Real-world routine diagnostic molecular analysis for TP53 mutational status is recommended over p53 immunohistochemistry in B-cell lymphomas

Haan, L.M. de; Groen, R.A.L. de; Groot, F.A. de; Noordenbos, T.; Wezel, T. van; Eijk, R. van; Ruano, D.; Diepstra, A.; Koens, L.; Nicolae-Cristea, A.; Hartog, W.C.E. den; Terpstra, V.; Ahsmann, E.; Dekker, T.J.A.; Sijs-Szabo, A.; Veelken, H.; Cleven, A.H.G.; Jansen, P.M.; Vermaat, J.S.P.

doi:doi:10.1007/s00428-023-03676-6

Previous studies in patients with mature B-cell lymphomas (MBCL) have shown that pathogenic TP53 aberrations are associated with inferior chemotherapeutic efficacy and survival outcomes. In solid malignancies, p53 immunohistochemistry is commonly used as a surrogate marker to assess TP53 mutations, but this correlation is not yet well-established in lymphomas. This study evaluated the accuracy of p53 immunohistochemistry as a surrogate marker for TP53 mutational analysis in a large real-world patient cohort of 354 MBCL patients within routine diagnostic practice. For each case, p53 IHC was assigned to one of three categories: wild type (staining 1-50% of tumor cells with variable nuclear staining), abnormal complete absence or abnormal overexpression (strong and diffuse staining > 50% of tumor cells). Pathogenic variants of TP53 were identified with a targeted next generation sequencing (tNGS) panel. Wild type p53 expression was observed in 267 cases (75.4%), complete absence in...Show morePrevious studies in patients with mature B-cell lymphomas (MBCL) have shown that pathogenic TP53 aberrations are associated with inferior chemotherapeutic efficacy and survival outcomes. In solid malignancies, p53 immunohistochemistry is commonly used as a surrogate marker to assess TP53 mutations, but this correlation is not yet well-established in lymphomas. This study evaluated the accuracy of p53 immunohistochemistry as a surrogate marker for TP53 mutational analysis in a large real-world patient cohort of 354 MBCL patients within routine diagnostic practice. For each case, p53 IHC was assigned to one of three categories: wild type (staining 1-50% of tumor cells with variable nuclear staining), abnormal complete absence or abnormal overexpression (strong and diffuse staining > 50% of tumor cells). Pathogenic variants of TP53 were identified with a targeted next generation sequencing (tNGS) panel. Wild type p53 expression was observed in 267 cases (75.4%), complete absence in twenty cases (5.7%) and the overexpression pattern in 67 cases (18.9%). tNGS identified a pathogenic TP53 mutation in 102 patients (29%). The overall accuracy of p53 IHC was 84.5% (95% CI 80.3-88.1), with a robust specificity of 92.1% (95% CI 88.0- 95.1), but a low sensitivity of 65.7% (95% CI 55.7-74.8). These results suggest that the performance of p53 IHC is insufficient as a surrogate marker for TP53 mutations in our real-world routine diagnostic workup of MBCL patients. By using p53 immunohistochemistry alone, there is a significant risk a TP53 mutation will be missed, resulting in misevaluation of a high-risk patient. Therefore, molecular analysis is recommended in all MBCL patients, especially for further development of risk-directed therapies based on TP53 mutation status.Show less

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Real-world routine diagnostic molecular analysis for TP53 mutational status is recommended over p53 immunohistochemistry in B-cell lymphomas