Aberrant p53 immunohistochemical staining is uncommon in serrated epithelial change, regardless of association with dysplasia.

AIMS: Serrated epithelial change (SEC) in inflammatory bowel disease (IBD) is most commonly defined as hyperplastic polyp-like mucosal changes lacking morphological evidence of dysplasia, identified on random or non-targeted colon biopsies. While some SEC cases harbour molecular abnormalities (e.g., TP53 mutations or aneuploidy) and are associated with an increased risk of synchronous and/or metachronous neoplasia, often in the same colonic segment as SEC, most patients with SEC do not develop colorectal neoplasia. Whether SEC constitutes a true precursor lesion or relates to neoplasia through alternative mechanisms remains unclear.

METHODS AND RESULTS: We performed p53 immunohistochemistry on 112 SEC biopsies from two cohorts: 75 biopsies from 28 IBD patients who had synchronous/metachronous dysplasia (study group) and 37 biopsies from 28 IBD patients without a history of colorectal neoplasia (control SEC group). None of the SEC biopsies in the study group showed dysplasia on the stained slides. Additionally, we stained all 76 available colon biopsies from 20 IBD patients without a history of SEC or colorectal neoplasia (control IBD group). Nuclear staining intensity was graded as weak (1+), moderate (2+), or strong (3+), while the extent of staining was categorized as negative (<10%), patchy (10%-50%), or diffuse (>50%). Compared with the control SEC group, the study group was older at the time of first SEC diagnosis (mean age: 57 vs. 47 years, P = 0.006), more frequently had Crohn's disease (CD) (21% vs. 0%, P = 0.023), and had a longer disease duration (mean: 26 vs. 13 years, P < 0.001). Also, SEC in the study group was more often multifocal (68% vs. 14%, P < 0.001) and distributed throughout the entire colon rather than predominantly left-sided (P < 0.05). Regardless of association with synchronous/metachronous dysplasia, most SEC biopsies demonstrated weak or moderate p53 staining (>80% of biopsies or patients). There was no significant difference in p53 staining patterns, including the frequency of strong p53 staining, between the study and control SEC groups (P > 0.05). While the combined SEC group showed a significantly higher frequency of moderate p53 staining (71% of biopsies vs. 13%, P < 0.001) and a lower frequency of weak p53 staining (17% of biopsies vs. 79%, P < 0.001) compared with the control IBD group, the frequency of strong p53 staining was similar between the two groups (13% of biopsies in the combined SEC group vs. 8% in the control IBD group, P = 0.315).

CONCLUSIONS: Although the absence of aberrant, strong p53 staining in most SEC cases, regardless of association with dysplasia, may argue against classifying SEC as a form of dysplasia potentially driven by TP53 alterations, it does not fully exclude a potential precursor role for SEC in a subset of cases. This finding also suggests that p53 immunohistochemistry may have limited clinical value for risk stratification of SEC. However, given its association with neoplasia in the same colonic segment and documented molecular abnormalities in some cases, a careful follow-up colonoscopy may be warranted following a new SEC diagnosis. This may be particularly important for patients with additional risk factors such as older age (>50 years), longer disease duration (>20 years), CD, or multifocal SEC.