Pathology focused review of morphologic subtypes and molecular variants of urothelial carcinoma with an emphasis on clinical/treatment relevance.

Urothelial carcinoma (UC) has significant morbidity, mortality, and remains the most financially costly carcinoma to manage and treat. This review will cover special morphologic features of UC that may be noted by the pathologist and any subsequent significance in terms of clinical management or treatment considerations as mentioned or recommended in the latest WHO 2022 classification of GU tumors. Many important potentially therapy altering morphologic findings can be consistently identified and reported on routine microscopic examination of hematoxylin and eosin (H&E) stained slides. Furthermore, there has been a rapid advancement of molecular diagnostics and tailored therapies throughout oncology, and we will briefly highlight some of these as they relate to the management of UC. We will actively attempt to limit the discussion of histologic descriptions or pathologic diagnostic criteria of these entities and focus rather on the recognition of their importance/implication for clinicians who must make clinical management decisions based upon these findings. Finally, the importance of open lines of communication with the pathologists who review clinical specimens as well as their practice and reporting methods cannot be overstated.

Comparison of urine cytology diagnostic reports before and after the implementation of the Paris System classification system in China.

OBJECTIVE: In 2013, The Paris System for Reporting Urinary Cytology (TPS) was developed as a uniform practical urine cytology system that could be applied worldwide. Here, we investigated the effectiveness of TPS diagnostic approach compared with that of the traditional urine cytological diagnosis method used in China. METHODS: Based on the diagnostic criteria of TPS, 412 urine samples from 143 patients with histological follow-up data were retrospectively analysed, and the diagnoses were compared with the original cytological diagnoses. RESULTS: In total, 110 patients were histologically diagnosed with high-grade urothelial carcinoma (HGUC), and 33 patients were diagnosed with low-grade urothelial neoplasia. Based on the traditional urine cytological analysis method, 50 patients (34.9%) were diagnosed as negative, 48 patients (33.6%) were diagnosed as having atypical urothelial cells, and 45 patients (31.5%) were diagnosed as positive. After reclassification using TPS, urine samples from 11 cases (7.7%) were categorised as unsatisfactory, 34 cases (23.8%) were negative, 21 cases (14.7%) were categorised as having atypical urothelial cells, 12 cases (8.4%) were diagnosed as suspicious for HGUC, 59 cases (41.2%) were diagnosed with HGUC, and six cases (4.2%) were reclassified as having low-grade urothelial neoplasia. Thus, after implementing TPS criteria, the sensitivity for positive malignancy diagnoses (HGUC alone) increased from 38.2% to 50.9%, while the specificity of the diagnosis was barely changed. CONCLUSIONS: The Paris System for Reporting Urinary Cytology greatly contributes to the standardisation of urine cytology reports and significantly improves the diagnostic sensitivity for HGUC.

Single-Port Robotic Urological Surgery Using Purpose-Built Single-Port Surgical System: Single-Institutional Experience With the First 100 Cases.

OBJECTIVES: To present a comprehensive report regarding our experience with single-port robotic surgery in our first 100 consecutive patients. We describe the diversity of procedures that can be performed with this platform as well as the challenges and complications we had with the application of this novel technology. METHODS: Between September 2018 and August 2019, data on 100 patients who underwent single-port robotic surgery were consecutively collected. Preoperative, intraoperative and early postoperative outcomes after various urologic procedures were recorded and analyzed. RESULTS: During the study period, 100 patients (age [range] 35-84 years; 88 [88%] Male) underwent various single-port robotic surgeries for different indications (Retroperitoneal [n = 14], Pelvic surgeries [n = 86]). Transperitoneal (n = 37), extraperitoneal (n = 53) and transvesical (n = 10) approaches have been used to access the target organs. Of these procedures, 73 (73%) were for different oncological indications: Radical prostatectomy (n = 60), Partial nephrectomy (n = 6), Retroperitoneal lymph node dissection (n = 1) and Radical cystectomy with intracorporeal diversion (n = 6). Surgery was successfully completed in all but 1 patient, in whom the surgery was converted to open surgery due to dense adhesions and failure to progress. Grades II-III postoperative complications were detected in (n = 9) patients. CONCLUSION: The purpose-built single-port robotic platform can be safely incorporated into the minimally invasive armamentarium. A wide range of pelvic and retroperitoneal urological procedures can be done with different approaches using this platform. Randomized trials with adequate sample size and postoperative follow up period is advisable for further evaluation of the outcomes and to determine the added value of this emerging technology.

