Reassessment of p53 immunohistochemistry thresholds in invasive high grade bladder cancer shows a better correlation with TP53 and FGFR3 mutations.

FGFR3 mutations are frequently mutually exclusive of TP53 mutations in invasive high grade urothelial carcinoma (HGUC) and p53 immunohistochemistry is often used as a surrogate for TP53 mutations. A 10 % staining cut off has been used in HGUC for designation as p53 positive or negative however, a novel contemporary method we have previously proposed (0% or >50 % - abnormal vs.

1-49 % - wild type) has shown significant correlation with oncologic outcome as well. We aimed to compare how a ≥10 % vs. 0 % and ≥ 50 % cut off p53 assessment method correlates with TP53 and FGFR3 mutation status. Tissue microarrays created from three retrospective cohorts (two cystectomy cohorts (cohort A, n = 206 and cohort B, n = 91; one T1 transurethral resection cohort (cohort C, n = 47)) were stained with p53 and scored by two blinded reviewers using both p53 scoring schemes. 50 cases from cohort A were assessed for TP53 and FGFR3 mutation status using next generation sequencing and FGFR3 mutation status was separately assessed in cohorts B and C using SNaPshot methodology. 202 (58.7 %) and 142 (41.3 %) cases showed abnormal and wild type p53 staining, respectively. Using the 10 % cut off, 254 cases were positive (73.8 %) and 90 cases were negative (26.2 %). 27 (14.4 %) and 15 (30 %) assessed cases demonstrated FGFR3 and TP53 mutations, respectively; 19/27 FGFR3 mutated showed a wild type pattern of p53 expression while 15/15 TP53 mutated tumours showed an abnormal pattern of p53 expression. There was a significant correlation between the contemporary p53 scoring scheme and TP53 and FGFR3 mutations (p < 0.0001 and p = 0.002, respectively). Improved sensitivity, specificity, positive predictive value, and negative predictive value for TP53 mutation was also seen compared to the 10 % cut off; specifically, the sensitivity and negative predictive value were 100 %. These findings might be of clinical relevance in the era of precision medicine.

Pathology, research and practice. 2020 Aug 23 [Epub ahead of print]

Anjelica Hodgson, Bas W G van Rhijn, Sung Sun Kim, Colleen Ding, Rola Saleeb, Danny Vesprini, Stanley K Liu, George M Yousef, Theodorus H van der Kwast, Bin Xu, Michelle R Downes

Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada., Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, Anatomic Pathology, St Michael's Hospital, Toronto, ON, Canada; Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea., Li Ka Shing Knowledge Institute, Anatomic Pathology, St Michael's Hospital, Toronto, ON, Canada., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, Anatomic Pathology, St Michael's Hospital, Toronto, ON, Canada., Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre and University of Toronto, 2075 Bayview Avenue, Toronto ON M4N 3M5, Canada., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, Anatomic Pathology, St Michael's Hospital, Toronto, ON, Canada; Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Laboratory Medicine Program, University Health Network, Toronto, ON, Canada., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: .

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