Flower isoforms promote competitive growth in cancer.

In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on 'fitness fingerprints', which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell's membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8-17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19-21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.

Primary mucinous adenocarcinoma of the urethra: A clinicopathological analysis of 35 cases.

AIM: Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS: Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear ß-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. CONCLUSION: Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.

Evaluation of intrinsic and extrinsic factors affecting pregnancy rate in dual-purpose cows under tropical conditions.

Embryo transfer (ET) in bovines was created with the purpose of increasing the pregnancy rate (PR) of animals with high genetic value; however, multiple factors have been found to affect the success of this reproductive biotechnology. These factors are frequently grouped in intrinsic and extrinsic factors. Thus, the objective of the present experiments was to assess the effect of intrinsic and extrinsic factors on the pregnancy rate under tropical conditions. To do this a total of 648 embryo transfer (ET) procedures were performed between January and December 2021. The intrinsic factors were size and location of the corpus luteum, body condition, genetic group, age and parity; while extrinsic factors were location of the farm, environmental comfort, season in which the ET was carried out, prevailing weather conditions, and the preservation, quality, and the development stage of embryos at the time of ET. A χi2 was used for analysis of main effects, and logistic regression analysis to calculate the probability of pregnancy and the association between intrinsic or extrinsic factors; additionally, a multivariate analysis of data clusters was used to find a linkage between the effects. While recipient female age had a negative effect (Odds ratio = 0.345-0.871) on PR (p < 0.05), being higher in younger cows, the rest of the intrinsic factors did not affect the PR. The significant (p < 0.05) extrinsic factors were THI category, season of year and type of embryo preservation, showing that the highest PR (p < 0.05) was obtained in the comfort THI category, during the winter season and using fresh embryos for transfer. The clustering analysis did not show any linkage between PR and intrinsic factors, while a linkage (p < 0.05) was found with season of the year and embryo preservation as extrinsic factors. It is concluded that age of the recipient cow and environmental conditions at the time of the embryo transfer are key factors to be considered for a successful pregnancy rate from in-vitro ET programs using dual-purpose cows under tropical conditions.

Frequent Telomerase Reverse Transcriptase Promoter and Fibroblast Growth Factor Receptor 3 Mutations Support the Precursor Nature of Papillary Urothelial Hyperplasia of the Urinary Bladder.

The precursor nature of papillary urothelial hyperplasia of the urinary bladder is uncertain. In this study, we investigated the telomerase reverse transcriptase (TERT) promoter and fibroblast growth factor receptor 3 (FGFR3) mutations in 82 patients with papillary urothelial hyperplasia lesions. Thirty-eight patients presented with papillary urothelial hyperplasia and concurrent noninvasive papillary urothelial carcinoma, and 44 patients presented with de novo papillary urothelial hyperplasia. The prevalence of the TERT promoter and FGFR3 mutations is compared between de novo papillary urothelial hyperplasia and those with concurrent papillary urothelial carcinoma. Mutational concordance between papillary urothelial hyperplasia and concurrent carcinoma was also compared. The TERT promoter mutations were detected in 44% (36/82) of papillary urothelial hyperplasia, including 23 (23/38, 61%) papillary urothelial hyperplasia with urothelial carcinoma and 13 (13/44, 29%) de novo papillary urothelial hyperplasia. The overall concordance of TERT promoter mutation status between papillary urothelial hyperplasia and concurrent urothelial carcinoma was 76%. The overall FGFR3 mutation rate of papillary urothelial hyperplasia was 23% (19/82). FGFR3 mutations were detected in 11 patients with papillary urothelial hyperplasia and concurrent urothelial carcinoma (11/38, 29%) and 8 patients with de novo papillary urothelial hyperplasia (8/44, 18%). Identical FGFR3 mutation status was detected in both papillary urothelial hyperplasia and urothelial carcinoma components in all 11 patients with FGFR3 mutations. Our findings provide strong evidence of a genetic association between papillary urothelial hyperplasia and urothelial carcinoma. High frequency of TERT promoter and FGFR3 mutations suggests the precursor role of papillary urothelial hyperplasia in urothelial carcinogenesis.

News in the classification of WHO 2022 bladder tumors.