Updates in Histologic Grading of Urologic Neoplasms.

CONTEXT.­: Tumor histology offers a composite view of the genetic, epigenetic, proteomic, and microenvironmental determinants of tumor biology. As a marker of tumor histology, histologic grading has persisted as a highly relevant factor in risk stratification and management of urologic neoplasms (ie, renal cell carcinoma, prostatic adenocarcinoma, and urothelial carcinoma). Ongoing research and consensus meetings have attempted to improve the accuracy, consistency, and biologic relevance of histologic grading, as well as provide guidance for many challenging scenarios. OBJECTIVE.­: To review the most recent updates to the grading system of urologic neoplasms, including those in the 2016 4th edition of the World Health Organization (WHO) Bluebook, with emphasis on issues encountered in routine practice. DATA SOURCES.­: Peer-reviewed publications and the 4th edition of the WHO Bluebook on the pathology and genetics of the urinary system and male genital organs. CONCLUSIONS.­: This article summarizes the recently updated grading schemes for renal cell carcinoma, prostate adenocarcinomas, and bladder neoplasms of the genitourinary tract.

HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter.

INTRODUCTION: Erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) gene amplification or protein overexpression occurs in certain types of urothelial carcinomas. Molecular pathologic classification of urinary bladder cancer using immunohistochemistry has identified basal and luminal subtypes with differing prognoses, but the HER2 status of these subtypes has not been investigated. In addition, research on urothelial carcinoma of the renal pelvis and ureter (UCRPU) has not progressed because of its rarity, though its prognosis is worse than that of bladder cancer. In this study, we evaluated the clinical significance of HER2 status in molecular subtypes of UCRPU. MATERIALS AND METHODS: HER2 status (protein overexpression and/or gene amplification) and molecular subtyping were determined for 148 cases of UCRPU (83 and 65 cases in the renal pelvis and ureter, respectively), using immunohistochemistry and fluorescent in situ hybridization, and compared with clinicopathologic factors. RESULTS: Subtype analysis revealed that the cases were 46% basal and 54% luminal. HER2 protein overexpression and/or gene amplification was observed in 14% of UCRPU cases and was significantly more frequent in the luminal subtype than in the basal (22% vs. 4%; P = .0030). Univariate analysis showed that the overall survival of patients with HER2-positive UCRPU was significantly shorter than those with HER2-negative tumors. CONCLUSIONS: HER2 protein overexpression and gene amplification were specifically observed in the luminal subtype of UCRPU, suggesting that these cases may respond to HER2-targeted therapies like trastuzumab.

What Is the Significance of Variant Histology in Urothelial Carcinoma?

CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Clinicopathologic study of 60 cases of urothelial neoplasms with inverted growth patterns: Reclassification by international consultation on urologic disease (ICUD) recommendations.

BACKGROUND: Most urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking. METHODS: Sixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed. RESULTS: A total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2. CONCLUSIONS: The 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.

[Morphological and immunohistochemical characteristics of the molecular subtypes of urothelial carcinomas]. / Morfologicheskaia i immunogistokhimicheskaia kharakteristika molekuliarnykh podtipov urotelial'nykh kartsinom.

