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      The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol


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          On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel.


          In this Consensus Statement, the pathology panel of the International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RSTG) present the pathology and molecular biology protocol for Wilms tumours in the UMBRELLA SIOP-RTSG 2016 protocol.

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          Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study.

          Detailed histological analysis of 427 cases entered on the first National Wilms' Tumor Study revealed that lesions with foci of marked cytological atypism (anaplasia), and those composed predominantly of sarcomatous stroma, were associated with unfavorable outcome. Twenty-five patients had anaplasia, and 24 had sarcomatous lesions of which a total of 28 (57.1%) died of tumor. Three hundred and seventy-eight patients had tumors which showed neither of these features, and only 26 (6.9%) died of tumor. Seven of ten deaths due to tumor in patients diagnosed before two years of age were associated with sarcomatous lesions. Three sarcomatous patterns were recognized, of which one, designated "clear cell" sarcoma, had a predilection for bony metastases. Using criteria defined and illustrated in this paper it is possible to identify in advance those patients likely to do poorly using current therapeutic approaches.
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            Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol

            The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.
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              Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group.

              To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth National Wilms Tumor Study (NWTS-5). Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q. ResultsLOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04). Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.

                Author and article information

                Nat Rev Urol
                Nat Rev Urol
                Nature Reviews. Urology
                Nature Publishing Group UK (London )
                11 October 2018
                11 October 2018
                : 15
                : 11
                : 693-701
                [1 ]Department of Pathology, Sidra Medicine, Doha, Qatar
                [2 ]ISNI 0000 0001 1378 7891, GRID grid.411760.5, Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, , Wuerzburg University, ; Wuerzburg, Germany
                [3 ]ISNI 0000 0001 1378 7891, GRID grid.411760.5, Comprehensive Cancer Center Mainfranken, , Wuerzburg University, ; Wuerzburg, Germany
                [4 ]Princess Maxima Centre for Pediatric Oncology, Utrecht, Netherlands
                [5 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Department of Diagnostic Pathology and Laboratory Medicine, , Fondazione IRCCS Istituto Nazionale dei Tumori, ; Milan, Italy
                [6 ]ISNI 0000 0001 2308 1657, GRID grid.462844.8, Sorbonne Université, Department of Pathology, Hopitaux Universitaires Est Parisien, ; Paris, France
                [7 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Pathology, , Oslo University Hospital, Rikshospitalet, ; Oslo, Norway
                [8 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, , Fondazione IRCCS Istituto Nazionale dei Tumori, ; Milan, Italy
                [9 ]ISNI 0000000121901201, GRID grid.83440.3b, Great Ormond Street Institute of Child Health, , University College London, ; London, UK
                [10 ]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Kiel Paediatric Tumour Registry, Department of Paediatric Pathology, , University Hospital of Kiel, ; Kiel, Germany
                [11 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Department of Paediatric Oncology & Haematology, , Saarland University, ; Homburg, Germany
                Author information
                © The Authors 2018

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                Consensus Statement
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                © Springer Nature Limited 2018

                paediatric cancer,renal cancer,pathology,molecular biology


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