 STUMPs. Prostatic stromal sarcomas were STAT6 negative (4/4); 2 of 4 were ALDH1 positive. The sensitivity and specificity for STAT6 for the diagnosis of SFT were 91% and 75%, respectively. Coexpression of STAT6 and ALDH1 yielded the same sensitivity but improved the specificity (100%) for the diagnosis of SFT. STAT6 is a useful marker in the differential diagnosis of SFT versus STUMP. Using STAT6 and ALDH1 together increases specificity. STUMPs can show STAT6 positivity, and when they do, it is likely to be weak or focal.
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Biomarcadores de Tumor/análisis , Inmunohistoquímica , Isoenzimas/análisis , Neoplasias de la Próstata/enzimología , Retinal-Deshidrogenasa/análisis , Factor de Transcripción STAT6/análisis , Sarcoma/enzimología , Tumores Fibrosos Solitarios/enzimología , Células del Estroma/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Familia de Aldehído Deshidrogenasa 1 , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/patología , Reproducibilidad de los Resultados , Sarcoma/patología , Tumores Fibrosos Solitarios/patología , Células del Estroma/patologíaRESUMEN
OBJECTIVE: To evaluate insulin-like growth factor-1 receptor (IGF1R) expression in penile cancer and its association with oncologic outcomes. METHODS: Tissue microarrays were constructed from 53 patients treated at our institution. Expression of IGF1R was evaluated using a Her2-like scoring system. Overexpression was defined as 1+ or greater membranous staining. Association of IGF1R expression with pathologic features was assessed with comparative statistics, and association with local recurrence, progression to nodal or distance metastases, or death was assessed with Kaplan-Meier survival analysis and Cox proportional hazard regression models. RESULTS: Overall, IGF1R overexpression was seen in 33 (62%) cases. With a median follow-up of 27.8 months, IGF1R overexpression was associated with inferior progression-free survival (PFS) (P = .003). In a multivariable model controlling for grade, T stage, perineural invasion, and lymphovascular invasion, IGF1R expression was independently associated with disease progression (hazard ratio 2.3, 95% confidence interval 1.1-5.1, P = .03. Comparing patients without IGF1R overexpression to those with overexpression, 5-year PFS was 94.1% vs 45.8%. CONCLUSION: IGF1R overexpression was associated with inferior PFS in penile cancer. Drugs that target IGF1R and downstream messengers may have a therapeutic benefit in patients that exhibit IGF1R overexpression.
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Neoplasias del Pene/etiología , Neoplasias del Pene/patología , Receptor IGF Tipo 1/biosíntesis , Anciano , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts.
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Adenocarcinoma/patología , Adenocarcinoma/cirugía , Prostatectomía/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Adulto , Anciano , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Próstata/patología , Factores de RiesgoRESUMEN
Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.
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Carcinoma de Células Renales/genética , Citosina/análogos & derivados , Metilación de ADN , Neoplasias Renales/genética , Neoplasias Urogenitales/genética , 5-Metilcitosina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Citosina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. OBJECTIVE: To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. RESULTS AND LIMITATIONS: Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. CONCLUSIONS: In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. PATIENT SUMMARY: The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy.