LAUSR

Background: Predicting malignancy in intraductal papillary mucinous neoplasm remains challenging. Integrated molecular pathology combines pancreatic fluid DNA and clinical factors into a malignant potential score. We sought to determine the utility of DNA components alone in predicting high‐grade dysplasia/invasive disease. Methods: We reviewed prospectively the records from 1,106 patients with intraductal papillary mucinous neoplasm. We excluded non‐intraductal papillary mucinous neoplasm cases and cases with definitive malignant cytology. A total 225 patients had 283 DNA profiles (98 followed by surgery, 185 followed by ≥23‐month surveillance). High‐grade dysplasia/invasive outcomes were high‐grade dysplasia, intraductal papillary mucinous neoplasm‐invasive, and adenocarcinoma on surgical pathology or mesenteric or vascular invasion, metastases, or biopsy with high‐grade dysplasia or adenocarcinoma during surveillance. Results: High‐quantity DNA predicted (P=.004) high‐grade dysplasia/invasive disease outcomes with sensitivity of 78.3%, but 52.7% specificity, indicating benign cases may exhibit high‐quantity DNA. High clonality loss of heterozygosity of tumor suppressor genes was 98.0% specific, strongly predicted high‐grade dysplasia/invasive disease but lacked sensitivity (20.0%). High‐quantity DNA+high clonality loss of heterozygosity had 99.0% specificity for high‐grade dysplasia/invasive disease. KRAS mutation alone did not predict high‐grade dysplasia/invasive disease, but, when combined with high‐quantity DNA (specificity 84.7%) and high clonality loss of heterozygosity (specificity 99.0%) strongly predicted high‐grade dysplasia/invasive outcomes. Conclusion: Certain DNA components are highly specific for high‐grade dysplasia/invasive disease and may indicate aggressive lesions, requiring resection when cytology fails.