Mo1896 Recognition of the Null Staining Pattern Increases the Utility of p53 IHC in Barrett's Esophagus

Background: Mutation and/or deletion of p53, a cell cycle regulatory gene, is a promising biomarker for predicting the risk of neoplastic progression in Barrett's esophagus (BE). Although overexpression of p53 by immunohistochemistry (IHC) is a useful surrogate for point mutations, complete absence of p53 protein by IHC in neoplastic cells (null pattern) has recently been shown to be highly correlated with truncation and deletion mutations. This study was designed to evaluate p53 expression patterns in BE with and without dysplasia. Design: 2,817 biopsies with a diagnosis of BE with and without dysplasia that also had a p53 IHC stain performed between Jan 1, 2010 and Nov 12, 2012 were identified in the files of Miraca Life Sciences. This included 139 with high grade dysplasia (HGD), 274 with low grade dysplasia (LGD), 214 indefinite for dysplasia (IND) and 2190 negative for dysplasia (ND). IHC stains were classified as: wild type (WT, 1-15% nuclear staining throughout); point mutation pattern (PMP, foci with .50% nuclear staining); and null mutation pattern (NMP, foci with complete absence of nuclear staining). Results: Abnormal p53 IHC expression patterns were detected in 442/2,817 (15.7%) biopsies, including 372/442 (84.2%) with PMP, 57/442 (12.9%) with NMP, and 13/442 (2.9%) with both patterns in the same biopsy; 70 (15.4%) of the putative p53 mutations were NMP. The frequency of p53 mutation patterns increased with increasing grades of dysplasia (Figure 1). While both PMP and NMP were identified in cases with and (rarely) without dysplasia, NMP was disproportionately found in biopsies with HGD than LGD, IND, and ND (32/133, 24.1% vs. 38/309, 12.3%; p=0.0019). 133/139 (95.7%) of HGD had abnormal p53 IHC. Conclusions: p53 null staining pattern is readily identifiable, and accounts for 15.4% of all p53 mutations detectable by IHC in BE in our series. Recognition of the NMP increases the sensitivity of detection of p53 IHC mutation patterns in BE, and the vast majority of biopsies with HGD were found to have abnormal p53 IHC. These results suggest that, due to historical lack of recognition of the null pattern, the utility of p53 IHC as an adjunctive diagnostic and predictive marker in BE biopsies may be underestimated.