The molecular subtypes of urothelial carcinoma in each classification scheme have characteristic immunohistochemical features. At the same time, the results of conducted studies often demonstrate a discrepancy between the genomic profile of urothelial carcinoma and its immunophenotype, which complicates the immunohistochemical verification of the molecular subtypes of these tumors. OBJECTIVE: To compare the morphological and immunophenotypic characteristics of the molecular subtypes of urothelial carcinoma. MATERIAL AND METHODS: Surgical specimens from 196 patients diagnosed with urothelial carcinoma of the renal pelvis and bladder were investigated. Paraffin-embedded sections were immunohistochemically examined using the standard protocol. Antibodies against CK5/6, CK17, Rb1 (Dako), CK14, CK18, CK20, Cyclin D1, Cyclin E1, Cyclin A, Cyclin B, Chromogranin, E-Cadherin, P-Cadherin, p16, Uroplakin II, TUBB2B, Vimentin, ZEB-2 ('Novocastra'), CD44, GATA-3, and Uroplakin III ('Cell Marque') were used. RESULTS: Out of 68 (35%) superficial papillary urothelial carcinomas, 24 (12%) tumors constituted Molecular Class I and 12 (6%) and 32 (16%) ones did Molecular Classes II and III, respectively. Of the 128 (65%) muscle-invasive urothelial carcinomas, 57 (29%) tumors were referred to as the luminal-papillary molecular subtype, and 24 (12%) and 14 (7%) were as the luminal-infiltrated and luminal molecular subtypes, respectively. The basal squamous molecular subtype was verified in 31 (16%) neoplasms and the neuronal phenotype was detected in 2 (1%) cases. CONCLUSION: Most pT1 tissues correspond to Molecular Class II. In the muscle-invasive urothelial carcinoma group, the neoplasms with a luminal phenotype predominate over the tumors with basal and neuronal phenotypes.

Shared Decision-Making for Patients with Advanced Urological Malignancies: Evaluation of a Joint Urological-Oncological Clinic Model.

BACKGROUND: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. METHOD: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). RESULTS: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. CONCLUSIONS: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.

Prognostic performance of the 1973 and 2004 WHO grading classification in upper tract urothelial carcinoma.

BACKGROUND: Grading of upper tract urothelial carcinoma (UTUC) is routinely used in clinical practice; however, reports concerning prognostic performance of different grading systems are contradictory. We aim to assess the clinical reliability of the 1973 and 2004 World Health Organization (WHO) grading classification systems in UTUC. PATIENTS AND METHODS: We retrospectively evaluated 458 consecutive patients with UTUC from 2008 to 2013. The postoperative tumor grades were evaluated by a single uropathologist using the 1973 and 2004 WHO grade classification systems. The Kaplan-Meier method was used to estimate cancer-specific survival (CSS) and overall survival (OS). Univariate and multivariate analyses were used to test the association between clinical variables and the CSS and OS rates. RESULTS: There were 133 (29.0%) low-grade patients and 325 (71.0%) high-grade patients. The 3-year CSS rates were 87.0% and 76.0% for G2 and G3 disease and 89.0% and 80.0% for low- and high-grade disease according to the 2004 system, respectively. For all UTUC patients, there were significant differences in the CSS and OS rates between G2 and G3 cases, as well as between the low- and high-grade groups. The CSS and OS rates were significantly different between the G2 and G3 cases for the overall high-grade population (CSS: P = 0.003; OS: P = 0.009), while no significant difference emerged between low- and high-grade tumors in G2 UTUC patients (CSS: P = 0.717; OS: P = 0.280). In the subgroup of high-grade non-muscle-invasive tumors, the 1973 WHO grading system was an independent predictor of CSS (P = 0.045). CONCLUSIONS: The results support the hypothesis that the 1973 WHO system is superior to the 2004 system for predicting clinical outcomes in patients with non-muscle-invasive UTUC.

The updated points of TNM classification of urological cancers in the 8th edition of AJCC and UICC.

The Tumor-Node-Metastasis (TNM) staging system, jointly developed by the American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC), is widely employed in clinical practice and research on patients with cancer. The definitions of TNM classification have recently been changed, improving patient stratification for management and prognosis. As the feature of new editions, biomarkers which are necessary for the stratification of patients are included to adapt for personalized medicine. Although it would be ideal for the AJCC and UICC have identical TNM staging systems, there are some differences between these two publications. In this review, we introduce the significant changes and differences in the eighth edition of the AJCC and UICC TNM staging systems for urologic cancers and summarize the evidence supporting these changes.

[Comparison of UICC and AJCC 8th edition TNM classifications in uropathology]. / Comparaison des classifications TNM des 8es éditions de l'UICC et de l'AJCC en uropathologie.

The pTNM stage is one of the most important parameters in the handling of tumor patients. The pathologist plays a major role in the determination of the stage. The classifications undergo an evolution according to the state of art. The TNM system is used worldwide and allows to precise the tumor (T) and lymph node stage and the presence of distant metastasis. This system helps to stratify patient groups and determine their prognosis. In 2017, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) published their 8th edition. Unluckily several differences exist between both classifications. The UICC neglected to make several recommendations according to the International Society of Urological Pathology (ISUP) decisions, which organises the consensus in uropathology.

