Victor E. Reuter

Annotation of prostate cancer genomes provides a foundation for discoveries that can impact disease understanding and treatment. Concordant assessment of DNA copy number, mRNA expression, and focused exon resequencing in 218 prostate cancer tumors identified the nuclear receptor coactivator NCOA2 as an oncogene in ∼11% of tumors. Additionally, the androgen-driven TMPRSS2-ERG fusion was associated with a previously unrecognized, prostate-specific deletion at chromosome 3p14 that implicates FOXP1, RYBP, and SHQ1 as potential cooperative tumor suppressors. DNA copy-number data from primary tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. The genomic and clinical outcome data from these patients are now made available as a public resource.

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “blue book”), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome–associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non–GCNIS-related tumours in the 2016 WHO classification. The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival “neuronal” subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

The development of decision support systems for pathology and their deployment in clinical practice have been hindered by the need for large manually annotated datasets. To overcome this problem, we present a multiple instance learning-based deep learning system that uses only the reported diagnoses as labels for training, thereby avoiding expensive and time-consuming pixel-wise manual annotations. We evaluated this framework at scale on a dataset of 44,732 whole slide images from 15,187 patients without any form of data curation. Tests on prostate cancer, basal cell carcinoma and breast cancer metastases to axillary lymph nodes resulted in areas under the curve above 0.98 for all cancer types. Its clinical application would allow pathologists to exclude 65-75% of slides while retaining 100% sensitivity. Our results show that this system has the ability to train accurate classification models at unprecedented scale, laying the foundation for the deployment of computational decision support systems in clinical practice.

It has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has been generated about the pathology and genetics of these tumours. Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 WHO classification. In most cases, it represents intraductal spread of aggressive prostatic carcinoma and should be separated from high-grade prostatic intraepithelial neoplasia. New acinar adenocarcinoma variants are microcystic adenocarcinoma and pleomorphic giant cell adenocarcinoma. Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7. The new WHO classification further recommends the recently developed prostate cancer grade grouping with five grade groups. For bladder cancer, the 2016 WHO classification continues to recommend the 1997 International Society of Urological Pathology grading classification. Newly described or better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential, which is frequently identified in patients with a prior history of urothelial carcinoma. Invasive urothelial carcinoma with divergent differentiation refers to tumours with some percentage of "usual type" urothelial carcinoma combined with other morphologies. Pathologists should mention the percentage of divergent histologies in the pathology report.Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 World Health Organization classification. Better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential.

This paper presents the conclusions of a workshop entitled 'Impact of Molecular Genetics on the Classification of Renal Cell Tumours', which was held in Heidelberg in October 1996. The focus on 'renal cell tumours' excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic to the kidneys. The proposed classification subdivides renal cell tumours into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most commonly documented genetic abnormalities. Benign tumours are subclassified into metanephric adenoma and adenofibroma, papillary renal cell adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and renal cell carcinoma, unclassified. This classification is based on current genetic knowledge, correlates with recognizable histological findings, and is applicable to routine diagnostic practice.

Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8-10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3+4=7 and 4+3=7 are often considered the same prognostic group.To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data.Between 2005 and 2014, 20,845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions.Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores.In the surgery cohort, we found large differences in recurrence rates between both Gleason 3+4 versus 4+3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3+4, 4+3, 8, and 9-10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five-grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death.The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer.A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of < or = 1.0 ng/ml and by sextant prostate biopsies performed > or = 2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1-7.6 years).Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir < or = 1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively (p < 0.001). The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1-2, pretreatment PSA < or = 10.0 ng/ml and Gleason score < or = 6) was 85%, compared to 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p < 0.001). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving > or = 75.6 Gy (p < 0.05). A positive biopsy at > or = 2.5 years after 3D-CRT was observed in only 1/15 (7%) of patients receiving 81.0 Gy, compared with 12/25 (48%) after 75.6 Gy, 19/42 (45%) after 70.2 Gy, and 13/23 (57%) after 64.8 Gy (p < 0.05).The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor ( AR ) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1 , AR , and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

To describe survival in previously treated patients with metastatic renal cell carcinoma (RCC) who are candidates for clinical trials of new agents as second-line therapy.The relationship between pretreatment clinical features and survival was studied in 251 patients with advanced RCC treated during 29 consecutive clinical trials between 1975 and 2002. Clinical features were first examined in univariate analyses, and then a stepwise modeling approach based on Cox regression was used to form a multivariate model.Median survival for the 251 patients was 10.2 months and differed according to year of treatment, with patients treated after 1990 showing longer survival. In this group, the median overall survival time was 12.7 months. Because the purpose of this analysis was to establish prognostic factors for present-day clinical trial design, prognostic factor analysis was performed on these patients. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status, low hemoglobin level, and high corrected serum calcium. These were used as risk factors to categorize patients into three different groups. The median time to death in patients with zero risk factors was 22 months. The median survival in patients with one of these prognostic factors was 11.9 months. Patients with two or three risk factors had a median survival of 5.4 months.Treatment with novel agents during a clinical trial is indicated for patients with metastatic RCC after progression to cytokine treatment. Three prognostic factors for predicting survival were used to categorize patients into risk groups. These risk categories can be used in clinical trial design and interpretation.

Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types. We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8+ T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number. Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Jul 2001A POSTOPERATIVE PROGNOSTIC NOMOGRAM FOR RENAL CELL CARCINOMA MICHAEL W. KATTAN, VICTOR REUTER, ROBERT J. MOTZER, JARED KATZ, and PAUL RUSSO MICHAEL W. KATTANMICHAEL W. KATTAN Requests for reprints: Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., C1075, New York, New York 10021. More articles by this author , VICTOR REUTERVICTOR REUTER More articles by this author , ROBERT J. MOTZERROBERT J. MOTZER More articles by this author , JARED KATZJARED KATZ More articles by this author , and PAUL RUSSOPAUL RUSSO More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)66077-6AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Few published studies have combined prognostic factors to predict the likelihood of recurrence after surgery for renal cell carcinoma. We developed a nomogram for this purpose. Materials and Methods: With Cox proportional hazards regression analysis, we modeled pathological data and disease followup for 601 patients with renal cell carcinoma who were treated with nephrectomy. Predictor variables were patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathological stage. Treatment failure was recorded when there was either clinical evidence of disease recurrence or death from disease. Validation was performed with a statistical (bootstrapping) technique. Results: Disease recurrence was noted in 66 of the 601 patients, and those in whom treatment was successful had a median and maximum followup of 40 and 123 months, respectively. The 5-year probability of freedom from failure for the patient cohort was 86% (95% confidence interval 82 to 89). With statistical validation, predictions by the nomogram appeared accurate and discriminating with an area under the receiver operating characteristic curve, that is a comparison of the predicted probability with the actual outcome of 0.74. Conclusions: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among patients with newly diagnosed renal cell carcinoma. The nomogram may be useful for patient counseling, clinical trial design and patient followup planning. References 1 : Cancer statistics, 2000. CA Cancer J Clin2000; 50: 7. Google Scholar 2 : The Heidelberg classification of renal cell tumors. J Pathol1997; 183: 131. Google Scholar 3 : Urological tumors. In: TMN Classification of Malignant Tumors. New York: Wiley-Liss1997: 165. Google Scholar 4 : Pathologic findings at the time of nephrectomy for renal mass. Ann Surg Oncol1997; 4: 570. Google Scholar 5 : Resection of metastatic renal cell carcinoma. J Clin Oncol1998; 16: 2261. 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Google Scholar From the Departments of Urology, Epidemiology and Biostatistics, Pathology, and Medicine (Genitourinary Oncology Service), Memorial Sloan-Kettering Cancer Center, New York, New York© 2001 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byCampbell S, Uzzo R, Karam J, Chang S, Clark P and Souter L (2021) Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-up: AUA Guideline: Part IIJournal of Urology, VOL. 206, NO. 2, (209-218), Online publication date: 1-Aug-2021.Laguna M (2019) Re: Adjuvant Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled AnalysisJournal of Urology, VOL. 201, NO. 6, (1050-1051), Online publication date: 1-Jun-2019.Sotimehin A, Patel H, Alam R, Gorin M, Johnson M, Chang P, Wagner A, McKiernan J, Allaf M and Pierorazio P (2019) Selecting Patients with Small Renal Masses for Active Surveillance: A Domain Based Score from a Prospective Cohort 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CarcinomasJournal of Urology, VOL. 179, NO. 5, (1719-1726), Online publication date: 1-May-2008.Raj G, Thompson R, Leibovich B, Blute M, Russo P and Kattan M (2008) Preoperative Nomogram Predicting 12-Year Probability of Metastatic Renal CancerJournal of Urology, VOL. 179, NO. 6, (2146-2151), Online publication date: 1-Jun-2008.Boorjian S, Crispen P, Lohse C, Leibovich B and Blute M (2008) Surgical Resection of Isolated Retroperitoneal Lymph Node Recurrence of Renal Cell Carcinoma Following NephrectomyJournal of Urology, VOL. 180, NO. 1, (99-103), Online publication date: 1-Jul-2008.Eggener S, Yossepowitch O, Kundu S, Motzer R and Russo P (2008) Risk Score and Metastasectomy Independently Impact Prognosis of Patients With Recurrent Renal Cell CarcinomaJournal of Urology, VOL. 180, NO. 3, (873-878), Online publication date: 1-Sep-2008.Fujii Y, Saito K, Iimura Y, Sakai Y, Koga F, Kawakami S, Kumagai J and Kihara K (2008) External Validation of the Mayo Clinic Cancer Specific Survival Score in a Japanese Series of Clear Cell Renal Cell CarcinomaJournal of Urology, VOL. 180, NO. 4, (1290-1296), Online publication date: 1-Oct-2008.Minervini A, Di Cristofano C, Gacci M, Serni S, Menicagli M, Lanciotti M, Salinitri G, Rocca C, Lapini A, Nesi G, Bevilacqua G, Minervini R and Carini M (2008) Prognostic Role of Histological Necrosis for Nonmetastatic Clear Cell Renal Cell Carcinoma: Correlation With Pathological Features and Molecular MarkersJournal of Urology, VOL. 180, NO. 4, (1284-1289), Online publication date: 1-Oct-2008.Borque Á (2018) Re: Prognostic Nomogram for Renal Insufficiency After Radical or Partial NephrectomyJournal of Urology, VOL. 177, NO. 3, (1201-1203), Online publication date: 1-Mar-2007.Rini B and Campbell S (2018) The Evolving Role of Surgery for Advanced Renal Cell Carcinoma in the Era of Molecular Targeted TherapyJournal of Urology, VOL. 177, NO. 6, (1978-1984), Online publication date: 1-Jun-2007.Lane B, Babineau D, Kattan M, Novick A, Gill I, Zhou M, Weight C and Campbell S (2007) A Preoperative Prognostic Nomogram for Solid Enhancing Renal Tumors 7 cm or Less Amenable to Partial NephrectomyJournal of Urology, VOL. 178, NO. 2, (429-434), Online publication date: 1-Aug-2007.Dall’Oglio M, Ribeiro-Filho L, Antunes A, Crippa A, Nesrallah L, Gonçalves P, Leite K and Srougi M (2007) Microvascular Tumor Invasion, Tumor Size and Fuhrman Grade: A Pathological Triad for Prognostic Evaluation of Renal Cell CarcinomaJournal of Urology, VOL. 178, NO. 2, (425-428), Online publication date: 1-Aug-2007.Donat S, Salzhauer E, Mitra N, Yanke B, Snyder M and Russo P (2018) Impact of Body Mass Index on Survival of Patients With Surgically Treated Renal Cell CarcinomaJournal of Urology, VOL. 175, NO. 1, (46-52), Online publication date: 1-Jan-2006.Bensalah K, Leray E, Fergelot P, Rioux-Leclercq N, Tostain J, Guillé F and Patard J (2018) Prognostic Value of Thrombocytosis in Renal Cell CarcinomaJournal of Urology, VOL. 175, NO. 3, (859-863), Online publication date: 1-Mar-2006.Ficarra V, Martignoni G, Lohse C, Novara G, Pea M, Cavalleri S and Artibani W (2018) External Validation of the Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) Score to Predict Cancer Specific Survival Using a European Series of Conventional Renal Cell CarcinomaJournal of Urology, VOL. 175, NO. 4, (1235-1239), Online publication date: 1-Apr-2006.Campbell S (2018) Prognostic Factors for Renal Cell Carcinoma: Integrating Laboratory and Molecular FactorsJournal of Urology, VOL. 175, NO. 3, (813-814), Online publication date: 1-Mar-2006.Sorbellini M, Kattan M, Snyder M, Hakimi A, Sarasohn D and Russo P (2018) Prognostic Nomogram for Renal Insufficiency After Radical or Partial NephrectomyJournal of Urology, VOL. 176, NO. 2, (472-476), Online publication date: 1-Aug-2006. (2018) Reply by AuthorsJournal of Urology, VOL. 176, NO. 4, (1363-1363), Online publication date: 1-Oct-2006.Dimashkieh H, Lohse C, Blute M, Kwon E, Leibovich B and Cheville J (2018) Extranodal Extension in Regional Lymph Nodes is Associated With Outcome in Patients With Renal Cell CarcinomaJournal of Urology, VOL. 176, NO. 5, (1978-1983), Online publication date: 1-Nov-2006.SORBELLINI M, KATTAN M, SNYDER M, REUTER V, MOTZER R, GOETZL M, McKIERNAN J and RUSSO P (2018) A POSTOPERATIVE PROGNOSTIC NOMOGRAM PREDICTING RECURRENCE FOR PATIENTS WITH CONVENTIONAL CLEAR CELL RENAL CELL CARCINOMAJournal of Urology, VOL. 173, NO. 1, (48-51), Online publication date: 1-Jan-2005.FRANK I, BLUTE M, LEIBOVICH B, CHEVILLE J, LOHSE C, KWON E and ZINCKE H (2018) pT2 CLASSIFICATION FOR RENAL CELL CARCINOMA. CAN ITS ACCURACY BE IMPROVED?Journal of Urology, VOL. 173, NO. 2, (380-384), Online publication date: 1-Feb-2005.LEIBOVICH B, CHEVILLE J, LOHSE C, ZINCKE H, KWON E, FRANK I, THOMPSON R and BLUTE M (2018) CANCER SPECIFIC SURVIVAL FOR PATIENTS WITH pT3 RENAL CELL CARCINOMA—CAN THE 2002 PRIMARY TUMOR CLASSIFICATION BE IMPROVED?Journal of Urology, VOL. 173, NO. 3, (716-719), Online publication date: 1-Mar-2005.LAM J, SHVARTS O, LEPPERT J, PANTUCK A, FIGLIN R and BELLDEGRUN A (2018) POSTOPERATIVE SURVEILLANCE PROTOCOL FOR PATIENTS WITH LOCALIZED AND LOCALLY ADVANCED RENAL CELL CARCINOMA BASED ON A VALIDATED PROGNOSTIC NOMOGRAM AND RISK GROUP STRATIFICATION SYSTEMJournal of Urology, VOL. 174, NO. 2, (466-472), Online publication date: 1-Aug-2005.MASTER V, GOTTSCHALK A, KANE C and CARROLL P (2018) MANAGEMENT OF ISOLATED RENAL FOSSA RECURRENCE FOLLOWING RADICAL NEPHRECTOMYJournal of Urology, VOL. 174, NO. 2, (473-477), Online publication date: 1-Aug-2005.LAM J, SHVARTS O, LEPPERT J, FIGLIN R and BELLDEGRUN A (2018) RENAL CELL CARCINOMA 2005: NEW FRONTIERS IN STAGING, PROGNOSTICATION AND TARGETED MOLECULAR THERAPYJournal of Urology, VOL. 173, NO. 6, (1853-1862), Online publication date: 1-Jun-2005.LEIBOVICH B, CHEVILLE J, LOHSE C, ZINCKE H, FRANK I, KWON E, MERCHAN J and BLUTE M (2018) A SCORING ALGORITHM TO PREDICT SURVIVAL FOR PATIENTS WITH METASTATIC CLEAR CELL RENAL CELL CARCINOMA: A STRATIFICATION TOOL FOR PROSPECTIVE CLINICAL TRIALSJournal of Urology, VOL. 174, NO. 5, (1759-1763), Online publication date: 1-Nov-2005.PATARD J, LERAY E, CINDOLO L, FICARRA V, RODRIGUEZ A, DE LA TAILLE A, TOSTAIN J, ARTIBANI W, ABBOU C, GUILLÉ F, CHOPIN D and LOBEL B (2018) MULTI-INSTITUTIONAL VALIDATION OF A SYMPTOM BASED CLASSIFICATION FOR RENAL CELL CARCINOMAJournal of Urology, VOL. 172, NO. 3, (858-862), Online publication date: 1-Sep-2004.PALAPATTU G, PANTUCK A, DOREY F, SAID J, FIGLIN R and BELLDEGRUN A (2018) Collecting System Invasion In Renal Cell Carcinoma: Impact on Prognosis And Future Staging StrategiesJournal of Urology, VOL. 170, NO. 3, (768-772), Online publication date: 1-Sep-2003.MÉJEAN A, OUDARD S and THIOUNN N (2018) Prognostic Factors of Renal Cell CarcinomaJournal of Urology, VOL. 169, NO. 3, (821-827), Online publication date: 1-Mar-2003.HERNANDEZ F, RHA K, PINTO P, KIM F, KLICOS N, CHAN T, KAVOUSSI L and JARRETT T (2018) Laparoscopic Nephrectomy: Assessment of Morcellation versus Intact Specimen Extraction on Postoperative StatusJournal of Urology, VOL. 170, NO. 2, (412-415), Online publication date: 1-Aug-2003.KIM H, BELLDEGRUN A, FREITAS D, BUI M, HAN K, DOREY F and FIGLIN R (2018) Paraneoplastic Signs and Symptoms of Renal Cell Carcinoma: Implications for PrognosisJournal of Urology, VOL. 170, NO. 5, (1742-1746), Online publication date: 1-Nov-2003.KATTAN M (2018) Comparison of Cox Regression With Other Methods for Determining Prediction Models and NomogramsJournal of Urology, VOL. 170, NO. 6S, (S6-S10), Online publication date: 1-Dec-2003.FRANK I, BLUTE M, CHEVILLE J, LOHSE C, WEAVER A, LEIBOVICH B and ZINCKE H (2018) A Multifactorial Postoperative Surveillance Model for Patients With Surgically Treated Clear Cell Renal Cell CarcinomaJournal of Urology, VOL. 170, NO. 6, (2225-2232), Online publication date: 1-Dec-2003.HAN K, BLEUMER I, PANTUCK A, KIM H, DOREY F, JANZEN N, ZISMAN A, DINNEY C, WOOD C, SWANSON D, SAID J, FIGLIN R, MULDERS P and BELLDEGRUN A (2018) Validation of an Integrated Staging System Toward Improved Prognostication of Patients With Localized Renal Cell Carcinoma in an International PopulationJournal of Urology, VOL. 170, NO. 6, (2221-2224), Online publication date: 1-Dec-2003.FRANK I, BLUTE M, CHEVILLE J, LOHSE C, WEAVER A and ZINCKE H (2018) An Outcome Prediction Model for Patients with Clear Cell Renal Cell Carcinoma Treated with Radical Nephrectomy Based on Tumor Stage, Size, Grade and Necrosis: The Ssign ScoreJournal of Urology, VOL. 168, NO. 6, (2395-2400), Online publication date: 1-Dec-2002.Russo P (2018) RE: LAPAROSCOPIC RADICAL NEPHRECTOMY: CANCER CONTROL FOR RENAL CELL CARCINOMAJournal of Urology, VOL. 168, NO. 3, (1109-1109), Online publication date: 1-Sep-2002. Volume 166Issue 1July 2001Page: 63-67 Advertisement Copyright & Permissions© 2001 by American Urological Association, Inc.Keywordscarcinomaabnormalitiesneoplasmsrenal cellMetricsAuthor Information MICHAEL W. KATTAN Requests for reprints: Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., C1075, New York, New York 10021. More articles by this author VICTOR REUTER More articles by this author ROBERT J. MOTZER More articles by this author JARED KATZ More articles by this author PAUL RUSSO More articles by this author Expand All Advertisement PDF downloadLoading ...

