The ubiquity of imaging has increased pancreatic cysts detection. The Kyoto pancreatic cyst guidelines include concerning characteristics such size > 3 cm, mural nodule, and dilated main pancreatic duct. Mucinous pancreatic cysts are potentially malignant neoplasms. GNAS and K-ras mutations have demonstrated good specificity for pancreatic lesions but sensitivity remains limited. Repetitive FNAs (fine needle aspiration) could increase this specificity by analyzing cysts’ DNA fluid longitudinally. We retrospectively analyzed patients who underwent pancreatic resections to assess their precursor cysts for their CEA and DNA.

We performed a retrospective review of patients with pancreatic cysts who underwent multiple EUS with FNA from 2012-2024 at a single tertiary care center. Aspirated cyst fluid was analyzed using the molecular pathology test PancraGen. DNA transformation was defined as presence of GNAS and KRAS from previous negative DNA analysis. Odds ratio was used for statistical analysis. Patients that ultimately underwent pancreatic resections were also specifically analyzed.

185 patients with pancreatic cysts underwent multiple EUS with FNA with a median of 4 (range 2 to 8). We observed GNAS and K-ras mutations at initial FNA in 22 patients (11.9%) with DNA transformation following serial EUS with FNA in 35 patients (18.9%). Among 82 patients with CEA > 192 ng/ml, 11 patients (13.4%) had GNAS and K-ras mutations at initial FNA with DNA transformation in 24 patients (29.3%). In contrast, among 103 patients with CEA < 192 ng/ml, only 11 patients (10.7%) had GNAS and K-ras mutations at initial FNA with DNA transformation in 24 patients (23.3%; OR: 3.46, p < 0.05). 33 patients (40.2%) underwent pancreatic resections. Surgical pathology revealed IPMN (intraductal papillary mucinous neoplasm) or MCN (mucinous cystic neoplasm) in 26 samples (78.8%) while 7 revealed serous pathology. 12 IPMN patients (46.2%) had KRAS mutations, but specificity of IPMN with positive KRAS mutations was 100%. None of the IPMN patients had GNAS mutations.

GNAS and K-ras mutations can transform across repetitive EUS with FNA particularly when CEA is greater than 192 ng/ml. These findings can validate serial cyst surveillance by EUS with FNA in selected patients. The specificity of K-ras was 100% in IPMN surgical pathologies.