Grading of Urothelial Carcinoma and The New "World Health Organisation Classification of Tumours of the Urinary System and Male Genital Organs 2016".

CONTEXT: In the management of urothelial carcinoma, determination of the pathological grade aims at stratifying tumours into different prognostic groups to allow evaluation of treatment results, and optimise patient management. This article reviews the principles behind different grading systems for urothelial bladder carcinoma discussing their reproducibility and prognostic value. OBJECTIVE: This paper aims to show the evolution of the World Health Organisation (WHO) grading system, discussing their reproducibility and prognostic value, and evaluating which classification system best predicts disease recurrence and progression. The most optimal classification system is robust, reproducible, and transparent with comprehensive data on interobserver and intraobserver variability. The WHO published an updated tumour classification in 2016, which presents a step forward, but its performance will need validation in clinical studies. EVIDENCE ACQUISITION: Medline and EMBASE were searched using the key terms WHO 1973, WHO/International Society of Urological Pathology 1998, WHO 2004, WHO 2016, histology, reproducibility, and prognostic value, in the time frame 1973 to May 2016. The references list of relevant papers was also consulted, resulting in the selection of 48 papers. EVIDENCE SYNTHESIS: There are still inherent limitations in all available tumour classification systems. The WHO 1973 presents considerable ambiguity for classification of the G2 tumour group and grading of the G1/2 and G2/3 groups. The 2004 WHO classification introduced the concept of low-grade and high-grade tumours, as well as the papillary urothelial neoplasm of low malignant potential category which is retained in the 2016 classification. Furthermore, while molecular markers are available that have been shown to contribute to a more accurate histological grading of urothelial carcinomas, thereby improving selection of treatment for a given patient, these are not (yet) part of standard clinical practice. CONCLUSIONS: The prognosis of patients diagnosed with urothelial carcinoma greatly depends on correct histological grading of the tumour. There is still limited data regarding intraobserver and interobserver variability differences between the WHO 1973 and 2004 classification systems. Additionally, reproducibility remains a concern: histological differences between the various types of tumour may be subtle and there is still no consensus amongst pathologists. The recent WHO 2016 classification presents a further improvement on the 2004 classification, but until further data becomes available, the European Association of Urology currently recommends the use of both WHO 1973 and WHO 2004/2016 classifications. PATIENT SUMMARY: Bladder cancer, when treated in time, has a good prognosis. However, selection of the most optimal treatment is largely dependent on the information your doctor will receive from the pathologist following evaluation of the tissue resected from the bladder. It is therefore important that the classification system that the pathologist uses to grade the tissue is transparent and clear for both urologists and pathologists. A reliable classification system will ensure that aggressive tumours are not misinterpreted, and less aggressive cancer is not overtreated.

Improved correlation of urinary cytology specimens using The Paris System in biopsy-proven upper tract urothelial carcinomas.

BACKGROUND: Urine cytology specimens are essential for screening and monitoring high-grade urothelial carcinomas. However, inconsistent reporting and equivocal diagnostic categories have remained a challenge. The Paris System for Reporting Urinary Cytology (TPS) was developed to provide clear cytomorphologic criteria for urine cytology specimens. Significant correlation between the surgical biopsy diagnosis (SD) and TPS diagnosis (PD) has been established in lower urothelial tract carcinomas, but to the authors' knowledge limited information is available regarding upper urinary tract carcinomas. METHODS: A total of 56 cytology specimens from 35 patients within 90 days of an SD of upper urinary tract carcinoma were included. Cytology was re-reviewed and assigned a PD. The original diagnosis (OD) and PD were compared with the corresponding SD to determine which correlated best. RESULTS: The PD corresponded to the SD in 35 of 56 cases (63%), which was greater than that for the OD and SD, which were concordant in 19 of 56 cases (34%). Both the OD and PD were concordant in 18 of 56 cases (32%), and neither corresponded in 20 of 56 cases (36%). A total of 27 of 33 cases of high-grade urothelial carcinoma/carcinoma in situ on SD (82%) were identified using the PD whereas only 15 cases (45%) were identified with the OD. The number of "atypical" diagnoses in the OD was reduced from 16 of 56 cases (29%) to 7 of 56 cases (13%) using the PD. Of the 14 of 56 "negative" OD (25%), only 4 remained after implementation of the PD. A diagnosis of low-grade urothelial neoplasm was established in 6 of 20 cases (30%) with the PD compared with 3 of 20 cases with the OD (15%). CONCLUSIONS: The authors found that reclassification with TPS improved correlation with the SD compared with previous methodologies. Specifically, TPS increased the number of high-grade urothelial carcinoma diagnoses and decreased the number of equivocal or "atypical" diagnoses. Cancer Cytopathol 2018. © 2018 American Cancer Society.

