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      Distinctive morphological and molecular features of urothelial carcinoma with an inverted growth pattern

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          Abstract

          Urothelial carcinoma with an inverted growth pattern (UC-IGP) is a peculiar entity within the spectrum of urothelial lesions. While efforts have been made over the last few decades to unravel its carcinogenesis and relationship with conventional urothelial carcinoma, the exact classification of inverted urothelial lesions is a matter of debate. The morphological features of UC-IGP pose several issues in differential diagnosis with other mostly benign lesions. Various techniques, including immunohistochemistry, UroVysion, and many molecular methods, have been employed to study the exact nature of this lesion. The aim of this review is to provide a comprehensive overview of the morphological and immunophenotypical aspects of UC-IGP. Moreover, we present and discuss the immunohistochemical and molecular markers involved in diagnosis and prognosis of UC-IGP lesions.

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          Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

          Nikolaus Schultz (2014)
          Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell cycle regulation, chromatin regulation, and kinase signaling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in miRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.
          Article 0 comments Cited 466 times – based on 0 reviews     Review now
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            HER2-targeted therapies — a role beyond breast cancer

            Do-Youn Oh, Yung-Jue Bang (2019)
            HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.
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              Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets

              Eugene K Cha, Aditya Bagrodia, Eugene Pietzak … (2017)
              Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes ( p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.
              Article 0 comments Cited 131 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Pathol Transl Med
                Journal ID (iso-abbrev): J Pathol Transl Med
                Journal ID (publisher-id): JPTM
                Title: Journal of Pathology and Translational Medicine
                Publisher: The Korean Society of Pathologists and the Korean Society for Cytopathology
                ISSN (Print): 2383-7837
                ISSN (Electronic): 2383-7845
                Publication date (Print): July 2021
                Publication date (Electronic): 14 June 2021
                Volume: 55
                Issue: 4
                Pages: 239-246
                Affiliations
                [1 ]Pathology Unit, University of Foggia, Foggia, Italy
                [2 ]Urology Unit, University of Foggia, Bonomo Teaching Hospital, Foggia, Italy
                [3 ]Urology and Renal Transplantation Unit, University of Foggia, Foggia, Italy
                [4 ]Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
                [5 ]Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
                [6 ]Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
                [7 ]Pathology Unit, Azienda Ospedaliera S. Maria di Terni, University of Perugia, Terni, Italy
                Author notes
                Corresponding Author: Francesca Sanguedolce, MD, PhD, Pathology Unit, University Hospital OO.RR., University of Foggia, Viale Pinto 1, 71122 Foggia, Italy Tel: +39-0881736315, Fax: +39-0881736334, E-mail: francesca.sanguedolce@ 123456unifg.it
                Author information
                http://orcid.org/0000-0001-7459-3521
                http://orcid.org/0000-0001-9285-9426
                http://orcid.org/0000-0002-0637-1481
                http://orcid.org/0000-0002-1152-3005
                http://orcid.org/0000-0002-7291-0316
                http://orcid.org/0000-0002-8733-9933
                http://orcid.org/0000-0001-8484-7871
                http://orcid.org/0000-0001-9841-7856
                http://orcid.org/0000-0002-4516-9040
                http://orcid.org/0000-0002-6609-6434
                http://orcid.org/0000-0002-1126-5368
                Article
                Publisher ID: jptm-2021-04-20
                DOI: 10.4132/jptm.2021.04.20
                PMC ID: 8353137
                PubMed ID: 34111910
                SO-VID: 885b3d76-f222-4e27-8af0-b499baf4bae9
                Copyright © © 2021 The Korean Society of Pathologists/The Korean Society for Cytopathology
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 4 March 2021
                Date revision received : 2 April 2021
                Date accepted : 20 April 2021
                Categories
                Subject: Review

                Keywords: urothelial carcinoma,inverted growth pattern,immunohistochemistry,molecular markers
                Data availability:
                Keywords: urothelial carcinoma, inverted growth pattern, immunohistochemistry, molecular markers

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