Aberrant p53 overexpression in benign colon biopsies may predict dysplasia risk in patients with primary sclerosing cholangitis and inflammatory bowel disease.

aimsPatients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), collectively termed PSC-IBD, have an increased risk of developing nonconventional and/or invisible colorectal dysplasia, particularly in the right/proximal colon, compared with patients with IBD alone. PSC-IBD patients are also more likely to exhibit abnormal DNA content (e.g. aneuploidy or an elevated 4N fraction) in the right/proximal colon, often preceding the detection of dysplasia. We therefore hypothesized that PSC-IBD patients who subsequently develop colorectal dysplasia may frequently demonstrate aberrant p53 immunohistochemical staining in histologically benign colon biopsies, particularly from the right/proximal colon, obtained prior to dysplasia detection. METHODS AND

resultsp53 immunohistochemistry was performed on 91 benign colon biopsies from 25 PSC-IBD patients obtained during the surveillance colonoscopy immediately preceding the procedure at which dysplasia was detected (mean interval: 20 months) (dysplasia group). As controls, p53 staining was performed on 76 benign colon biopsies from 20 IBD patients (10 PSC-IBD and 10 IBD-only) without a history of colorectal neoplasia. Nuclear staining intensity was graded as weak (1+), moderate (2+) or strong (3+), and staining extent was categorized as negative (<10%), patchy (10%-50%) or diffuse (>50%). Aberrant p53 overexpression was defined as strong nuclear staining in ≥10% of epithelial cells (patchy or diffuse). These results were compared with previously reported DNA flow cytometric findings from the same samples. Aberrant p53 overexpression was significantly more frequent in the dysplasia group than in controls (20% vs. 3% per biopsy, P < 0.001; 36% vs. 5% per patient, P = 0.027). Conversely, weak p53 staining was more common in controls (79% vs. 44% per biopsy, P < 0.001; 65% vs. 28% per patient, P = 0.013). Concordance between abnormal DNA content and aberrant p53 overexpression was 19% at the biopsy level and 42% at the patient level. Both aberrant p53 overexpression (72%) and abnormal DNA content (67%) were more frequently localized to the right/proximal colon. For predicting subsequent dysplasia, aberrant p53 overexpression demonstrated a sensitivity of 36%, specificity of 95%, positive predictive value (PPV) of 90% and negative predictive value (NPV) of 54%. Abnormal DNA content showed a sensitivity of 48%, specificity of 95%, PPV of 92% and NPV of 59%. When both markers were used together, sensitivity increased to 64%, with a specificity of 90%, PPV of 89% and NPV of 67%.

conclusionsPSC-IBD patients who subsequently develop colorectal dysplasia exhibit a significantly higher frequency of aberrant p53 overexpression in benign colon biopsies, particularly from the right/proximal colon, obtained prior to dysplasia detection compared with IBD patients who do not develop dysplasia. These findings suggest that aberrant p53 overexpression in benign colon biopsies may help identify PSC-IBD patients at increased risk for colorectal dysplasia.