A 20-year and 46,000-specimen journey to Paris reveals the influence of reporting systems and passive peer feedback on pathologist practice patterns.

BACKGROUND: An important goal of The Paris System for Reporting Urinary Cytology (TPS) is to reduce unnecessary atypical diagnoses given to urinary tract cytology (UTC) specimens. Since implementation of TPS at the study institution in 2016, the institutional atypical rate has declined only slightly. The authors speculated that TPS might not have had an immediate impact because several faculty members were involved in TPS committees and because TPS contains elements that already had been integrated into institutional practice. To identify factors contributing to alterations in the institutional atypical rate, the authors examined their practice over the last 22 years. METHODS: UTC specimens submitted to the study laboratory between August 11, 1995, and August 10, 2017, were identified. Specimens were linked to the responsible pathologist, specimen diagnosis and type, association with high-grade urothelial carcinoma, and relevant cytomorphologic features. RESULTS: An increase in the institutional atypical rate occurred between 2002 and 2005. The atypical rate among individual pathologists also peaked during this same time. The increase coincided with an increase in the use of UTC and the arrival of a pathologist with a higher rate of atypical diagnoses. A substantial decrease in the institutional atypical rate occurred between 2005 and 2010 and coincided with the creation of the Johns Hopkins Hospital Template, the authors' first standardized reporting system for UTC specimens. CONCLUSIONS: The use of reporting systems (Johns Hopkins Hospital Template and TPS) has coincided with decreases in the institutional atypical rate at the study institution. An individual pathologist may influence the practice patterns of his or her colleagues, resulting in fluctuations in the institutional rate of atypia over time. Cancer Cytopathol 2018;126:381-9. © 2018 American Cancer Society.

One year of experience using the Paris System for Reporting Urinary Cytology.

BACKGROUND: The Paris System for Reporting Urinary Cytology (TPS) was published in November 2015. It focuses on the diagnosis of high-grade urothelial carcinoma (HGUC) and provides criteria with which to define the category of atypical urothelial cells (AUC). The objective of the current study was to compare two 1-year consecutive periods before and after use of TPS. METHODS: A total of 1634 and 1814 urine cytology cases, respectively, were analyzed before and after use of TPS. Histological diagnosis within 6 months was available for 330 and 299 cases, respectively. RESULTS: After use of TPS, the authors reported significantly fewer low-grade urothelial neoplasms (0.94% vs 1.84%; P<.05) and more cases that were suspicious for HGUC (2.09% vs 0.73%; P<.01) compared with before use of TPS. For the AUC category, there was no significant change in frequency noted for before versus after TPS (6.12% vs 5.18%), whereas the rate of detection of HGUC on histology significantly increased after TPS when compared with before TPS (49.02% vs 28.17%; P<.02). For the HGUC category, neither the frequency (4.69% vs 4.47%) nor the risk of malignancy (89.39% vs 91.04% with HGUC on histology) were found to be significantly different when comparing before and after use of TPS. CONCLUSIONS: In the authors' practice, TPS helped to better characterize the categories of AUC, low-grade urothelial neoplasm, and suspicious for HGUC, which were associated with a higher risk of HGUC compared with the authors' previous classification. Cancer Cytopathol 2018;126:430-6. © 2018 American Cancer Society.

Revisiting the Prognostic Heterogeneity of AJCC Stage IV Carcinomas of the Upper Urinary Tract.