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Sep 2001HIGH DOSE RADIATION DELIVERED BY INTENSITY MODULATED CONFORMAL RADIOTHERAPY IMPROVES THE OUTCOME OF LOCALIZED PROSTATE CANCERis corrected byOUTCOME OF LOCALIZED PROSTATE CANCER MICHAEL J. ZELEFSKY, ZVI FUKS, MARGIE HUNT, HENRY J. LEE, DANNA LOMBARDI, CLIFTON C. LING, VICTOR E. REUTER, E.S. VENKATRAMAN, and STEVEN A. LEIBEL MICHAEL J. ZELEFSKYMICHAEL J. ZELEFSKY , ZVI FUKSZVI FUKS , MARGIE HUNTMARGIE HUNT , HENRY J. LEEHENRY J. LEE , DANNA LOMBARDIDANNA LOMBARDI , CLIFTON C. LINGCLIFTON C. LING , VICTOR E. REUTERVICTOR E. REUTER , E.S. VENKATRAMANE.S. VENKATRAMAN , and STEVEN A. LEIBELSTEVEN A. LEIBEL View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)65855-7AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We present the long-term outcome and tolerance of 3-dimensional (D) conformal and intensity modulated radiation therapy for localized prostate cancer. Materials and Methods: Between October 1988 and December 1998, 1,100 patients with clinical stages T1c-T3 prostate cancer were treated with 3-D conformal or intensity modulated radiation therapy. Patients were categorized into prognostic risk groups based on pretreatment prostate specific antigen (PSA), Gleason score and clinical stage. Sextant biopsies were performed 2.5 years or greater after treatment to assess local control. PSA relapse was defined according to the consensus guidelines of the American Society for Therapeutic Radiation Oncology. Late toxicity was classified according to the Radiation Therapy Oncology Group morbidity grading scale. Median followup was 60 months. Results: At 5 years the PSA relapse-free survival rate in patients at favorable, intermediate and unfavorable risk was 85% (95% confidence interval [CI] ± 4), 58% (95% CI ± 6) and 38% (95% CI ± 6), respectively (p <0.001). Radiation dose was the most powerful variable impacting PSA relapse-free survival in each prognostic risk group. The 5-year actuarial PSA relapse-free survival rate for patients at favorable risk who received 64.8 to 70.2 Gy. was 77% (95% CI ± 8) compared to 90% (95% CI ± 8) for those treated with 75.6 to 86.4 Gy. (p = 0.05). The corresponding rates were 50% (95% CI ± 8) versus 70% (95% CI ± 6) in intermediate risk cases (p = 0.001), and 21% (95% CI ± 8) versus 47% (95% CI ± 6) in unfavorable risk cases (p = 0.002). Only 4 of 41 patients (10%) who received 81 Gy. had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. The incidence of toxicity after 3-D conformal radiation therapy was dose dependent. The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy. or greater was 14% (95% CI ± 2) compared with 5% (95% CI ± 2) in those treated at lower dose levels (p <0.001). Treatment with intensity modulated radiation therapy significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy. was 2% (95% CI ± 2) compared with 14% (95% CI ± 2) in 61 managed by the same dose of 3-D conformal radiation therapy (p = 0.005). The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy. or greater 3-D conformal radiation therapy was 13% compared with 4% in those treated up to lower doses (p <0.001). Intensity modulated radiation therapy did not affect the incidence of urinary toxicity. Conclusions: Sophisticated conformal radiotherapy techniques with high dose 3-D conformal and intensity modulated radiation therapy improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer. Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio. References 1 : Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA1999; 281: 1598. Google Scholar 2 : The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. 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Google Scholar From the Departments of Radiation Oncology, Medical Physics, Pathology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York© 2001 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited ByMahal B, O'Leary M and Nguyen P (2018) Hydrogel Spacing for Radiotherapy of Prostate Cancer: A Review of the LiteratureUrology Practice, VOL. 1, NO. 2, (79-85), Online publication date: 1-Jul-2014.Stone N, Stone M, Rosenstein B, Unger P and Stock R (2018) Influence of Pretreatment and Treatment Factors on Intermediate to Long-Term Outcome After Prostate BrachytherapyJournal of Urology, VOL. 185, NO. 2, (495-500), Online publication date: 1-Feb-2011.Kapoor D, Zimberg S, Ohrin L, Underwood W and Olsson C (2018) Utilization Trends in Prostate Cancer TherapyJournal of Urology, VOL. 186, NO. 3, (860-864), Online publication date: 1-Sep-2011.Stone N, Stock R, White I and Unger P (2018) Patterns of Local Failure Following Prostate BrachytherapyJournal of Urology, VOL. 177, NO. 5, (1759-1764), Online publication date: 1-May-2007.Zelefsky M, Chan H, Hunt M, Yamada Y, Shippy A and Amols H (2018) Long-Term Outcome of High Dose Intensity Modulated Radiation Therapy for Patients With Clinically Localized Prostate CancerJournal of Urology, VOL. 176, NO. 4, (1415-1419), Online publication date: 1-Oct-2006.TOUMA N, IZAWA J and CHIN J (2018) CURRENT STATUS OF LOCAL SALVAGE THERAPIES FOLLOWING RADIATION FAILURE FOR PROSTATE CANCERJournal of Urology, VOL. 173, NO. 2, (373-379), Online publication date: 1-Feb-2005.ZIETMAN A, CHUNG C, COEN J and SHIPLEY W (2018) 10-Year Outcome for Men With Localized Prostate Cancer Treated With External Radiation Therapy:: Results of a Cohort StudyJournal of Urology, VOL. 171, NO. 1, (210-214), Online publication date: 1-Jan-2004.POLLACK A, HANLON A, HORWITZ E, FEIGENBERG S, UZZO R and HANKS G (2018) Prostate Cancer Radiotherapy Dose Response: An Update of the Fox Chase ExperienceJournal of Urology, VOL. 171, NO. 3, (1132-1136), Online publication date: 1-Mar-2004.KOH H, KATTAN M, SCARDINO P, SUYAMA K, MARU N, SLAWIN K, WHEELER T and OHORI M (2018) A Nomogram to Predict Seminal Vesicle Invasion by the Extent and Location of Cancer in Systematic Biopsy ResultsJournal of Urology, VOL. 170, NO. 4 Part 1, (1203-1208), Online publication date: 1-Oct-2003.ZELEFSKY M, MARION C, FUKS Z and LEIBEL S (2018) Improved Biochemical Disease-Free Survival of Men Younger Than 60 Years With Prostate Cancer Treated With High Dose Conformal External Beam RadiotherapyJournal of Urology, VOL. 170, NO. 5, (1828-1832), Online publication date: 1-Nov-2003.Related articlesJournal of UrologyNov 9, 2018, 11:31:10 AMOUTCOME OF LOCALIZED PROSTATE CANCER Volume 166Issue 3September 2001Page: 876-881 Advertisement Copyright & Permissions© 2001 by American Urological Association, Inc.Keywordsradiation dosageprostatic neoplasmsradiotherapy, conformalriskprostateMetricsAuthor Information MICHAEL J. ZELEFSKY More articles by this author ZVI FUKS More articles by this author MARGIE HUNT More articles by this author HENRY J. LEE More articles by this author DANNA LOMBARDI More articles by this author CLIFTON C. LING More articles by this author VICTOR E. REUTER More articles by this author E.S. VENKATRAMAN More articles by this author STEVEN A. LEIBEL More articles by this author Expand All Advertisement PDF DownloadLoading ...

