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      WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies

      research-article
      1 , , 2
      World Journal of Urology
      Springer Berlin Heidelberg
      Renal cell carcinoma, Pathology, Grading, Staging, Review

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          Abstract

          Purpose

          Pathological parameters assessed on biopsies and resection specimens have a pivotal role in the diagnosis, prognosis and management of patients with renal cell carcinoma (RCC).

          Methods

          A non-systematic literature search was performed, updated to January 2018, to identify key standards and controversies in the pathological classification, grading and staging of RCC.

          Results

          Although most RCCs exhibit characteristic morphology that enables easy categorisation, RCCs show considerable morphological heterogeneity and it is not uncommon for there to be difficulty in assigning a tumour type, especially with rarer tumour subtypes. The differentiation between benign and malignant oncocytic tumours remains a particular challenge. The development of additional immunohistochemical and molecular tests is needed to facilitate tumour typing, because of the prognostic and therapeutic implications, and to enable more reliable identification of poorly differentiated metastatic tumours as being of renal origin. Any new tests need to be applicable to small biopsy samples, to overcome the heterogeneity of renal tumours. There is also a need to facilitate identification of tumour types that have genetic implications, to allow referral and management at specialist centres. Digital pathology has a potential role in such referral practice.

          Conclusion

          Much has been done to standardise pathological assessment of renal cell carcinomas in recent years, but there still remain areas of difficulty in classification and grading of these heterogeneous tumours.

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          Most cited references106

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          Prognostic significance of morphologic parameters in renal cell carcinoma.

          The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
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            Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.

            Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.
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              Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.

              To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
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                Author and article information

                Contributors
                01223 216742 , anne.warren@nhs.net
                Journal
                World J Urol
                World J Urol
                World Journal of Urology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0724-4983
                1433-8726
                19 August 2018
                19 August 2018
                2018
                : 36
                : 12
                : 1913-1926
                Affiliations
                [1 ]ISNI 0000 0004 0383 8386, GRID grid.24029.3d, Department of Histopathology, , Cambridge University Hospitals NHS Foundation Trust, ; Cambridge, CB2 0QQ UK
                [2 ]ISNI 0000 0001 0721 1626, GRID grid.11914.3c, School of Medicine, , University of St Andrews, ; St Andrews, KY16 9TF UK
                Author information
                http://orcid.org/0000-0002-1170-7867
                http://orcid.org/0000-0001-9041-9988
                Article
                2447
                10.1007/s00345-018-2447-8
                6280811
                30123932
                9f21eafb-2e3d-47a1-8375-7b57cc6a3dd8
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 1 May 2018
                : 12 August 2018
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                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Urology
                renal cell carcinoma,pathology,grading,staging,review
                Urology
                renal cell carcinoma, pathology, grading, staging, review

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