The fifth-edition of World Health Organization (WHO) Classification of Tumors series for urinary and male genital tract tumors has been published, six years later the fourth-edition. In these years, new treatment approaches have been implemented and new molecular data on urological cancers are known.Morphology remains the groundwork for taxonomy of the urinary tract tumors. However, a molecular approach to classification of urothelial carcinomas and the management of selected neoplasms with new therapeutic modalities such as immunotherapy are emerging. More data are needed for the application of these advances in routine pathology practice and patient management.The 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System and Male Genital Organs represents an update in classification on urinary tract tumors. It also offers new insights with regards to the grading of heterogeneous non-invasive urothelial neoplasms, the definition of inverted neoplasms, the grading of invasive urothelial carcinomas, the diversity of morphological appearance of urothelial carcinomas, the definition of precursor lesions and the lineage of differentiation of the tumors.

Cell competition and tumor heterogeneity.

Cancers exhibit a remarkable degree of intratumoral heterogeneity (ITH), which results from complex cellular interactions amongst various cell types. This phenomenon provides an opportunity for clonal selection and growth advantages to aggressive cancer cell types, resulting in worse prognosis and challenges to anti-cancer therapy. Cell competition is a conserved mechanism operational in cellular and organ systems, which allows neighboring cells to compare their relative fitness levels and results in the elimination of viable but suboptimal cells. By abuse of this conserved homeostasis mechanism, aggressive cancer cell types gain an advantage over normal cell types by achieving traits like increased proliferation, de-differentiation, and stemness. This review presents recent evidence that cell competition mechanisms actively participate in the regulation of intratumoral cell-cell interactions and thus contribute to ITH, and this process is essential for cancer development and progression.

Telomerase reverse transcriptase (TERT) promoter mutations in primary adenocarcinoma of bladder and urothelial carcinoma with glandular differentiation: pathogenesis and diagnostic implications.

Telomerase reverse transcriptase (TERT) promoter mutations have been implicated in urothelial carcinogenesis and are present in 60-80% of conventional and variants of urothelial carcinomas. We investigated the prevalence of TERT promoter mutations in 46 cases of bladder nonurachal adenocarcinoma, 30 cases of urothelial carcinoma with glandular differentiation, 24 cases of nephrogenic adenoma, eight cases of villous adenoma, 31 cases of florid cystitis glandularis, and 20 cases of intestinal metaplasia of the bladder. TERT promoter mutations were detected in 33% of adenocarcinomas of urinary bladder and in 67% of urothelial carcinomas with glandular differentiation. All 30 cases of urothelial carcinoma with glandular differentiation harbored identical TERT promoter mutation in both glandular and urothelial carcinoma components from the same tumor, suggesting a common clonal origin. TERT promoter mutations were absent in nephrogenic adenoma, villous adenoma, florid cystitis glandularis, and intestinal metaplasia of the bladder. TERT promoter mutation analysis may be a useful ancillary study in the differential diagnosis.

Predicting future cancer burden in the United States by artificial neural networks.

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018-2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.

HIF-transcribed p53 chaperones HIF-1α.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic.

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.

The Impact of Implementing an Intensivist Model With Nighttime In-Hospital Nocturnist and Effect on ICU Outcomes.

BACKGROUND: Various intensivist staffing models have been suggested, but the long-term sustainability and outcomes vary and may not be sustained. We examined the impact of implementing a high-intensity intensivist coverage model with a nighttime in-house nocturnist (non-intensivist) and its effect on intensive care unit (ICU) outcomes. METHODS: We obtained historical control baseline data from 2007 to 2011 and compared the same data from 2011 to 2015. The Acute Physiological and Chronic Health Evaluation outcomes system was utilized to collect clinical, physiological, and outcome data on all adult patients in the medical ICU and to provide severity-adjusted outcome predictions. The model consists of a mandatory in-house daytime intensivist service that leads multidisciplinary rounds, and an in-house nighttime coverage is provided by nocturnist (nonintensivists) with current procedural skills in airways management, vascular access, and commitment to supervise house staff as needed. The intensivist continues to be available remotely at nighttime for house staff and consultation with the nocturnist. A backup intensivist is available for surge management. RESULTS: First year yielded improved throughput (2428 patients/year to 2627 then 2724 at fifth year). Case mix stable at 53.7 versus 55.2. The ICU length of stay decreased from 4.7 days (predicted 4.25 days) to 3.8 days (4.15) in first year; second year: 3.63 days (4.29 days); third year: 3.24 days (4.37), fourth year: 3.34 days (4.45), and fifth year: 3.61 days (4.42). Intensive care unit <24 hours readmission remained at 1%; >24 hours increased from 4% to 6%. Low-risk monitoring admissions remained at an average 17% (benchmark 17.18%). Intensive care unit mortality improved with standardized mortality ration averaging at 0.84. Resident satisfaction surveys improved. CONCLUSIONS: Implementing an intensivist service with nighttime nocturnist staffing in a high-intensity large teaching hospital is feasible and improved ICU outcomes in a sustained manner that persisted after the initial implementation phase. The model resulted in reduced and sustained observed-to-predicted length of ICU stay.