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Mar 2000SURGICAL MANAGEMENT OF RENAL TUMORS 4 CM. OR LESS IN A CONTEMPORARY COHORT CHERYL T. LEE, JARED KATZ, WEIJI SHI, HOWARD T. THALER, VICTOR E. REUTER, and PAUL RUSSO CHERYL T. LEECHERYL T. LEE , JARED KATZJARED KATZ , WEIJI SHIWEIJI SHI , HOWARD T. THALERHOWARD T. THALER , VICTOR E. REUTERVICTOR E. REUTER , and PAUL RUSSOPAUL RUSSO View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)67793-2AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We evaluated a patient cohort with renal tumors 4 cm. or less treated with partial or radical nephrectomy. We compared patient and tumor characteristics, and survival in these 2 groups. Materials and Methods: We retrospectively analyzed the records of 670 patients with a median age of 63 years treated surgically for renal cell carcinoma between July 31, 1989 and July 31, 1997. Renal tumors 4.0 cm. or less were noted in 252 patients (38%) who underwent a total of 262 procedures, including 183 radical (70%) and 79 partial (30%) nephrectomies. Ten patients required 2 operations each because of bilateral renal cell carcinoma. Median followup was 40 months. We compared clinicopathological parameters in the partial and radical nephrectomy groups using chi-square or Wilcoxon analysis as appropriate. Survival analysis was determined by the log rank test and Cox regression model. Results: The partial and radical nephrectomy groups were comparable with respect to gender ratio, tumor presentation, histological classification, pathological stage and complication rate. Median tumor size was 2.5 and 3.0 cm. in the partial and radical nephrectomy groups, respectively (p = 0.0001). Resection was incomplete in 1 patient (1.3%) in the partial and none in the radical nephrectomy group. There was no local recurrence after either procedure, and no significant difference in disease specific, disease-free and overall survival (p = 0.98, 0.23 and 0.20, respectively). Conclusions: Patients with a small renal tumor have similar perioperative morbidity, pathological stage and outcome regardless of treatment with partial or radical nephrectomy. Therefore, partial nephrectomy remains a safe alternative for tumors of this size. References 1 : Cancer statistics. CA Cancer J Clin1999; 49: 8. Google Scholar 2 : Radical nephrectomy for renal cell carcinoma. J Urol1963; 89: 37. Link, Google Scholar 3 : The results of radical nephrectomy for renal cell carcinoma. J Urol1969; 101: 297. Link, Google Scholar 4 : Nephron-sparing surgery for renal cell carcinoma. J Urol1993; 149: 1. 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Google Scholar From the Departments of Urology, Pathology and Epidemiology, and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York© 2000 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byWood E, Adibi M, Qiao W, Brandt J, Zhang M, Tamboli P, Matin S, Wood C and Karam J (2018) Local Tumor Bed Recurrence Following Partial Nephrectomy in Patients with Small Renal MassesJournal of Urology, VOL. 199, NO. 2, (393-400), Online publication date: 1-Feb-2018.Lallas C, Scotland K, Zhang M, Schaeffer D, Calvaresi A, Gomella L, Brown D, Shaw C and Trabulsi E (2018) Clinical Influences in the Multidisciplinary Management of Small Renal Masses at a Tertiary Referral CenterUrology Practice, VOL. 3, NO. 6, (468-474), Online publication date: 1-Nov-2016.Laguna M (2018) Re: Renal Tumor Contact Surface Area: A Novel Parameter for Predicting Complexity and Outcomes of Partial NephrectomyJournal of Urology, VOL. 193, NO. 5, (1515-1515), Online publication 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Volume 163Issue 3March 2000Page: 730-736 Advertisement Copyright & Permissions© 2000 by American Urological Association, Inc.Keywordsnephrectomykidneycarcinoma, renal cellMetricsAuthor Information CHERYL T. LEE More articles by this author JARED KATZ More articles by this author WEIJI SHI More articles by this author HOWARD T. THALER More articles by this author VICTOR E. REUTER More articles by this author PAUL RUSSO More articles by this author Expand All Advertisement PDF downloadLoading ...

The unbalanced translocation, der(17)t(X;17)(p11.2;q25), is characteristic of alveolar soft part sarcoma (ASPS). We have recently shown that this translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL, a novel gene at 17q25. We describe herein eight morphologically distinctive renal tumors occurring in young people that bear the identical ASPL-TFE3 fusion transcript as ASPS, with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction. The morphology of these eight ASPL-TFE3 fusion-positive renal tumors, although overlapping in some aspects that of classic ASPS, more closely resembles renal cell carcinoma (RCC), which was the a priori diagnosis in all cases. These tumors demonstrate nested and pseudopapillary patterns of growth, psammomatous calcifications, and epithelioid cells with abundant clear cytoplasm and well-defined cell borders. By immunohistochemistry, four tumors were negative for all epithelial markers tested, whereas four were focally positive for cytokeratin and two were reactive for epithelial membrane antigen (EMA) (one diffusely, one focally). Electron microscopy of six tumors demonstrated a combination of ASPS-like features (dense granules in four cases, rhomboid crystals in two cases) and epithelial features (cell junctions in six cases, microvilli and true glandular lumens in three cases). Overall, although seven of eight tumors demonstrated at least focal epithelial features by electron microscopy or immunohistochemistry, the degree and extent of epithelial differentiation was notably less than expected for typical RCC. We confirmed the balanced nature of the t(X;17) translocation by fluorescence in situ hybridization in all seven renal tumors thus analyzed, which contrasts sharply with the unbalanced nature of the translocation in ASPS. In summary, a subset of tumors previously considered to be RCC in young people are in fact genetically related to ASPS, although their distinctive morphological and genetic features justify their classification as a distinctive neoplastic entity. Finally, the finding of distinctive tumors being associated with balanced and unbalanced forms of the same translocation is to our knowledge, unprecedented.

We report the aberrantly strong nuclear immunoreactivity for the C-terminal portion of TFE3 protein in tumors characterized by chromosome translocations involving the TFE3 gene at Xp11.2. This group of tumors includes alveolar soft part sarcoma and a specific subset of renal carcinomas that tend to affect young patients. They contain fusion genes that encode chimeric proteins consisting of the N-terminal portion of different translocation partners fused to the C-terminal portion of TFE3. We postulated that expression of these fusion proteins may be dysregulated in these specific tumors and detectable by immunohistochemistry. We performed immunohistochemistry using a polyclonal antibody to the C-terminal portion of TFE3 in 40 formalin-fixed, paraffin-embedded tumors characterized by TFE3 gene fusions, including 19 alveolar soft part sarcoma (of which nine were molecularly confirmed) and 21 renal carcinomas with cytogenetically confirmed characteristic Xp11.2 translocations and/or fusion transcripts involving TFE3 (11 PRCC-TFE3, 7 ASPL-TFE3, 3 PSF-TFE3). We also screened 1476 other tumors of 64 histologic types from 16 sites for TFE3 immunoreactivity using tissue microarrays and evaluated a broad range of normal tissues. Thirty-nine of 40 neoplasms characterized by TFE3 gene fusions (19 of 19 alveolar soft part sarcoma, 20 of 21 renal carcinomas) demonstrated moderate or strong nuclear TFE3 immunoreactivity. In contrast, only 6 of 1476 other neoplasms labeled for TFE3 (sensitivity 97.5%, specificity 99.6%). Nuclear immunoreactivity in normal tissues was extremely rare. We then applied this assay to a set of 11 pediatric renal carcinomas for which only paraffin-embedded tissue was available, to assess if morphologic features could predict TFE3 immunoreactivity. Of the eight cases in which we suspected that a TFE3 gene rearrangement might be present based on morphology, seven scored positive for nuclear TFE3 labeling. Of the three tumors whose morphology did not suggest the presence of a TFE3 gene fusion, none showed nuclear TFE3 labeling. In summary, we find that nuclear immunoreactivity for TFE3 protein by routine immunohistochemistry is a highly sensitive and specific assay for neoplasms bearing TFE3 gene fusions. Furthermore, the finding in our set of test cases (i.e., that morphologic features can be used to predict TFE3 immunoreactivity) further supports the notion that renal carcinomas with TFE3 gene fusions have a distinctive morphology that corresponds to their genetic distinctiveness. Carcinomas associated with TFE3 gene fusions may account for a significant proportion of pediatric renal carcinomas, and this immunohistochemistry assay may help to clarify their true prevalence.

We postulate that the number of lymph nodes examined in cystectomy specimens can have an impact on the outcome of patients with bladder cancer.We analyzed data on 322 patients with muscle invasive bladder cancer who underwent radical cystectomy and bilateral pelvic lymphadenectomy. We evaluated the associations of the number of lymph nodes identified by the pathologist in the surgical specimen with the local recurrence rate and survival outcome.Patients were divided into groups by lymph node status and the distribution of the number of lymph nodes examined. In stages pN0 and pN+ cases improved survival was associated with a greater number of lymph nodes examined. We determined that at least 9 lymph nodes should be studied to define lymph node status accurately.These results indicate that surgical resection and pathological assessment of an adequate number of lymph nodes in cystectomy specimens increases the likelihood of proper staging and impacts patient outcome. Such information is important not only for the therapy and prognosis of individuals, but also for identifying those who may benefit from adjuvant chemotherapy.

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease.We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance.Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide.This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells.These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor.Expression profiles of androgen ablationresistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone.Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation.Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones.The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort.

Approximately one third of the patients with superficially infiltrative transitional cell (T1-TNM pathological staging system) bladder carcinoma who are treated with transurethral resection alone have disease progression. Despite precise pathologic staging and grading, clinical outcome in these patients is not predictable. Recent reports reveal that mutations of the p53 tumor suppressor gene (also known as TP53) occur commonly in bladder cancers.The aim of this study was to investigate the hypothesis that altered patterns of expression of the protein product(s) of the mutated p53 tumor suppressor gene are associated with tumor progression in patients with T1 bladder cancer.We examined deparaffinized tumor tissue specimens from transurethral resection in 43 patients with T1 bladder cancer who had not received adjuvant therapy. Nuclear overexpression of p53 protein was detected by immunohistochemical analysis using the mouse monoclonal antibody PAb1801, which stains both wild-type and mutant p53 proteins. The data were then correlated with the following conventional prognostic variables: age, sex, histologic presence of associated carcinoma in situ, and vascular invasion of tumor. Disease progression rates per 100 person-years were calculated.Median follow-up was 119 months. None of the urothelial and stromal cells from normal bladder specimens showed nuclear overexpression of p53 protein, but patients with T1 bladder tumors could be stratified into two groups with different patterns of staining for p53 protein. Eighteen patients (42%) had no more than 20% tumor cells with positive nuclear staining (group A), while the remaining 25 patients (58%) had 20% or more tumor cells with nuclear immunoreactivity (group B). Patients in group B had a significantly lower progression-free interval (P < .001). Disease progression rates were 20.5% per year for group B and 2.5% for group A.These results suggest that T1 bladder cancers exhibiting nuclear overexpression of p53 protein have a higher probability of disease progression. This study also suggests that p53 overexpression is an important prognostic factor in these patients and may be useful in selecting appropriate therapy.Large prospective studies are needed to confirm these results and to evaluate nuclear overexpression of p53 protein as a prognostic marker in bladder cancer.

Abstract Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q &amp;lt; 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma. Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR. See related commentary by Turchi et al., p. 1118 This article is highlighted in the In This Issue feature, p. 1103

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

Few published studies have simultaneously analyzed multiple prognostic factors to predict recurrence after surgery for conventional clear cell renal cortical carcinomas. We developed and performed external validation of a postoperative nomogram for this purpose. We used a prospectively updated database of more than 1,400 patients treated at a single institution.From January 1989 to August 2002, 833 nephrectomies (partial and radical) for renal cell carcinoma of conventional clear cell histology performed at Memorial Sloan-Kettering Cancer Center were reviewed from the center's kidney database. Patients with von Hippel-Lindau disease or familial syndromes, as well as patients presenting with synchronous bilateral renal masses, or distant metastases or metastatic regional lymph nodes before or at surgery were excluded from study. We modeled clinicopathological data and disease followup for 701 patients with conventional clear cell renal cell carcinoma. Prognostic variables for the nomogram included pathological stage, Fuhrman grade, tumor size, necrosis, vascular invasion and clinical presentation (ie incidental asymptomatic, locally symptomatic or systemically symptomatic).Disease recurrence was noted in 72 of 701 patients. Those patients without evidence of disease had a median and maximum followup of 32 and 120 months, respectively. The 5-year probability of freedom from recurrence for the patient cohort was 80.9% (95% confidence interval 75.7% to 85.1%). A nomogram was designed based on a Cox proportional hazards regression model. Following external validation predictions by the nomogram appeared accurate and discriminating, and the concordance index was 0.82.A nomogram has been developed that can be used to predict the 5-year probability of freedom from recurrence for patients with conventional clear cell renal cell carcinoma. This nomogram may be useful for patient counseling, clinical trial design and effective patient followup strategies.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

To define outcome data for patients with metastatic renal cell carcinoma (RCC) with histology other than clear-cell type, including collecting duct (or medullary carcinoma), papillary, chromophobe, and unclassified histologies.Sixty-four patients with metastatic non-clear-cell RCC histology were the subjects of this retrospective review. Included in the analysis were 22 (8%) of 286 patients from a clinical trials database, 19 of 1,166 patients from a surgery database, and 23 of 357 patients from a pathology database.The prevalent histology was collecting duct, present in 26 (41%) patients. The number of patients with chromophobe and papillary histologies was 12 (19%) and 18 (28%), respectively. Eight (12%) of the patients had tumors that could not be classified for specific tumor histology. Among the 43 patients treated with 86 systemic therapies, including 37 cytokine therapies, two patients (5%) were observed to have a partial response. The median overall survival time was 9.4 months (95% confidence interval, 8 to 14 months). The survival was longer for patients with chromophobe tumors compared with collecting duct or papillary histology, and this group included four patients with survival of greater than 3 years.RCC consists of a heterogeneous group of tumors including clear-cell, papillary, chromophobe, collecting duct, and unclassified cell types. Non-clear-cell histologies constitute less than 10% of patients in general populations of patients with advanced RCC treated on clinical trials. Metastatic non-clear-cell RCC is characterized by a resistance to systemic therapy and poor survival, with the survival for patients with chromophobe tumors longer than that for patients with metastatic collecting duct or papillary RCC. Treatment with novel agents on clinical trials is warranted.

Tumor-infiltrating cytotoxic T lymphocytes (TILs), including CD8 TILs, have been associated with favorable clinical outcomes in multiple tumor types. Tumor-infiltrating CD8 T cells and major histocompatibility complex (MHC) class I expression in urothelial carcinoma (UC) have not been previously reported. Most immune responses are mediated by local cytotoxic lymphocytes (CD8 T cells), which can eradicate tumor cells by recognizing tumor-associated antigens presented by MHC class I molecules. Here we analyzed the presence of intratumoral CD8 T cells, the expression of MHC class I antigen, and the expression of the NY-ESO-1 tumor antigen in UC samples and correlated our findings with clinical outcome. Immunohistochemical staining for intratumoral CD8 T cells in tissue samples from 69 patients with UC showed that patients with advanced UC (pT2, pT3, or pT4) and higher numbers of CD8 TILs within the tumor (> or =8) had better disease-free survival (P < 0.001) and overall survival (P = 0.018) than did patients with similar-staged UC and fewer intratumoral CD8 TILs. We conclude that the extent of intratumoral CD8 TILs is an important prognostic indicator in advanced UC.