BACKGROUND: Current staging paradigms from the American Joint Committee on Cancer (AJCC) staging system for upper urinary tract carcinomas treat locoregionally advanced (T4 and N+) and metastatic (M1) patients as a single entity (stage IV). The current study proposes a modification of the AJCC staging system where these 2 entities are separated. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (2004-2014) was accessed through SEER*Stat program. Overall survival (OS) analyses according to AJCC and modified staging systems were conducted through Kaplan-Meier analysis. Moreover, cancer-specific survival analysis was conducted through a Cox proportional hazard model. RESULTS: OS was compared according to AJCC and modified AJCC staging systems. The P value for OS trend for both staging systems was < .0001. This was also found when OS was stratified by the site of the primary (renal pelvis vs. ureter) as well as when stratified by the staging approach (pathologic vs. clinical) (P < .0001). Cancer-specific Cox proportional hazard analysis (adjusted for age, grade, histology, and surgical treatment) was conducted for both staging systems. Pairwise hazard ratio comparisons between different stage categories for both staging systems were significant (P < .0001). The c index for cancer-specific survival for the AJCC staging system was 0.706 with standard error 0.006 (95% confidence interval, 0.695-0.717), while the c index for cancer-specific survival for the modified AJCC staging system was 0.714 with standard error 0.006 (95% confidence interval, 0.702-0.725). CONCLUSION: Dividing stage IV upper urinary tract carcinomas into locoregionally advanced and metastatic disease subcategories improves the prognostic utility of the staging system compared to the current AJCC staging system. Given the limitations of a SEER-based study, this concept needs to be externally validated in various settings.

Effects of primary care physician density, urologist presence, and insurance status on stage of diagnosis for urologic malignancies.

OBJECTIVE: To evaluate effects of PCP density, insurance status, and urologist presence on stage of diagnosis for urologic malignancies. Cancer stage at diagnosis is an important outcome predictor. Studies have shown an inverse relationship to primary care physician (PCP) density and insurance coverage with stage of cancer diagnosis. METHODS: Data was obtained from OK2Share, an Oklahoma Central Cancer Registry, for bladder, kidney, and prostate cancer from 2000 to 2010. Physician data was obtained through the State Licensing Board. The 2010 national census was used for population data. High PCP density was defined as greater than or equal to the median value: 3.17 PCP/10,000 persons. Chi-square and multivariate logistic regressions were used to analyze effects of PCP density, insurance status, and urologist presence on advanced stage diagnosis. RESULTS: 27,086 patients were identified across 77 counties. As PCP density increased by 1 PCP/10,000 persons, the odds ratios (OR) of an advanced stage at diagnosis were 0.383, 0.468, 0.543 for bladder, kidney, and prostate cancer respectively. Compared to private insurance, being uninsured had OR of 1.61 and 2.45 respectively for kidney and prostate cancers. The OR of an advanced stage diagnosis for bladder and prostate cancer were 3.77 and 1.73, respectively, in counties with a urologist. CONCLUSIONS: Increased PCP density and insurance coverage reduced the odds of an advanced diagnosis. Implementation of policies to improve access to healthcare including through increasing PCP density and reducing the number of uninsured patients should result in diagnosis at an earlier stage, which will likely improved cancer-related outcomes.

Pan-urologic cancer genomic subtypes that transcend tissue of origin.

Urologic cancers include cancers of the bladder, kidney, prostate, and testes, with common molecular features spanning different types. Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression). Tissue dominant effects are first removed computationally in order to define these subtypes, which reveal common processes-reflecting in part tumor microenvironmental influences-driving cellular behavior across tumor lineages. Six of the subtypes feature a mixture of represented cancer types as defined by tissue or cell of origin. Differences in patient survival and in the manifestation of specific pathways-including hypoxia, metabolism, NRF2-ARE, Hippo, and immune checkpoint-can further distinguish the subtypes. Immune checkpoint markers and molecular signatures of macrophages and T cell infiltrates are relatively high within distinct subsets of each cancer type studied. The pan-urologic cancer genomic subtypes would facilitate information sharing involving therapeutic implications between tissue-oriented domains.Urological cancers have disparate tissues and cells of origin but share many molecular features. Here, the authors use multidimensional and comprehensive molecular characterization to classify urological cancers into nine major genomic subtypes, highlighting potential therapeutic targets.

Pathology Imagebase-a reference image database for standardization of pathology.

AIMS: Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. METHODS AND RESULTS: The International Society of Urological Pathology (ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non-public database. The remaining 23 experts were asked to vote from a multiple-choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two-thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at www.isupweb.org. Non-members may access a selected number of cases. CONCLUSIONS: It is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases.