Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme
A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5–10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with three-tiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff’s alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient’s age (> 65 vs ≤ 65), lymph node and/or distant metastasis, and the two-tiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multi-institutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.
KeywordsChromophobe renal cell carcinoma Kidney Mitosis Necrosis Prognosis Sarcomatoid differentiation The Cancer Genome Atlas (TCGA) Tumor grade
The authors thank the following individuals: Susanne Dettwiler and Fabiola Prutek (Department of Pathology and Molecular Pathology, University Hospital Zurich), Kazue Kobayashi, Ayako Maruyama, Naoyuki Yamaguchi (Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences), Chikashi Ikegame, Kanae Takahashi, Yukie Kawaguchi and Chiaki Yokoyama (Division of Pathology, Niigata University Medical & Dental Hospital) for their outstanding technical assistance; Aashil Batavia for critical manuscript reading (Department of Pathology and Molecular Pathology, University Hospital Zurich); Takahiro Tanaka, Nobutaka Kitamura (Clinical and Translational Research Center, Niigata University Medical & Dental Hospital) and Daisuke Tokita (Clinical and Academic Research Promotion center, Tokyo Women’s Medical University) for assistance with the statistical analysis; Toshio Takagi (Department of Urology, Tokyo Women's Medical University) for insightful discussions on clinical aspects.
RO and HM designed the research and wrote the paper. All authors acquired the data. RO, GM, AH, AC, DS, and HM analyzed and interpreted the pathological data. RO performed statistical analysis. All authors critically reviewed, edited, and approved the manuscript. RO and HM provided funding. HM supervised the study and is the guarantor of the study.
This work was supported in part by Niigata Foundation for the Promotion of Medicine (2015) to RO and the Swiss National Science Foundation grant to HM (No. S-87701-03-01).
Compliance with ethical standards
This study was approved by the institutional review board of each contributing institutions.
Conflict of interest
The authors declare that they have no conflict of interest.
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