The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population.In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018.Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases.Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks.The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was initially characterized by the monoclonal antibody (mAb) 7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and prostate cancer as well as in several extraprostatic tissues. Recent evidence suggests that PSMA is also expressed in tumor-associated neovasculature. We examined the immunohistochemical characteristics of 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA. Using the streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer cell lines and various fresh-frozen benign and malignant tissue specimens. In the latter, we compared the localization of the anti-PSMA mAbs to that of the anti-endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted strongly with the neovasculature of a wide spectrum of malignant neoplasms: conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5 of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5 cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6 cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti-PSMA mAbs to tumor-associated neovasculature was confirmed by CD34 immunohistochemistry in sequential tissue sections. Normal vascular endothelium in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases) but not with the neoplastic cells of any other tumor type, including those of benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1 hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5 of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7 cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently expressed in the neovasculature of a wide variety of malignant neoplasms and may be an effective target for mAb-based antineovasculature therapy.

On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine (NE) differentiation in prostate cancer. New clinical and molecular data emerging from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, have highlighted the need for refinement of diagnostic terminology to encompass the full spectrum of NE differentiation. The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma. The article also highlights "prostate carcinoma with overlapping features of small cell carcinoma and acinar adenocarcinoma" and "castrate-resistant prostate cancer with small cell cancer-like clinical presentation". It is envisioned that specific criteria associated with the refined diagnostic terminology will lead to clinically relevant pathologic diagnoses that will stimulate further clinical and molecular investigation and identification of appropriate targeted therapies.

(Cell 161, 1215–1228; May 21, 2015) Our paper presented an integrated sequencing analysis of clinical samples from advance prostate cancer patients. Parts of the findings were listed in Table S3, Mutations Identified in the 150 Cases. During the preparation of our table, we inadvertently mislabeled three gene names. In row 14118, 11-Sep should be SEPT11. In row 22306, 12-Sep should be SEPT12. In row 22927, 1-Mar should be MARCH1. These errors do not affect any conclusions of the paper, and the corrected version of Table S3 has been updated online. We apologize for any inconvenience this may have caused. Integrative Clinical Genomics of Advanced Prostate CancerRobinson et al.CellMay 21, 2015In BriefA multi-institutional integrative clinical sequencing analysis reveals that the majority of affected individuals with metastatic castration-resistant prostate cancer harbor clinically actionable molecular alterations, highlighting the need for genetic counseling to inform precision medicine in affected individuals with advanced prostate cancer. Full-Text PDF Open Archive

New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5' (labelled green) and 3' (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.

The recently recognized Xp11 translocation renal cell carcinomas (RCCs), all of which bear gene fusions involving the TFE3 transcription factor gene, comprise at least one-third of pediatric RCC. Only rare adult cases have been reported, without detailed pathologic analysis. We identified and analyzed 28 Xp11 translocation RCC in patients over the age of 20 years. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of neoplasms with TFE3 gene fusions, which can be applied to archival material. Three cases were also confirmed genetically. Patients ranged from ages 22 to 78 years, with a strong female predominance (F:M=22:6). These cancers tended to present at advanced stage; 14 of 28 presented at stage 4, whereas lymph nodes were involved by metastatic carcinoma in 11 of 13 cases in which they were resected. Previously not described and distinctive clinical presentations included dense tumor calcifications such that the tumor mimicked renal lithiasis, and obstruction of the renal pelvis promoting extensive obscuring xanthogranulomatous pyelonephritis. Previously unreported morphologic variants included tumor giant cells, fascicles of spindle cells, and a biphasic appearance that simulated the RCC characterized by a t(6;11)(p21;q12) chromosome translocation. One case harbored a novel variant translocation, t(X;3)(p11;q23). Five of 6 patients with 1 or more years of follow-up developed hematogenous metastases, with 2 dying within 1 year of diagnosis. Xp11 translocation RCC can occur in adults, and may be aggressive cancers that require morphologic distinction from clear cell and papillary RCC. Although they may be uncommon on a percentage basis, given the vast predominance of RCC in adults compared with children, adult Xp11 translocation RCC may well outnumber their pediatric counterparts.

To determine whether hydrogen 1 magnetic resonance (MR) spectroscopic imaging can be used to predict aggressiveness of prostate cancer.All patients gave informed consent according to an institutionally approved research protocol. A total of 123 patients (median age, 58 years; age range, 40-74 years) who underwent endorectal MR imaging and MR spectroscopic imaging between January 2000 and December 2002 were included. MR imaging and spectroscopy were performed by using combined pelvic phased-array and endorectal probe. Water and lipids were suppressed, and phase-encoded data were acquired with 6.2-mm resolution. Voxels in the peripheral zone were considered suspicious for cancer if (Cho + Cr)/Cit was at least two standard deviations above the normal level, where Cho represents choline-containing compounds, Cr represents creatine and phosphocreatine, and Cit represents citrate. Correlation between metabolite ratio and four Gleason score groups identified at step-section pathologic evaluation (3 + 3, 3 + 4, 4 + 3, and > or =4 + 4) was assessed with generalized estimating equations.Data from 94 patients were included. Pathologic evaluation was used to identify 239 lesions. Overall sensitivity of MR spectroscopic imaging was 56% for tumor detection, increasing from 44% in lesions with Gleason score of 3 + 3 to 89% in lesions with Gleason score greater than or equal to 4 + 4. There was a trend toward increasing (Cho + Cr)/Cit with increasing Gleason score in lesions identified correctly with MR spectroscopic imaging. Tumor volume assessed with MR spectroscopic imaging increased with increasing Gleason score.MR spectroscopic imaging measurement of prostate tumor (Cho + Cr)/Cit and tumor volume correlate with pathologic Gleason score. There is overlap between MR spectroscopic imaging parameters at various Gleason score levels, which may reflect methodologic and physiologic variations. MR spectroscopic imaging has potential in noninvasive assessment of prostate cancer aggressiveness.

No AccessJournal of UrologyClinical Urology: Original Articles1 Jan 1998TERATOMA WITH MALIGNANT TRANSFORMATION: DIVERSE MALIGNANT HISTOLOGIES ARISING IN MEN WITH GERM CELL TUMORS Robert J. Motzer, Alison Amsterdam, Victor Prieto, Joel Sheinfeld, V.V.V.S. Murty, Madhu Mazumdar, George J. Bosl, R.S.K. Chaganti, and Victor E. Reuter Robert J. MotzerRobert J. Motzer More articles by this author , Alison AmsterdamAlison Amsterdam More articles by this author , Victor PrietoVictor Prieto More articles by this author , Joel SheinfeldJoel Sheinfeld More articles by this author , V.V.V.S. MurtyV.V.V.S. Murty More articles by this author , Madhu MazumdarMadhu Mazumdar More articles by this author , George J. BoslGeorge J. Bosl More articles by this author , R.S.K. ChagantiR.S.K. Chaganti More articles by this author , and Victor E. ReuterVictor E. Reuter More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(01)64035-7AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Teratoma with malignant transformation refers to a form of germ cell tumor in which a somatic teratomatous component becomes morphologically malignant and develops aggressive growth. We evaluated the spectrum of histologies, chromosomal abnormalities and clinical outcome in patients with teratoma with malignant transformation. Materials and Methods: We identified 46 patients with germ cell tumor meeting morphologic criteria for malignant transformation. Histology, disease extent and treatment were correlated with survival. Tumors in 12 patients were studied by conventional cytogenetics or molecular genetic techniques for the isochromosome 12p [i(12p)], a marker for germ cell tumor, as well as other chromosomal abnormalities. Results: The site of first detection of malignant transformation occurred in the primary tumor of 21 cases (44%), at a metastatic site in 20 (43%) and in both sites in 5 (10%). Sarcoma was the most frequent histology, identified in 29 patients (63%) with rhabdomyosarcoma the most common subtype. Seventeen tumors (37%) contained a solid tumor histology other than sarcoma, with adenocarcinoma and primitive neuroectodermal tumor as the most common histologies. Four patients with mediastinal germ cell tumor containing sarcoma also had hematological malignancies, including a focus of nonHodgkin's lymphoma in the mediastinal primary tumor (1) and nonlymphocytic leukemia in spleen or bone marrow (3). Patients who had teratoma with malignant transformation components confined to the testis or retroperitoneum completely resected experienced a longer survival than those with distant metastases or incompletely resected tumors (p = 0.003). Chromosomal abnormalities associated with germ cell tumor (i [12p]) were identified in 11 of 12 tumors containing adenocarcinoma, primitive neuroectodermal tumor, sarcoma and leukemia. In addition to i (12p), chromosomal rearrangements characteristic of the transformed histology were detected in 4 tumors. Conclusions: A variety of nongerm cell histologies, including sarcoma, adenocarcinoma, primitive neuroectodermal tumor and leukemia, may occur in association with germ cell tumor. Chromosomal abnormalities in these tumors include i (12p), reflecting germ cell tumor clonality, as well as chromosomal abnormalities associated with the transformed histology. These tumors do not respond like germ cell tumor to cisplatin-containing chemotherapy regimens. Treatment should be tailored according to that used in standard management of the transformed histology, and surgical resection is the mainstay of therapy. 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Google Scholar From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Department of Pathology (Surgical Pathology and Cytogenetic Services), Department of Biostatistics, and Division of Urology, Department of Surgery, Memorial Hospital, New York, and Cell Biology and Genetics Program, Sloan-Kettering Institute, New York, New YorkAccepted for publication June 20, 1997© 1998 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited bySheinfeld J, Becerra M and Feldman D (2016) Are Some Cases of Somatic Type Malignancy Potentially Avoidable?Journal of Urology, VOL. 196, NO. 1, (11-13), Online publication date: 1-Jul-2016.Giannatempo P, Pond G, Sonpavde G, Albany C, Loriot Y, Sweeney C, Salvioni R, Colecchia M, Nicolai N, Raggi D, Rice K, Flack C, El Mouallem N, Feldman H, Fizazi K, Einhorn L, Foster R, Necchi A and Cary C (2015) Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International CollaborationJournal of Urology, VOL. 196, NO. 1, (95-100), Online publication date: 1-Jul-2016.Silberstein J (2014) Outcomes of Retroperitoneal Lymph Node Dissection for the Most Challenging CasesJournal of Urology, VOL. 192, NO. 5, (1320-1321), Online publication date: 1-Nov-2014.Rice K, Magers M, Beck S, Cary K, Einhorn L, Ulbright T and Foster R (2014) Management of Germ Cell Tumors with Somatic Type Malignancy: Pathological Features, Prognostic Factors and Survival OutcomesJournal of Urology, VOL. 192, NO. 5, (1403-1409), Online publication date: 1-Nov-2014. (2018) Reply by AuthorsJournal of Urology, VOL. 177, NO. 3, (942-943), Online publication date: 1-Mar-2007.Carver B, Bianco F, Shayegan B, Vickers A, Motzer R, Bosl G and Sheinfeld J (2018) Predicting Teratoma in the Retroperitoneum in Men Undergoing Post-Chemotherapy Retroperitoneal Lymph Node DissectionJournal of Urology, VOL. 176, NO. 1, (100-104), Online publication date: 1-Jul-2006.SHEINFELD J, MOTZER R, RABBANI F, McKIERNAN J, BAJORIN D and BOSL G (2018) Incidence and Clinical Outcome of Patients with Teratoma in the Retroperitoneum Following Primary Retroperitoneal Lymph Node Dissection for Clinical Stages I and IIA Nonseminomatous Germ Cell TumorsJournal of Urology, VOL. 170, NO. 4 Part 1, (1159-1162), Online publication date: 1-Oct-2003.POHAR K, RABBANI F, BOSL G, MOTZER R, BAJORIN D and SHEINFELD J (2018) Results of Retroperitoneal Lymph Node Dissection for Clinical Stage I and II Pure Embryonal Carcinoma of the TestisJournal of Urology, VOL. 170, NO. 4 Part 1, (1155-1158), Online publication date: 1-Oct-2003.GANJOO K, FOSTER R, MICHAEL H, DONOHUE J and EINHORN L (2018) GERM CELL TUMOR ASSOCIATED PRIMITIVE NEUROECTODERMAL TUMORSJournal of Urology, VOL. 165, NO. 5, (1514-1516), Online publication date: 1-May-2001.STEELE G, CLANCY T, DATTA M, WEINSTEIN M and RICHIE J (2018) ANGIOSARCOMA ARISING IN A TESTICULAR TERATOMAJournal of Urology, VOL. 163, NO. 6, (1872-1873), Online publication date: 1-Jun-2000. Volume 159Issue 1January 1998Page: 133-138 Advertisement Copyright & Permissions© 1998 by American Urological Association, Inc.MetricsAuthor Information Robert J. Motzer More articles by this author Alison Amsterdam More articles by this author Victor Prieto More articles by this author Joel Sheinfeld More articles by this author V.V.V.S. Murty More articles by this author Madhu Mazumdar More articles by this author George J. Bosl More articles by this author R.S.K. Chaganti More articles by this author Victor E. Reuter More articles by this author Expand All Advertisement PDF downloadLoading ...

We developed a preoperative nomogram for prediction of lymph node metastases in patients with clinically localized prostate cancer.The study was a retrospective, nonrandomized analysis of 7,014 patients treated with radical prostatectomy at 6 institutions between 1985 and 2000. Exclusion criteria consisted of preoperative androgen ablation therapy, salvage radical prostatectomy and pretreatment prostate specific antigen (PSA) greater than 50 ng/ml. Preoperative predictors of lymph node metastases consisted of pretreatment PSA, clinical stage (1992 TNM) and biopsy Gleason sum. These predictors were used in logistic regression analysis based nomograms to predict the probability of lymph node metastases.Overall 5,510 patients with complete clinical and pathological information were included in the study. Lymph nodes metastases were present in 206 patients (3.7%). Pretreatment PSA, biopsy Gleason sum, clinical stage and institution represented predictors of lymph node status (p <0.001). Bootstrap corrected predictive accuracy of the 3-variable nomogram (clinical stage, Gleason sum and PSA) was 0.76. Inclusion of a fourth variable, which accounts for institutional differences in lymph node metastases, yielded an area under the receiver operating characteristics curve of 0.78. The negative predictive value of our nomograms was 0.99 when they predicted 3% or less chance of positive lymph nodes.Using clinical information, we produced 2 calibrated and validated nomograms, which accurately predict pathologically negative lymph nodes in men with localized prostate cancer who are candidates for radical prostatectomy.

