p53 null phenotype is a positive result in urothelial carcinoma in situ

The concept of a p53 null phenotype (complete loss of staining) is well-recognized in the gynecologic pathology literature, implicitly reflecting that this staining pattern represents a TP53 mutation. However, in the genitourinary pathology literature, a p53 null phenotype has only been addressed regarding the prognosis of invasive urothelial carcinoma, and not as a diagnostic biomarker for urothelial carcinoma in situ (CIS). Herein, 25 cases of urothelial carcinoma in situ [diagnoses made on hematoxylin and eosin (H&E) stained sections] showing null pattern p53 staining were retrieved from 22 different patients (16 males and 6 females, age range 52-85 years; average 69.6 years), most commonly showing large cell pleomorphic pattern morphology. One representative tissue block per case was selected for next-generation DNA sequencing (NGS). All 21 cases (100%) passing quality control for NGS showed at least 1 TP53 mutation (majority nonsense or frameshift mutations), including 3 cases with 2 mutations and 3 cases with 3 mutations. Three patients with multiple available samples harbored 1 or more shared TP53 mutations at 2 different time points, indicating clonality of the temporally distinct lesions. Additionally, 2 patients had an additional unique TP53 mutation at a later time point, suggesting intratumoral heterogeneity and/or temporal clonal evolution. While urothelial CIS remains an H&E diagnosis in most cases, a p53 immunostain may be useful in a subset of challenging cases. This study demonstrates that a p53 null phenotype represents an aberrant result in urothelial CIS with supportive molecular analysis showing a previously unknown level of complexity for TP53 mutations among these noninvasive lesions. Adequate recognition of the p53 null phenotype as a biologically supportive result, similar to strong and diffuse staining with p53, is important and may warrant a formal consensus statement for recommended p53 reporting (i.e., wild type versus aberrant or mutant).

Automated summary

This study reveals that the p53 null phenotype is associated with TP53 gene mutations in urothelial carcinoma in situ. The study also demonstrates the complexity of TP53 mutations, including clonality and heterogeneity, in urothelial carcinoma in situ.