The role of molecular analysis in the diagnosis and surveillance of pancreatic cystic neoplasms.

Abstract

Context: Molecular analysis of pancreatic cyst fluid obtained by EUS-FNA may increase diagnostic accuracy. We evaluated the utility of cyst-fluid molecular analysis, including mutational analysis of K-ras, loss of heterozygosity (LOH) at tumor suppressor loci, and DNA content in the diagnoses and surveillance of pancreatic cysts.

Methods: We retrospectively reviewed the Columbia University Pancreas Center database for all patients who underwent EUS/FNA for the evaluation of pancreatic cystic lesions followed by surgical resection or surveillance between 2006-2011. We compared accuracy of molecular analysis for mucinous etiology and malignant behavior to cyst-fluid CEA and cytology and surgical pathology in resected tumors. We recorded changes in molecular features over serial encounters in tumors under surveillance. Differences across groups were compared using Student's t or the Mann-Whitney U test for continuous variables and the Fisher's exact test for binary variables.

Results: Among 40 resected cysts with intermediate-risk features, molecular characteristics increased the diagnostic yield of EUS-FNA (n=11) but identified mucinous cysts less accurately than cyst fluid CEA (P=0.21 vs. 0.03). The combination of a K-ras mutation and ≥2 loss of heterozygosity was highly specific (96%) but insensitive for malignant behavior (50%). Initial data on surveillance (n=16) suggests that molecular changes occur frequently, and do not correlate with changes in cyst size, morphology, or CEA.

Conclusions: In intermediate-risk pancreatic cysts, the presence of a K-ras mutation or loss of heterozygosity suggests mucinous etiology. K-ras mutation plus ≥2 loss of heterozygosity is strongly associated with malignancy, but sensitivity is low; while the presence of these mutations may be helpful, negative findings are uninformative. Molecular changes are observed in the course of cyst surveillance, which may be significant in long-term follow-up.