Background Preoperative identification of tumour type could have important implications for the choice of treatment for renal cancers. Antibody cG250 reacts against carbonic anhydrase-IX, which is over-expressed in clear-cell renal carcinomas. We aimed to assess whether iodine-124-labelled antibody chimeric G250 (124I-cG250) PET predicts clear-cell renal carcinoma, the most common and aggressive renal tumour. Methods 26 patients with renal masses who were scheduled to undergo surgical resection by laparotomy received a single intravenous infusion of 185 MBq/10 mg of 124I-cG250 over 20 min in this open-label pilot study. Surgery was scheduled 1 week after 124I-cG250 infusion. PET and CT scanning of the abdomen, including the kidneys, within 3 h before surgery was planned for all patients. The obtained images were graded as positive (defined as a tumour-to-healthy-kidney ratio >3 to 1) or negative for antibody uptake, and the surgeon was informed of the scan results before surgery. After surgery, resected tumours were histopathologically classified as clear-cell renal carcinoma or otherwise. The trial is registered on the clinical trials site of the National Cancer Institute website http://clinicaltrials.gov/ct/show/NCT00199888. Findings One patient received inactive antibody and was excluded from analysis. 15 of 16 clear-cell carcinomas were identified accurately by antibody PET, and all nine non-clear-cell renal masses were negative for the tracer. The sensitivity of 124I-cG250 PET for clear-cell kidney carcinoma in this trial was 94% (95% CI 70–100%); the negative predictive value was 90% (55–100%), and specificity and positive predictive accuracy were both 100% (66–100% and 78–100%, respectively). Interpretation PET with 124I-cG250 can identify accurately clear-cell renal carcinoma; a negative scan is highly predictive of a less aggressive phenotype. Stratification of patients with renal masses by 124I-cG250 PET can identify aggressive tumours and help decide treatment.

A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in the disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic non-castrate, and metastatic castration-resistant prostate cancer (CRPC).Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was employed to identify single nucleotide variations, small insertions and deletions, copy number alterations and structural rearrangements in over 300 cancer-related genes in tumors and matched normal blood.We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair (DDR), PI3K, and MAP kinase pathways. 27% of patients harbored a germline or a somatic alteration in a DDR gene that may predict for response to PARP inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, while ATM alterations were specifically enriched in CRPC.Through genomic profiling of prostate tumors representing the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis and castration-resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer, for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

B7-H3 and B7x are recently discovered members of the B7-CD28 family thought to dampen peripheral immune responses via negative costimulation. We evaluated their potential expression in human prostate cancer using a large cohort of patients with 7 years of follow-up. We identified 823 patients with tissue available treated with radical prostatectomy between 1985 and 2003. Immunohistochemistry was performed on tissue microarray sections using anti-B7-H3 and -B7x. The percentage and intensity of immunoreactivity by tumor cells were blindly evaluated by two urological pathologists, and outcome analyses were conducted. Both B7-H3 and B7x were highly expressed; 93% and 99% of tumors had aberrant expression, respectively. The median percentage of tumor cells staining positive was 80% for each molecule. Strong intensity for B7-H3 and B7x was noted in 212 (26%) and 120 (15%) patients, respectively. Patients with strong intensity for B7-H3 and B7x were significantly more likely to have disease spread at time of surgery ( P &lt; 0.001 and P = 0.005, respectively). Additionally, patients with strong intensity for B7-H3 and B7x were at significantly increased risk of clinical cancer recurrence ( P &lt; 0.001 and P = 0.005) and cancer-specific death ( P = 0.004 and P = 0.04, respectively). To our knowledge, we present the largest investigation of B7 family molecules in a human malignancy and a previously undescribed evaluation of B7x in prostate cancer. B7-H3 and B7x are abundantly expressed in prostate cancer and associated with disease spread and poor outcome. Given the proposed immune-inhibitory mechanisms of B7-H3 and B7x, these molecules represent attractive targets for therapeutic manipulation in prostate cancer.

Journal Article Altered Expression of the Retinoblastoma Gene Product: Prognostic Indicator in Bladder Cancer Get access Carlos Cordon-Cardo, Carlos Cordon-Cardo * Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. * Correspondence to: Carlos Cordon-Cardo, M.D., Ph.D., Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Mew York, NY 10021. Search for other works by this author on: Oxford Academic PubMed Google Scholar David Wartinger, David Wartinger Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar Daniel Petrylak, Daniel Petrylak Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar Guido Dalbagni, Guido Dalbagni Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar William R. Fair, William R. Fair Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar Zvi Fuks, Zvi Fuks Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar Victor E. Reuter Victor E. Reuter Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, N.Y. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 16, 19 August 1992, Pages 1251–1256, https://doi.org/10.1093/jnci/84.16.1251 Published: 19 August 1992 Article history Received: 13 March 1992 Revision received: 30 April 1992 Accepted: 15 May 1992 Published: 19 August 1992

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

To investigate Haralick texture analysis of prostate MRI for cancer detection and differentiating Gleason scores (GS).One hundred and forty-seven patients underwent T2- weighted (T2WI) and diffusion-weighted prostate MRI. Cancers ≥0.5 ml and non-cancerous peripheral (PZ) and transition (TZ) zone tissue were identified on T2WI and apparent diffusion coefficient (ADC) maps, using whole-mount pathology as reference. Texture features (Energy, Entropy, Correlation, Homogeneity, Inertia) were extracted and analysed using generalized estimating equations.PZ cancers (n = 143) showed higher Entropy and Inertia and lower Energy, Correlation and Homogeneity compared to non-cancerous tissue on T2WI and ADC maps (p-values: <.0001-0.008). In TZ cancers (n = 43) we observed significant differences for all five texture features on the ADC map (all p-values: <.0001) and for Correlation (p = 0.041) and Inertia (p = 0.001) on T2WI. On ADC maps, GS was associated with higher Entropy (GS 6 vs. 7: p = 0.0225; 6 vs. >7: p = 0.0069) and lower Energy (GS 6 vs. 7: p = 0.0116, 6 vs. >7: p = 0.0039). ADC map Energy (p = 0.0102) and Entropy (p = 0.0019) were significantly different in GS ≤3 + 4 versus ≥4 + 3 cancers; ADC map Entropy remained significant after controlling for the median ADC (p = 0.0291).Several Haralick-based texture features appear useful for prostate cancer detection and GS assessment.• Several Haralick texture features may differentiate non-cancerous and cancerous prostate tissue. • Tumour Energy and Entropy on ADC maps correlate with Gleason score. • T2w-image-derived texture features are not associated with the Gleason score.

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.

(Cell 171, 540–556; October 19, 2017) It has come to our attention that we inadvertently used the wrong synonymous name for PD-L1 in the Discussion section on page 551. Instead of CD270, which is a synonymous name for the HVEM receptor, we should have used CD274 in that sentence. This error has been corrected online. We apologize for any confusion this may have caused. Comprehensive Molecular Characterization of Muscle-Invasive Bladder CancerRobertson et al.CellOctober 5, 2017In BriefA multiplatform analysis of 412 muscle-invasive bladder cancer patients provides insights into mutational profiles with prognostic value and establishes a framework associating distinct tumor subtypes with clinical options. Full-Text PDF Open Archive

Abstract Purpose: To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer-specific survival (CSS) of 609 patients with clear cell renal cell carcinoma (ccRCC) from 2 distinct cohorts. Experimental Design: Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was conducted to interrogate the genotype–phenotype associations. These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The Cancer Genome Atlas (TCGA) cohort of 421 patients with primary ccRCC. Results: 3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts [MSKCC, P = 0.002; HR 7.71; 95% confidence interval (CI)2.08–28.6; TCGA, P = 0.002; HR 2.21; 95% CI 1.35–3.63]. SETD2 are associated with worse CSS in the TCGA cohort (P = 0.036; HR 1.68; 95% CI 1.04–2.73). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusion: The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6%–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30%–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic, and molecular interrogation of this novel class of tumor suppressors. Clin Cancer Res; 19(12); 3259–67. ©2013 AACR.

Background: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM).However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. Methods:We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease.Results: There were 37 patients (26 men with a median age of 54 years).The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%).The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died.At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor.Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence.Additional salvage chemotherapy after bevacizumab failure was given to 19 patients.The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. Conclusions:Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM).A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival.Treatments after bevacizumab failure provide only transient tumor control.

To evaluate the recommendations for multiparametric prostate MRI (mp-MRI) interpretation introduced in the recently updated Prostate Imaging Reporting and Data System version 2 (PI-RADSv2), and investigate the impact of pathologic tumour volume on prostate cancer (PCa) detectability on mpMRI. This was an institutional review board (IRB)-approved, retrospective study of 150 PCa patients who underwent mp-MRI before prostatectomy; 169 tumours ≥0.5-mL (any Gleason Score [GS]) and 37 tumours <0.5-mL (GS ≥4+3) identified on whole-mount pathology maps were located on mp-MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted (DW)-MRI, and dynamic contrast-enhanced (DCE)-MRI. Corresponding PI-RADSv2 scores were assigned on each sequence and combined as recommended by PI-RADSv2. We calculated the proportion of PCa foci on whole-mount pathology correctly identified with PI-RADSv2 (dichotomized scores 1–3 vs. 4–5), stratified by pathologic tumour volume. PI-RADSv2 allowed correct identification of 118/125 (94 %; 95 %CI: 90–99 %) peripheral zone (PZ) and 42/44 (95 %; 95 %CI: 89–100 %) transition zone (TZ) tumours ≥0.5 mL, but only 7/27 (26 %; 95 %CI: 10–42 %) PZ and 2/10 (20 %; 95 %CI: 0–52 %) TZ tumours with a GS ≥4+3, but <0.5 mL. DCE-MRI aided detection of 4/125 PZ tumours ≥0.5 mL and 0/27 PZ tumours <0.5 mL. PI-RADSv2 correctly identified 94–95 % of PCa foci ≥0.5 mL, but was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL. DCE-MRI offered limited added value to T2WI+DW-MRI. • PI-RADSv2 correctly identified 95 % of PCa foci ≥0.5 mL • PI-RADSv2 was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL • DCE-MRI offered limited added value to T2WI+DW-MRI

Abstract Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray (∼83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell–associated genes in embryonal carcinoma, including several core “stemness” genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas. (Cancer Res 2006; 66(2): 820-7)

We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery.An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing.Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively).High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.

Abstract Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.

The purpose of this guideline is to provide a clinical framework for follow-up of clinically localized renal neoplasms undergoing active surveillance, or following definitive therapy.A systematic literature review identified published articles in the English literature between January 1999 and 2011 relevant to key questions specified by the Panel related to kidney neoplasms and their follow-up (imaging, renal function, markers, biopsy, prognosis). Study designs consisting of clinical trials (randomized or not), observational studies (cohort, case-control, case series) and systematic reviews were included.Guideline statements provided guidance for ongoing evaluation of renal function, usefulness of renal biopsy, timing/type of radiographic imaging and formulation of future research initiatives. A lack of studies precluded risk stratification beyond tumor staging; therefore, for the purposes of postoperative surveillance guidelines, patients with localized renal cancers were grouped into strata of low- and moderate- to high-risk for disease recurrence based on pathological tumor stage.Evaluation for patients on active surveillance and following definitive therapy for renal neoplasms should include physical examination, renal function, serum studies and imaging and should be tailored according to recurrence risk, comorbidities and monitoring for treatment sequelae. Expert opinion determined a judicious course of monitoring/surveillance that may change in intensity as surgical/ablative therapies evolve, renal biopsy accuracy improves and more long-term follow-up data are collected. The beneficial impact of careful follow-up will also need critical evaluation as further study is completed.

We evaluated our experience with renal cortical tumors to determine whether tumor size is associated with malignant histology and/or nuclear grade.We identified 2,675 patients treated surgically at our institution for renal cell carcinoma or a benign tumor between 1989 and 2007. Histological subtype and tumor size were obtained from our kidney cancer database and logistic regression analysis was performed.Of the 2,675 tumors 311 (12%) were benign and 2,364 (88%) were renal cell carcinoma. The OR for the association of malignancy with tumor size was 1.16 (95% CI 1.11-1.22, p <0.001), indicating that each 1 cm increase in tumor size was associated with a 16% increase in the odds of malignancy. The incidence of benign tumors decreased from 38% for tumors less than 1 cm to 7% for tumors 7 cm or greater. In patients with clear cell renal cell carcinoma each 1 cm increase in tumor size increased the odds of high grade disease (Fuhrman grade 3-4) compared with low grade disease (Fuhrman grade 1-2) by 25% (OR 1.25, 95% CI 1.21-1.30, p <0.001). In this subset the incidence of high grade lesions increased from 0% for tumors less than 1 cm to 59% for tumors greater than 7 cm.Our results confirm previous observations suggesting that the risks of malignancy and high grade tumors increase with tumor size. Patients with small renal masses are at low risk for harboring a high grade clear cell malignancy, which may be useful during initial consultation.

A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen-regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression, which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear, and in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization in 521 cases of clinically localized surgically treated prostate cancer with 95 months of median follow-up and also in 40 unmatched metastases. Forty-two percent of primary tumors and 40% of metastases had rearrangements. Eleven percent had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases, or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome, and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.

The discovery of ERG/ETV 1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV 1 gene rearrangements and PTEN gene loss status. We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV 1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data. ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a ‘good prognosis’ population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the ‘good prognosis’ group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved. Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management.