B Cells in the Gastrointestinal Tumor Microenvironment with a Focus on Pancreatic Cancer: Opportunities for Precision Medicine?

We review state-of-the-art in translational and clinical studies focusing on the tumor microenvironment (TME) with a focus on tumor-infiltrating B cells (TIBs). The TME is a dynamic matrix of mutations, immune-regulatory networks, and distinct cell-to-cell interactions which collectively impact on disease progress. We discuss relevant findings concerning B cells in pancreatic cancer, the concepts of "bystander" B cells, the role of antigen-specific B cells contributing to augmenting anticancer-directed immune responses, the role of B cells as prognostic markers for response to checkpoint inhibitors (ICBs), and the potential use in adoptive cell tumor-infiltrating lymphocyte (TIL) products.

Genito-urinary genomics and emerging biomarkers for immunomodulatory cancer treatment.

Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with genito-urinary (GU) cancers at different stages of disease. Robust and reliable biomarkers are crucial for an appropriate inclusion of patients in clinical trials and for a reliable patient selection for treatments with immunomodulatory drugs. The increasing knowledge on the genomic landscape of GU cancers supports stratification of patients for targeted therapies. This review focusses on emerging biomarkers and the role of genomics in predicting clinical benefit to immunomodulatory agents in GU cancers. Based on cancer incidences and available data we restricted this overview to bladder, prostate and renal cancer.

Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate.

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low-grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high-grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty-two percent of AAH lesions had α-methylacyl-CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

MYB-NFIB gene fusion in prostatic basal cell carcinoma: clinicopathologic correlates and comparison with basal cell adenoma and florid basal cell hyperplasia.

Prostatic basal cell carcinoma is a malignant neoplasm composed of basaloid cells forming infiltrative nests and tubules, which may potentially be misdiagnosed as benign basal cell proliferations (i.e., florid basal cell hyperplasia or basal cell adenoma) and also closely resembles adenoid cystic carcinoma of the salivary gland. MYB-NFIB gene rearrangement occurs in 30-86% of salivary gland adenoid cystic carcinomas. We sought to further characterize MYB gene rearrangement in prostatic basal cell carcinoma and correlate MYB-NFIB fusion status with other clinicopathologic characteristics. To this end, FISH analysis for MYB-NFIB gene fusion using fusion probes was performed on formalin-fixed, paraffin-embedded tissue sections from prostatic basal cell carcinoma (n = 30), florid basal cell hyperplasia (n = 18), and basal cell adenoma (n = 4). Fourteen of 30 (47%) cases of basal cell carcinoma were positive for MYB-NFIB gene fusion FISH, and no cases of benign basal cell proliferations were positive (p < 0.05). FISH-positive patients (mean age = 63 years, range: 35-81) tended to be younger than FISH-negative patients (mean age = 70 years, range: 55-93). Most FISH-positive cases demonstrated adenoid cystic carcinoma-like morphology (57%), and most FISH-negative cases demonstrated nonadenoid cystic carcinoma-like morphology (93%); one case (FISH-positive) demonstrated areas with both adenoid cystic carcinoma-like and nonadenoid cystic carcinoma-like morphology. FISH-positive cases more frequently demonstrated perineural invasion (50% vs. 14%, p < 0.05) compared to FISH-negative cases. Conversely, tall basal cells (i.e., neoplastic cells at least two times taller than wide) were more frequent in FISH-negative cases than FISH-positive cases (93% vs. 36%, p < 0.05). Approximately, 50% of prostatic basal cell carcinoma harbor MYB-NFIB gene fusion. The majority of these cases were characterized by adenoid cystic carcinoma-like morphology, perineural invasion, and lack tall basal cells. Florid basal cell hyperplasia and basal cell adenoma are negative for MYB-NFIB gene fusion.