Urachal carcinomas occur mostly in the bladder dome, comprising 22% to 35% of vesical adenocarcinomas, and are generally treated by partial cystectomy with en bloc resection of the median umbilical ligament and umbilicus. Detailed pathologic studies with clinical outcome correlation are few.We reviewed histologic material and clinical data from 24 cases selected from a database of 67 dome-based tumors diagnosed and treated at our institution from 1984 to 2005. Follow-up information was available for all 24 patients.The mean age at diagnosis was 52 years (range: 26 to 68 y). Fifteen patients were male and 9 were female. Location was the dome in 23 and dome and anterior wall in 1. Thirteen cases were pure adenocarcinoma, not otherwise specified, 9 were enteric type adenocarcinoma, and 2 were adenocarcinoma with focal components of lymphoepithelioma-like carcinoma and urothelial carcinoma with cytoplasmic clearing. Signet ring cell features were focally seen in 2 cases. Cystitis cystica and cystitis glandularis were seen in 4 and 2 cases, respectively. In all instances but 1, cystitis cystica/glandularis was focal and predominantly in the bladder overlying the urachal neoplasm. Urachal remnants were identified in 15 cases: the urachal epithelium was benign urothelial-type in 6 cases and showed adenomatous changes in 9. The overlying bladder urothelium was colonized by adenocarcinoma in 3 cases. In all 3, urachal remnants were identified and showed transition from benign to adenomatous epithelium. On immunohistochemistry, these tumors were positive for CK20 and variably positive for CK7 and 34BE12. The majority showed a cytoplasmic membranous staining pattern for beta-catenin, although in 1 case, focal nuclear immunoreactivity was identified. The Sheldon pathologic stage was pT1 in 0, pT2 in 2, pT3a in 8, pT3b in 11, pT3c in 1, pT4a in 1, and pT4b in 1 patient. One patient had a positive soft tissue margin. The mean follow-up period was 40 months (range: 0.3 to 157.6 mo). Seven of 24 (29%) cases recurred locally. The incidence of local recurrence was higher in patients who underwent a partial cystectomy alone (37.5%) versus those who had a more radical surgery (27%). Distant metastases occurred in 9 (37.5%) patients, 4 of whom had no prior local recurrence. Seven patients (29%) died of the disease. All cases with locally recurrent and metastatic disease belonged to stage pT3 or higher.Pathologic stage is an important prognostic factor in urachal carcinoma. Surface urothelial involvement by carcinoma and presence of cystitis cystica/glandularis do not necessarily exclude the diagnosis of urachal carcinoma. Immunostains do not unequivocally discriminate a urachal from a colorectal carcinoma, but diffuse positivity for 34BE12 would support, and diffuse nuclear immunoreactivity for beta-catenin would militate against, a diagnosis of urachal carcinoma. Local recurrence may be owing to seeding within the distal urothelial tract, particularly in tumors with a configuration that is polypoid and which open into the bladder cavity. The type of surgery performed may have an effect on local recurrence despite negative margins of resection.

Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features.Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal-Wallis or Fisher exact tests. All statistical tests were two-sided.Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox.Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase (FH) gene confer an increased risk of cutaneous and uterine leiomyomas and renal cancer. HLRCC-associated renal cancer is highly aggressive and frequently presents as a solitary mass. We reviewed the clinicopathologic features of 9 patients with renal tumors presenting as sporadic cases but who were later proven to have FH germline mutations. Histologically, all tumors showed mixed architectural patterns, with papillary as the dominant pattern in only 3 cases. Besides papillary, tubular, tubulopapillary, solid, and cystic elements, 6 of 9 tumors contained collecting duct carcinoma-like areas with infiltrating tubules, nests, or individual cells surrounded by desmoplastic stroma. Prominent tubulocystic carcinoma-like component and sarcomatoid differentiation were identified. Although all tumors exhibited the proposed hallmark of HLRCC (large eosinophilic nucleolus surrounded by a clear halo), this feature was often not uniformly present throughout the tumor. Prior studies have shown that a high level of fumarate accumulated in HLRCC tumor cells causes aberrant succination of cellular proteins by forming a stable chemical modification, S-(2-succino)-cysteine (2SC), which can be detected by immunohistochemistry. We thus explored the utility of detecting 2SC by immunohistochemistry in the differential diagnosis of HLRCC tumors and other high-grade renal tumors and investigated the correlation between 2SC staining and FH molecular alterations. All confirmed HLRCC tumors demonstrated diffuse and strong nuclear and cytoplasmic 2SC staining, whereas all clear cell (184/184, 100%), most high-grade unclassified (93/97, 96%), and the large majority of "type 2" papillary (35/45, 78%) renal cell carcinoma cases showed no 2SC immunoreactivity. A subset of papillary (22%) and rare unclassified (4%) tumors showed patchy or diffuse cytoplasmic staining without nuclear labeling, unlike the pattern seen with confirmed HLRCC tumors. Sequencing revealed no germline or somatic FH alterations in 14 tumors that either exhibited only cytoplasmic 2SC staining (n=5) or were negative for 2SC (n=9), despite their HLRCC-like morphologic features. Our results emphasize the pivotal role of pathologic examination in the diagnosis of HLRCC patients and indicate immunohistochemical detection of 2SC as a useful ancillary tool in the differentiation of HLRCC renal tumors from other high-grade renal cell carcinomas.

The primary proceedings of the 2014 International Society of Urological Pathology Grading Conference were published promptly in 2015 and dealt with: (1) definition of various grading patterns of usual acinar carcinoma, (2) grading of intraductal carcinoma; and (3) support for the previously proposed new Grade Groups. The current manuscript in addition to highlighting practical issues to implement the 2014 recommendations, provides an updated perspective based on numerous studies published after the 2014 meeting. A major new recommendation that came from the 2014 Consensus Conference was to report percent pattern 4 with Gleason score 7 in both needle biopsies and radical prostatectomy (RP) specimens. This manuscript gives the options how to record percentage pattern 4 and under which situations recording this information may not be necessary. Another consensus from the 2014 meeting was to replace the term tertiary-grade pattern with minor high-grade pattern. Minor high-grade indicates that the term tertiary should not merely be just the third most common pattern but that it should be minor or limited in extent. Although a specific cutoff of 5% was not voted on in the 2014 Consensus meeting, the only quantification of minor high-grade pattern that has been used in the literature with evidence-based data correlating with outcome has been the 5% cutoff. At the 2014 Consensus Conference, there was agreement that the grading rule proposed in the 2005 Consensus Conference on needle biopsies be followed, that tertiary be not used, and that the most common and highest grade patterns be summed together as the Gleason score. Therefore, the term tertiary or minor high-grade pattern should only be used in RP specimens when there are 3 grade patterns, such as with 3+4=7 or 4+3=7 with &lt;5% Gleason pattern 5. It was recommended at the 2014 Conference that for the foreseeable future, the new Grade Groups would be reported along with the Gleason system. The minor high-grade patterns do not change the Grade Groups, such that in current practice one would, for example, report Gleason score 3+4=7 (Grade Group 2) with minor (tertiary) pattern 5. It was discussed at the 2014 Consensus Conference how minor high-grade patterns would be handled if Grade Groups 1 to 5 eventually were to replace Gleason scores 2 to 10. In the above example, it could be reported as Grade Group 2 with minor high-grade pattern or potentially this could be abbreviated to Grade Group 2+. The recommendation from the 2014 meeting was the same as in the 2005 consensus for grading separate cores with different grades: assign individual Gleason scores to separate cores as long as the cores were submitted in separate containers or the cores were in the same container yet specified by the urologist as to their location (ie, by different color inks). It is the practice of the majority of the authors of this manuscript that if the cores are submitted in a more specific anatomic manner than just left versus right (ie, per sextant site, MRI targets, etc.), that the grade of multiple cores in the same jar from that specific site are averaged together, given they are from the same location within the prostate. In cases with multiple fragmented cores in a jar, there was agreement to give a global Gleason score for that jar. The recommendation from the 2014 meeting was the same as in the 2005 consensus for grading separate nodules of cancer in RP specimens: one should assign a separate Gleason score to each dominant nodule(s). In the unusual occurrence of a nondominant nodule (ie, smaller nodule) that is of higher stage, one should also assign a grade to that nodule. If one of the smaller nodules is the highest grade focus within the prostate, the grade of this smaller nodule should also be recorded. An emerging issue in the studies and those published subsequent to the meeting was that cribriform morphology is associated with a worse prognosis than poorly formed or fused glands and in the future may be specifically incorporated into grading practice. We believe that the results from the 2014 Consensus Conference and the updates provided in this paper are vitally important to our specialty to promote uniformity in reporting of prostate cancer grade and in the contemporary management of prostate cancer.

Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded.The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]).PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events.Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.

Abstract Purpose: Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity. Experimental Design: We analyzed archived tumor tissue of 5 patients with renal cell carcinoma, who previously achieved durable disease control with rapalogs (median duration, 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultradeep sequencing was used to identify alterations across 230 target genes. Whole-exome sequence analysis was added to investigate genes beyond this original target list. Results: Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1 and MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In 1 patient, concurrent genomic events occurred in two separate pathway components across different tumor regions. Conclusions: Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents. Clin Cancer Res; 20(7); 1955–64. ©2014 AACR.

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations. Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.

Abstract Metastasis remains the main reason for renal cell carcinoma (RCC)–associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most patients with RCC, but the determinants of response are poorly understood. We report an integrated genomic and transcriptomic analysis of patients with metastatic clear cell RCC (ccRCC) treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis, and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests that the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC. Significance: The determinants of response to TKI therapy in metastatic ccRCC remain unknown. Our study demonstrates that key angiogenic and immune profiles of the tumor microenvironment may affect TKI response. These findings have the potential to inform treatment personalization in patients with RCC. This article is highlighted in the In This Issue feature, p. 453

Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.

Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ ( PSF ), 16 PRCC , 12 ASPSCR1 ( ASPL ), 6 NONO , and 1 DVL2 . We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3 , NONO-TFE3 , DVL2-TFE3 , and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCCs are the only known Xp11 translocation RCC molecular subtype that are consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions and should allow for more meaningful clinicopathologic associations to be drawn.

(Cell Reports 23, 313–326; April 3, 2018) In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online. The authors regret this error. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell CarcinomaRicketts et al.Cell ReportsApril 5, 2018In BriefRicketts et al. find distinctive features of each RCC subtype, providing the foundation for development of subtype-specific therapeutic and management strategies. Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes. Full-Text PDF Open Access

Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of (89)Zr-DFO-huJ591 ((89)Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology.Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of (89)Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites.Median standardized uptake value for (89)Zr-J591-positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). (89)Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, (89)Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 (89)Zr-J591-positive osseous sites and 14 of 16 (89)Zr-J591-positive soft tissue sites were positive for prostate cancer. The overall accuracy of (89)Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions.(89)Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although (89)Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

Purpose Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture–based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease.

Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.

Abstract Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo–YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR , TSC1 , TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

Intraductal carcinoma (IDC) and cribriform architecture (CA) represent unfavorable subpathologies in localized prostate cancer. We recently showed that IDC shares a clonal ancestry with the adjacent glandular adenocarcinoma. We investigated for the co-occurrence of “aggression” factors, genomic instability and hypoxia, and performed gene expression profiling of these tumors. A total of 1325 men were treated for localized prostate cancer from four academic institutions (University Health Network, CHU de Québec-Université Laval, Memorial Sloan Kettering Cancer Center [MSKCC], and Erasmus Medical Center). Pathological specimens were centrally reviewed. Gene copy number and expression, and intraprostatic oxygenation were assessed. IDC/CA was separately assessed for biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled for analyses on metastasis. Presence of IDC/CA independently predicted for increased risks of biochemical relapse (HRCanadian 2.17, p < 0.001; HRMSKCC 2.32, p = 0.0035) and metastasis (HRpooled 3.31, p < 0.001). IDC/CA+ cancers were associated with an increased percentage of genome alteration (PGA [median] 7.2 vs 3.0, p < 0.001), and hypoxia (64.0% vs 45.5%, p = 0.17). Combinatorial genomic–pathological indices offered the strongest discrimination for metastasis (C-index 0.805 [clinical + IDC/CA + PGA] vs 0.786 [clinical + IDC/CA] vs 0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1, was the only gene expressed at >3-fold higher (p < 0.0001) in IDC/CA+ than in IDC/CA– tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal. Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing. The poor outcome associated with IDC and CA subpathologies is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a novel concept in IDC/CA+ prostate cancer, “nimbosus” (gathering of stormy clouds, Latin), which manifests as increased metastatic capacity and lethality. A constellation of unfavorable molecular characteristics co-occur with intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveillance and treatment intensification trials should be considered in this adverse subgroup.

Whole slide imaging is Food and Drug Administration-approved for primary diagnosis in the United States of America; however, relatively few pathology departments in the country have fully implemented an enterprise wide digital pathology system enabled for primary diagnosis. Digital pathology has significant potential to transform pathology practice with several published studies documenting some level of diagnostic equivalence between digital and conventional systems. However, whole slide imaging also has significant potential to disrupt pathology practice, due to the differences in efficiency of manipulating digital images vis-à-vis glass slides, and studies on the efficiency of actual digital pathology workload are lacking. Our randomized, equivalency and efficiency study aimed to replicate clinical workflow, comparing conventional microscopy to a complete digital pathology signout using whole slide images, evaluating the equivalency and efficiency of glass slide to whole slide image reporting, reflective of true pathology practice workloads in the clinical setting. All glass slides representing an entire day's routine clinical signout workload for six different anatomic pathology subspecialties at Memorial Sloan Kettering Cancer Center were scanned on Leica Aperio AT2 at ×40 (0.25 µm/pixel). Integration of whole slide images for each accessioned case is through an interface between the Leica eSlide manager database and the laboratory information system, Cerner CoPathPlus. Pathologists utilized a standard institution computer workstation and viewed whole slide images through an internally developed, vendor agnostic whole slide image viewer, named the "MSK Slide Viewer". Subspecialized pathologists first reported on glass slides from surgical pathology cases using routine clinical workflow. Glass slides were de-identified, scanned, and re-accessioned in the laboratory information system test environment. After a washout period of 13 weeks, pathologists reported the same clinical workload using whole slide image integrated within the laboratory information system. Intraobserver equivalency metrics included top-line diagnosis, margin status, lymphovascular and/or perineural invasion, pathology stage, and the need to order ancillary testing (i.e., recuts, immunohistochemistry). Turnaround time (efficiency) evaluation was defined by the start of each case when opened in the laboratory information system and when the case was completed for that day (i.e., case sent to signout queue or pending ancillary studies). Eight pathologists participated from the following subspecialties: bone and soft tissue, genitourinary, gastrointestinal, breast, gynecologic, and dermatopathology. Glass slides signouts comprised of 204 cases, encompassing 2091 glass slides; and digital signouts comprised of 199 cases, encompassing 2073 whole slide images. The median whole slide image file size was 1.54 GB; scan time/slide, 6 min 24 s; and scan area 32.1 × 18.52 mm. Overall diagnostic equivalency (e.g., top-line diagnosis) was 99.3% between digital and glass slide signout; however, signout using whole slide images showed a median overall 19% decrease in efficiency per case. No significant difference by reader, subspecialty, or specimen type was identified. Our experience is the most comprehensive study to date and shows high intraobserver whole slide image to glass slide equivalence in reporting of true clinical workflows and workloads. Efficiency needs to improve for digital pathology to gain more traction among pathologists.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

Remote digital pathology allows healthcare systems to maintain pathology operations during public health emergencies. Existing Clinical Laboratory Improvement Amendments regulations require pathologists to electronically verify patient reports from a certified facility. During the 2019 pandemic of COVID-19 disease, caused by the SAR-CoV-2 virus, this requirement potentially exposes pathologists, their colleagues, and household members to the risk of becoming infected. Relaxation of government enforcement of this regulation allows pathologists to review and report pathology specimens from a remote, non-CLIA certified facility. The availability of digital pathology systems can facilitate remote microscopic diagnosis, although formal comprehensive (case-based) validation of remote digital diagnosis has not been reported. All glass slides representing routine clinical signout workload in surgical pathology subspecialties at Memorial Sloan Kettering Cancer Center were scanned on an Aperio GT450 at ×40 equivalent resolution (0.26 µm/pixel). Twelve pathologists from nine surgical pathology subspecialties remotely reviewed and reported complete pathology cases using a digital pathology system from a non-CLIA certified facility through a secure connection. Whole slide images were integrated to and launched within the laboratory information system to a custom vendor-agnostic, whole slide image viewer. Remote signouts utilized consumer-grade computers and monitors (monitor size, 13.3-42 in.; resolution, 1280 × 800-3840 × 2160 pixels) connecting to an institution clinical workstation via secure virtual private network. Pathologists subsequently reviewed all corresponding glass slides using a light microscope within the CLIA-certified department. Intraobserver concordance metrics included reporting elements of top-line diagnosis, margin status, lymphovascular and/or perineural invasion, pathology stage, and ancillary testing. The median whole slide image file size was 1.3 GB; scan time/slide averaged 90 s; and scanned tissue area averaged 612 mm2. Signout sessions included a total of 108 cases, comprised of 254 individual parts and 1196 slides. Major diagnostic equivalency was 100% between digital and glass slide diagnoses; and overall concordance was 98.8% (251/254). This study reports validation of primary diagnostic review and reporting of complete pathology cases from a remote site during a public health emergency. Our experience shows high (100%) intraobserver digital to glass slide major diagnostic concordance when reporting from a remote site. This randomized, prospective study successfully validated remote use of a digital pathology system including operational feasibility supporting remote review and reporting of pathology specimens, and evaluation of remote access performance and usability for remote signout.

Prostate cancer (PrCa) is the second most common cancer among men in the United States. The gold standard for detecting PrCa is the examination of prostate needle core biopsies. Diagnosis can be challenging, especially for small, well-differentiated cancers. Recently, machine learning algorithms have been developed for detecting PrCa in whole slide images (WSIs) with high test accuracy. However, the impact of these artificial intelligence systems on pathologic diagnosis is not known. To address this, we investigated how pathologists interact with Paige Prostate Alpha, a state-of-the-art PrCa detection system, in WSIs of prostate needle core biopsies stained with hematoxylin and eosin. Three AP-board certified pathologists assessed 304 anonymized prostate needle core biopsy WSIs in 8 hours. The pathologists classified each WSI as benign or cancerous. After ~4 weeks, pathologists were tasked with re-reviewing each WSI with the aid of Paige Prostate Alpha. For each WSI, Paige Prostate Alpha was used to perform cancer detection and, for WSIs where cancer was detected, the system marked the area where cancer was detected with the highest probability. The original diagnosis for each slide was rendered by genitourinary pathologists and incorporated any ancillary studies requested during the original diagnostic assessment. Against this ground truth, the pathologists and Paige Prostate Alpha were measured. Without Paige Prostate Alpha, pathologists had an average sensitivity of 74% and an average specificity of 97%. With Paige Prostate Alpha, the average sensitivity for pathologists significantly increased to 90% with no statistically significant change in specificity. With Paige Prostate Alpha, pathologists more often correctly classified smaller, lower grade tumors, and spent less time analyzing each WSI. Future studies will investigate if similar benefit is yielded when such a system is used to detect other forms of cancer in a setting that more closely emulates real practice.

Metabolic imaging using hyperpolarized magnetic resonance can increase the sensitivity of MRI, though its ability to inform on relevant changes to biochemistry in humans remains unclear. In this work, we image pyruvate metabolism in patients, assessing the reproducibility of delivery and conversion in the setting of primary prostate cancer. We show that the time to max of pyruvate does not vary significantly within patients undergoing two separate injections or across patients. Furthermore, we show that lactate increases with Gleason grade. RNA sequencing data demonstrate a significant increase in the predominant pyruvate uptake transporter, monocarboxylate transporter 1. Increased protein expression was also observed in regions of high lactate signal, implicating it as the driver of lactate signal in vivo. Targeted DNA sequencing for actionable mutations revealed the highest lactate occurred in patients with PTEN loss. This work identifies a potential link between actionable genomic alterations and metabolic information derived from hyperpolarized pyruvate MRI.

The original guideline, "Validating Whole Slide Imaging for Diagnostic Purposes in Pathology," was published in 2013 and included 12 guideline statements. The College of American Pathologists convened an expert panel to update the guideline following standards established by the National Academies of Medicine for developing trustworthy clinical practice guidelines.To assess evidence published since the release of the original guideline and provide updated recommendations for validating whole slide imaging (WSI) systems used for diagnostic purposes.An expert panel performed a systematic review of the literature. Frozen sections, anatomic pathology specimens (biopsies, curettings, and resections), and hematopathology cases were included. Cytology cases were excluded. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the panel reassessed and updated the original guideline recommendations.Three strong recommendations and 9 good practice statements are offered to assist laboratories with validating WSI digital pathology systems.Systematic review of literature following release of the 2013 guideline reaffirms the use of a validation set of at least 60 cases, establishing intraobserver diagnostic concordance between WSI and glass slides and the use of a 2-week washout period between modalities. Although all discordances between WSI and glass slide diagnoses discovered during validation need to be reconciled, laboratories should be particularly concerned if their overall WSI-glass slide concordance is less than 95%.

The field of anatomic pathology has been evolving in the last few decades and the advancements have been largely fostered by innovative technology. Immunohistochemistry enabled a paradigm shift in discovery and diagnostic evaluation, followed by booming genomic advancements which allowed for submicroscopic pathologic characterization, and now the field of digital pathology coupled with machine learning and big data acquisition is paving the way to revolutionize the pathology medical domain. Whole slide imaging (WSI) is a disruptive technology where glass slides are digitized to produce on-screen whole slide images. Specifically, in the past decade, there have been significant advances in digital pathology systems that have allowed this technology to promote integration into clinical practice. Whole slide images (WSI), or digital slides, can be viewed and navigated comparable to glass slides on a microscope, as digital files. Whole slide imaging has increased in adoption among pathologists, pathology departments, and scientists for clinical, educational, and research initiatives. Integration of digital pathology systems requires a coordinated effort with numerous stakeholders, not only within the pathology department, but across the entire enterprise. Each pathology department has distinct needs, use cases and blueprints, however the framework components and variables for successful clinical integration can be generalized across any organization seeking to undergo a digital transformation at any scale. This article will review those components and considerations for integrating digital pathology systems into clinical practice.

Prostate cancer diagnosis rests on accurate assessment of tissue by a pathologist. The application of artificial intelligence (AI) to digitized whole slide images (WSIs) can aid pathologists in cancer diagnosis, but robust, diverse evidence in a simulated clinical setting is lacking.To compare the diagnostic accuracy of pathologists reading WSIs of prostatic biopsy specimens with and without AI assistance.Eighteen pathologists, 2 of whom were genitourinary subspecialists, evaluated 610 prostate needle core biopsy WSIs prepared at 218 institutions, with the option for deferral. Two evaluations were performed sequentially for each WSI: initially without assistance, and immediately thereafter aided by Paige Prostate (PaPr), a deep learning-based system that provides a WSI-level binary classification of suspicious for cancer or benign and pinpoints the location that has the greatest probability of harboring cancer on suspicious WSIs. Pathologists' changes in sensitivity and specificity between the assisted and unassisted modalities were assessed, together with the impact of PaPr output on the assisted reads.Using PaPr, pathologists improved their sensitivity and specificity across all histologic grades and tumor sizes. Accuracy gains on both benign and cancerous WSIs could be attributed to PaPr, which correctly classified 100% of the WSIs showing corrected diagnoses in the PaPr-assisted phase.This study demonstrates the effectiveness and safety of an AI tool for pathologists in simulated diagnostic practice, bridging the gap between computational pathology research and its clinical application, and resulted in the first US Food and Drug Administration authorization of an AI system in pathology.

We reviewed 954 primary nonurothelial epithelial renal neoplasms with primary resection at Memorial Sloan-Kettering Cancer Center between the years 1980 and 1995 and classified 70 cases (7%) as renal oncocytomas. The study population was composed of 39 men and 31 women, and the mean age was 65 years (range 25 to 86 years). Fifty-six patients (80%) were asymptomatic at presentation, six (4%) had flank pain, six (4%) presented with a mass, and two (3%) had hematuria. Sixty-one were treated with total or radical nephrectomy, nine with partial nephrectomy. The right kidney was involved in 35 cases (50%), the left kidney in 32 (46%). Three cases (4%) were bilateral. Sixty-one cases (87%) were unifocal, nine (13%) multifocal. All the tumors were well circumscribed but unencapsulated. Forty-five (64%) were described as brown or red, whereas the remainder were variously described as tan to yellow. Central fibrosis or scar was described in 23 cases (33%), and gross areas of hemorrhage or cystic changes in 14 (20%). The mean size was 5.2 cm and median 5.0 cm (range 1.5 cm to 14 cm). Histologically, the tumors were characterized by a mixture of architectural patterns: compact cellular nests and acini embedded in a hyalinized, hypocellular stroma were present in 62 cases (89%), a solid nested architecture in 47 cases (67%), and a variable tubular component in 50 cases (71%). Small papillae, pseudopapillae, and intratubular epithelial tufts were seen in 19 cases (27%). Cytologically, the neoplasms also showed a mixture of cell types, the most common being the classic oncocyte, which consisted of round or polygonal cells with moderate to abundant granular, eosinophilic cytoplasm, and small round nuclei with evenly dispersed granular chromatin. Small basophilic nucleoli were visible in many of these cells in all cases. Thirty-one cases (44%) had a variable number of oncocytic cells with pyknotic nuclei and 20 (30%) contained clusters of small cells with a high nuclear/cytoplasmic ratio and dense hyperchromatic nuclei (so-called oncoblasts). Foci of tubules with clear cells embedded in a hyalinized stroma were present in six cases (9%). Cellular atypia was evident in 42 cases (60%) and was marked in 21 (30%). Eleven cases (16%) exhibited mitotic activity, albeit low. No case had atypical mitoses or necrosis. Twenty-two cases (31%) had areas of calcification within the hyalinized stroma, 12 (17%) had calcospherites, and three (4%) had osseous and myeloid metaplasia. Vascular invasion was present in three cases (4%), and invasion of perinephric fat in 14 (20%). One patient presented with liver metastasis. Fourteen cases (20%) were pT1, 42 (60%) pT2, and 14 (20%) pT3. After a mean follow-up of 58 months (range 1 to 181), 62 patients (89%) were alive with no evidence of tumor, six (9%) had died of other causes, one was alive with stable metastatic disease in the liver 58 months after diagnosis, and one died with metastatic disease to bone and liver. We conclude that renal oncocytomas have a varied morphologic appearance and their pathologic diagnosis should be based on a constellation of architectural and cytologic features. The overwhelming majority of cases behave in a benign fashion, although in rare instances they can metastasize. The presence of atypical morphologic features do not alter the excellent prognosis associated with oncocytomas and do not predict an aggressive clinical course.

Cancer at the resection margin (a positive surgical margin) after radical prostatectomy is associated with an increased risk of recurrence even after adjusting for other known risk factors, including pretreatment serum prostate specific antigen (PSA), clinical stage, grade and pathological stage (level of extracapsular extension, seminal vesicle invasion and pelvic lymph node status). Of these prognostic factors only surgical margin status can be influenced by surgical technique. We examined variations in the rate of positive surgical margins among surgeons after controlling for the severity of disease and volume of cases per surgeon.A total of 4,629 men were treated with radical prostatectomy by 1 of 44 surgeons at 2 large urban centers between 1983 and 2002 for clinical stage T1-T3NxM0 prostate cancer. Patients were excluded if they had previously received androgen deprivation therapy or radiation therapy to the pelvis. Positive surgical margins were defined as cancer at the inked resection margin. Other risk factors analyzed were serum PSA, grade (Gleason sum), extracapsular extension level (none, invasion into the capsule, present [not otherwise specified], focal extracapsular extension or established extracapsular extension), seminal vesicle invasion, pelvic lymph node metastases, surgery date, surgeon and volume of cases per surgeon.For the 26 surgeons who each treated more than 10 patients in the study the rate of positive surgical margins was 10% to 48%. On multivariable analysis higher serum PSA, extracapsular extension level, higher radical prostatectomy Gleason sum, surgery date, surgical volume and surgeon were associated with surgical margin status after controlling for all other clinical and pathological variables.While the clinical and pathological features of cancer are associated with the risk of a positive margin in radical prostatectomy specimens, the technique used by individual surgeons is also a factor. Lower rates of positive surgical margins for high volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with radical prostatectomy.

The reappraisal of genetically defined subsets of renal tumors can help to highlight the key pathologic features of specific neoplastic entities. We report the morphologic, immunophenotypic, ultrastructural, and molecular features of 11 renal carcinomas bearing a t(X;1)(p11.2;q21) and/or the resulting PRCC-TFE3 gene fusion. The male/female ratio was 4:7. Ten patients were in the age range of 9-29 years and one was 64 years old (mean 21.3 years, median 15 years). The predominant histologic pattern was nested, with islands of tumor cells compartmentalized by thin-walled capillary vasculature. Minor variations on this pattern yielded solid, acinar, alveolar, and tubular architecture. Papillary architecture was seen in nine cases, usually as a minor component. Neoplastic cells were typically characterized by irregularly shaped nuclei with vesicular chromatin and small nucleoli not visible with a 10x objective, and cytoplasm that ranged from clear to densely granular and eosinophilic. Mitoses were extremely rare; 5 were found in 900 high power fields examined from the 11 neoplasms. The most distinctive immunohistochemical feature of these neoplasms was moderate to intense nuclear labeling for TFE3 protein. These tumors were also consistently immunoreactive for the RCC antigen (10 of 11) and CD10 (9 of 9), whereas cytokeratin and epithelial membrane antigen were negative in four cases and were positive focally in the others. Ultrastructurally, all of the six neoplasms examined showed features consistent with conventional-type (clear cell) renal carcinoma, although two demonstrated distinctive intracisternal microtubules. Both tumors tested contained PRCC-TFE3 fusion transcripts. The differential diagnosis includes conventional-type papillary renal cell carcinoma, conventional-type (clear cell) renal carcinoma, and the ASPL-TFE3 renal carcinomas associated with the t(X;17)(p11.2;q25), with the latter two being morphologically the most similar to the t(X;1) renal carcinomas. Aside from their distinctive clinicopathologic features described here, there is experimental evidence suggesting that these tumors may show differential sensitivity to certain chemotherapeutic agents.