Variants and new entities of bladder cancer.

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

Staging of bladder cancer.

Urothelial carcinoma of the urinary bladder is a heterogeneous disease with multiple possible treatment modalities and a wide spectrum of clinical outcome. Treatment decisions and prognostic expectations hinge on accurate and precise staging, and the recently published American Joint Committee on Cancer (AJCC) Staging Manual, 8th edition, should be the basis for staging of urinary bladder tumours. It is unfortunate that the International Union Against Cancer (UICC) 8th edition failed to incorporate new data which is considered in the AJCC 8th edition. Thus, the AJCC 8th edition is the focus of this review. Several critical changes and clarifications are made by the AJCC 8th edition relative to the 7th edition. Although the most obvious changes in the 8th edition are in the N (i.e. perivesical lymph node involvement now classified as N1) and M (i.e. M1 is subdivided into M1a and M1b) categories, several points are clarified in the T category (e.g. substaging of pT1 should be attempted). Further optimisation, however, is required. No particular method of substaging pT1 is formally recommended. In this review, these modifications are discussed, as well as points, which require further study and optimisation.

Dataset for reporting of carcinoma of the urethra (in urethrectomy specimens): recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organisation sponsored by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the American Society of Clinical Pathology and the Faculty of Pathology, Royal College of Physicians of Ireland. Its goal is to produce standardised, internationally agreed-upon, evidence-based datasets for cancer pathology reporting throughout the world. This paper describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of carcinoma of the urethra in urethrectomy specimens. The dataset is composed of 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are based on a review of the most recent evidence and supported by explanatory commentary. Fourteen required elements and eight recommended elements were agreed by the international dataset authoring committee to represent the essential/required (core) and recommended (non-core) information for the reporting of carcinoma of the urethra in urethrectomy specimens. Use of an internationally agreed, structured pathology dataset for reporting carcinoma of the urethra (in urethrectomy specimens) will provide the necessary information for optimal patient management, will facilitate consistent data collection and will provide valuable data for research and international benchmarking. The dataset will be valuable for those countries and institutions that are not in a position to develop their own datasets.

Data set for the reporting of carcinoma of renal tubular origin: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. METHODS AND RESULTS: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: pre-operative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). CONCLUSIONS: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations.

Update of the International Consultation on Urological Diseases on bladder cancer 2018: non-urothelial cancers of the urinary bladder.

PURPOSE: To provide a comprehensive update of the joint consultation of the International Consultation on Urological Diseases (ICUD) for the diagnosis and management of non-urothelial cancer of the urinary bladder. METHODS: A detailed analysis of the literature was conducted reporting on the epidemiology, etiology, diagnosis, treatment and outcomes of non-urothelial cancer of the urinary bladder. An international, multidisciplinary expert committee evaluated and graded the evidence according to the Oxford System of Evidence-based Medicine modified by the ICUD. RESULTS: The major non-urothelial cancers of the urinary bladder are squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors. Several other non-urothelial tumors are rare but important to identify because of their aggressive behavior when compared to urothelial bladder tumors. Radical cystectomy and urinary diversion, preceded by neoadjuvant radiation or chemotherapy in some of these tumors, is the main method or treatment for resectable disease. Adjuvant therapy is not usually successful and no novel targeted or immunotherapeutic agents have been identified to provide benefit. Patients with small cell neuroendocrine tumors of the bladder should be offered chemotherapy before surgery. Because non-urothelial cancers are usually locally advanced and/or metastatic at the time of diagnosis, 5-year survival is generally poor. CONCLUSIONS: Non-urothelial cancers of the urinary bladder are rare and mostly lack established protocols for treatment. The prognosis of most of these tumors is poor because they are usually advanced at the time of diagnosis. A multimodal treatment approach should be considered to improve outcomes.