Gleason grading is now the most widely used grading system for prostatic carcinoma in the United States. However, there are only a few studies of the interobserver reproducibility of this system, and no extensive study of interobserver reproducibility among a large number of experienced urologic pathologists exists. Forty-six needle biopsies containing prostatic carcinoma were assigned Gleason scores by 10 urologic pathologists. The overall weighted kappa coefficient kappa(w) for Gleason score for each of the urologic pathologists compared with each of the remaining urologic pathologists ranged from 0.56 to 0.70, all but one being at least 0.60 (substantial agreement). The overall kappa coefficient kappa for each pathologist compared with the others for Gleason score groups 2-4, 5-6, 7, and 8-10 ranged from 0.47 to 0.64 (moderate-substantial agreement), only one less than 0.50. At least 70% of the urologic pathologists agreed on the Gleason grade group (2-4, 5-6, 7, 8-10) in 38 ("consensus" cases) of the 46 cases. The 8 "nonconsensus" cases included low-grade tumors, tumors with small cribriform proliferations, and tumors whose histology was on the border between Gleason patterns. Interobserver reproducibility of Gleason grading among urologic pathologists is in an acceptable range.

The identification of genes that contribute to the biological basis for clinical heterogeneity and progression of prostate cancer is critical to accurate classification and appropriate therapy. We performed a comprehensive gene expression analysis of prostate cancer using oligonucleotide arrays with 63,175 probe sets to identify genes and expressed sequences with strong and uniform differential expression between nonrecurrent primary prostate cancers and metastatic prostate cancers. The mean expression value for >3,000 tumor-intrinsic genes differed by at least 3-fold between the two groups. This includes many novel ESTs not previously implicated in prostate cancer progression. Many differentially expressed genes participate in biological processes that may contribute to the clinical phenotype. One example was a strong correlation between high proliferation rates in metastatic cancers and overexpression of genes that participate in cell cycle regulation, DNA replication, and DNA repair. Other functional categories of differentially expressed genes included transcriptional regulation, signaling, signal transduction, cell structure, and motility. These differentially expressed genes reflect critical cellular activities that contribute to clinical heterogeneity and provide diagnostic and therapeutic targets.

Understanding the distribution of tumor-associated antigens on cancers and normal tissues is essential for selection of targets for cancer immunotherapy. Seven carbohydrate antigens, potential targets for immunotherapy, were studied using a panel of well-characterized MAbs by immunohistochemistry on cryostat-cut tissue sections of 13 types of cancers and 18 normal tissues. GD2 and GD3 were present on most cancers of neuroectodermal origin and GD2 was also present on B cell lymphomas. 9-O-acetyl-GD3 was detected only on melanoma while fucosyl GM1 was detected only on small cell lung cancers (SCLC). Surprisingly, GM2 was strongly expressed on all tested tumors, including cancers of neuroectodermal origin and cancers of epithelial origin. Polysialic acid was primarily expressed on SCLC and neuroblastomas. Globo H was present on most cancers of epithelial origin. These antigens were also identified in normal tissues. Fucosyl GM1 was not expressed significantly on any of the normal tissues analyzed. GD3, GD2, GM2 and polysialic acid were detected in normal brain to varying degrees. GM2 and Globo H were expressed on the luminal surface of epithelia of a variety of organs. The unexpected expression of GM2 on a broad range of cancers and normal epithelial tissues was confirmed by loss after methanol fixation and by immune thin layer chromatography. Int. J. Cancer 73:42–49, 1997. © 1997 Wiley-Liss, Inc.

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing “MiTF/TFE family” of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 May 2004Predicting the Presence and Side of Extracapsular Extension: A Nomogram for Staging Prostate Cancer MAKOTO OHORI, MICHAEL W. KATTAN, HIDESHIGE KOH, NORIO MARU, KEVIN M. SLAWIN, SHAHROKH SHARIAT, MASATOSHI MURAMOTO, VICTOR E. REUTER, THOMAS M. WHEELER, and PETER T. SCARDINO MAKOTO OHORIMAKOTO OHORI More articles by this author , MICHAEL W. KATTANMICHAEL W. KATTAN More articles by this author , HIDESHIGE KOHHIDESHIGE KOH More articles by this author , NORIO MARUNORIO MARU More articles by this author , KEVIN M. SLAWINKEVIN M. SLAWIN More articles by this author , SHAHROKH SHARIATSHAHROKH SHARIAT More articles by this author , MASATOSHI MURAMOTOMASATOSHI MURAMOTO More articles by this author , VICTOR E. REUTERVICTOR E. REUTER More articles by this author , THOMAS M. WHEELERTHOMAS M. WHEELER Financial interest and/or other relationship with Pintex Pharmaceuticals. More articles by this author , and PETER T. SCARDINOPETER T. SCARDINO More articles by this author View All Author Informationhttps://doi.org/10.1097/01.ju.0000121693.05077.3dAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We developed a model to predict the side specific probability of extracapsular extension (ECE) in radical prostatectomy (RP) specimens based on the clinical features of the cancer. Materials and Methods: We studied 763 patients with clinical stage T1c-T3 prostate cancer who were diagnosed by systematic needle biopsy and subsequently treated with RP. Candidate predictor variables associated with ECE were clinical T stage, the highest Gleason sum in any core, percent positive cores, percent cancer in the cores from each side and serum prostate specific antigen (PSA). Receiver operating characteristic (ROC) analyses were performed to assess the predictive value of each variable alone and in combination. We constructed and internally validated nomograms to predict the side specific probability of ECE based on logistic regression analysis. Results: Overall 30% of the patients and 17% of 1,526 prostate lobes (left or right) had ECE. The areas under the ROC curves (AUC) of the standard features in predicting side specific probability of ECE were 0.627 for PSA, 0.695 for clinical T stage on each side and 0.727 for Gleason sum on each side. When these features were combined predictive accuracy increased to 0.788. The highest value (0.806) was achieved by adding the percent positive cores and the percent cancer in the biopsy specimen to the standard features. The resulting nomograms were internally validated and had excellent calibration and discrimination accuracy. Conclusions: Standard clinical features of prostate cancer in each lobe—PSA, palpable induration and biopsy Gleason sum—can be used to predict the side specific probability of ECE in RP specimens. The predictive accuracy is increased by adding information from systematic biopsy results. The predictive nomograms are sufficiently accurate for use in clinical practice in decisions such as wide versus close dissection of the cavernous nerves from the prostate. References 1 : Factors predicting recovery of erections after radical prostatectomy. J Urol2000; 164: 1929. Link, Google Scholar 2 : Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA1997; 277: 1445. Crossref, Medline, Google Scholar 3 : Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology2001; 58: 843. Google Scholar 4 : Systematic sextant biopsies in the prediction of extracapsular extension at radical prostatectomy. Urology1997; 50: 373. 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Era of Magnetic Resonance Imaging–targeted Biopsy: A Study That Challenges the DogmaJournal of Urology, VOL. 210, NO. 1, (117-127), Online publication date: 1-Jul-2023.Martini A, Soeterik T, Haverdings H, Rahota R, Checcucci E, De Cillis S, Hermanns T, Fankhauser C, Afferi L, Moschini M, Mattei A, Kesch C, Heidegger I, Preisser F, Zattoni F, Marquis A, Marra G, Gontero P, Briganti A, Montorsi F, Porpiglia F, Van Basten J, Van den Bergh R, Van Melick H, Ploussard G, Gandaglia G and Valerio M (2021) An Algorithm to Personalize Nerve Sparing in Men with Unilateral High-Risk Prostate CancerJournal of Urology, VOL. 207, NO. 2, (350-357), Online publication date: 1-Feb-2022.von Bodman C, Brock M, Roghmann F, Byers A, Löppenberg B, Braun K, Pastor J, Sommerer F, Noldus J and Palisaar R (2013) Intraoperative Frozen Section of the Prostate Decreases Positive Margin Rate While Ensuring Nerve Sparing Procedure During Radical ProstatectomyJournal of Urology, VOL. 190, NO. 2, (515-520), Online 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Volume 171Issue 5May 2004Page: 1844-1849 Advertisement Copyright & Permissions© 2004 by American Urological Association, Inc.Keywordsbiopsycell surface extensionsprostatic neoplasmsclassificationMetrics Author Information MAKOTO OHORI More articles by this author MICHAEL W. KATTAN More articles by this author HIDESHIGE KOH More articles by this author NORIO MARU More articles by this author KEVIN M. SLAWIN More articles by this author SHAHROKH SHARIAT More articles by this author MASATOSHI MURAMOTO More articles by this author VICTOR E. REUTER More articles by this author THOMAS M. WHEELER Financial interest and/or other relationship with Pintex Pharmaceuticals. More articles by this author PETER T. SCARDINO More articles by this author Expand All Advertisement PDF downloadLoading ...

The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size.Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided.Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm3, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score > or = 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups.Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.

To see whether genetic alterations follow a sequence of events leading to bladder cancer progression, 60 paired bladder tumours and normal tissues were analysed with polymorphic DNA markers, correlating loss of heterozygosity (LOH) at candidate tumour suppressor gene sites with pathological indices of poor clinical outcome. Distinct genotypic patterns were associated with early and late stages of bladder cancer. 9q deletions were observed in all superficial papillary tumours (Ta) and almost all tumours invading the lamina propria (T1), suggesting that this event associates with the development of superficial bladder tumours. However, 3p, 5q, and 17p deletions were absent in the Ta tumours but were identified in invasive bladder cancers. Two genetic pathways characterise the evolution of superficial bladder tumours. 9qLOH was detected in most Ta tumours, but in only 43% of muscle invasive neoplasms. Our hypothesis is that certain chromosomal abnormalities have a defined role in bladder tumour development, whereas others correlate with pathological indices of poor clinical outcome.

Abstract The objective of this study was to characterize the pattern of p53 mutations in bladder cancer. The sensitivity and specificity to detect these mutations using clinical material was assessed for the following assays: immunohistochemistry, restriction‐fragment‐length polymorphism, single‐strand‐conformation polymorphism, and sequencing. Discrepancies of reported results aimed at the identification of genetic alterations in the p53 gene may be due to differences in methodology, as well as to deficient morphological evaluation of the source of tissue utilized. In order to address these critical issues, we have implemented a novel experimental design that permits analysis by molecular genetics and immunopathology techniques in any given tissue specimen, allowing morphological correlation with genotypic and phenotypic characteristics of the tissue analyzed. Forty‐two patients affected with bladder tumors in whom paired normal and tumor tissues were available were used for the present study. Nuclear immunoreactivities were observed in 26 out of 42 bladder tumors analyzed. Abnormal shifts in mobility were noted in 14 of the 42 cases in distinct exons, with one tumor revealing 3 mutations. There was a strong association between p53 nuclear over‐expression and 17p LOH, as well as p53 nuclear over‐expression and detection of mutations by SSCP and sequencing. According to receiver‐operating‐curve statistical analysis, the accuracy of detecting p53 mutations by IHC was estimated to be 90.3%. It is our conclusion that, when properly used, this is a highly sensitive and specific method with simple application using clinical material.

PURPOSE This study sought to examine the prognostic role of p53 nuclear overexpression in muscle-invasive bladder cancer because of its correlation with progression of superficial bladder cancer. PATIENTS AND METHODS Ninety of 111 patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with a median follow-up duration of 5.8 years were evaluated. p53 nuclear overexpression was determined by immunohistochemistry on deparaffinized tissue sections. Patients were stratified into two groups according to the percent of tumor cells with positive nuclear reactivity. Overexpression was defined as tumors with &gt; or = 20% cells with positive nuclear reactivity and nonoverexpression as tumors with less than 20% reactivity. RESULTS Nuclear overexpression was observed in 47 patients and nonoverexpression in 43 patients. Patients whose tumors had p53 overexpression had a significantly higher proportion of cancer deaths. A multivariate analysis that evaluated the pretreatment variables p53 nuclear overexpression, age, sex, palpable mass, prechemotherapy tumor stage, performance status, ureteral obstruction, tumor size, multifocality, and grade showed that p53 overexpression had independent significance for survival (P = .001; relative risk ratio, 3.1). The impact of p53 overexpression on survival was predominantly in T2 and T3a tumors. Long-term survival was evident in seven of 17 patients (41%) with p53 overexpression versus 20 of 26 (77%) in whom p53 was not overexpressed (P = .007). CONCLUSION p53 nuclear overexpression has independent prognostic value for survival in patients with invasive bladder cancer treated with neoadjuvant chemotherapy.

Children who survive cancer are at more than 19-fold increased risk of developing another malignancy. Renal cell carcinoma (RCC) occurring as a secondary malignancy is uncommon. Translocation RCC, bearing TFE3 or TFEB gene fusions, are recently recognized entities for which risk factors have not been identified.We describe the clinical, pathologic, cytogenetic, and molecular data on six translocation RCCs that arose in five young patients who had received chemotherapy.The ages at time of diagnosis of the RCC ranged from 6 to 22 years. Histologically, these tumors showed typical features previously described for translocation RCCs. At the molecular level, three tumors contained the ASPL-TFE3 fusion, two contained Alpha-TFEB, and one contained PRCC-TFE3. The intervals between chemotherapy and the diagnosis of RCC ranged from 4 to 13 years. The indications for the antecedent chemotherapy were varied and included acute promyelocytic leukemia, acute myeloid leukemia with t(9;11), bilateral Wilms' tumor, systemic lupus erythematosus, and conditioning regimen of bone marrow transplant for Hurler's syndrome. Only the latter patient had also received radiation. Hence, among 39 genetically confirmed translocation RCCs in our personal experience, six (15%) have arisen in patients who had received cytotoxic chemotherapy.Cytotoxic chemotherapy may predispose to the development of renal translocation carcinomas.