Next-generation sequencing improves diagnostic accuracy of imaging and carcinoembryonic antigen alone for pancreatic cystic neoplasms.

Background: New tools are needed to determine the pancreatic cysts that require surgical resection. This study aimed to evaluate whether next-generation sequencing (NGS) is useful for identifying mucinous, malignant, or pre-malignant cysts leading to surgery.

Methods: Laboratory, cytological, and histological data from 97 patients with worrisome features on imaging or an unclear pancreatic cystic lesion (PCL) who were indicated for further investigation and who underwent endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) between 2018 and 2022 were analyzed. A multidisciplinary team evaluated MRI, CT, EUS-FNA, and NGS findings.

Results: Among the 40 mucinous cysts, 53 % had KRAS and/or GNAS mutations, yielding a sensitivity of 53 % and specificity of 92 % compared to 33 and 100 % for cytology and 53 and 89 % for cystic fluid CEA. Combining NGS findings with CEA levels increased sensitivity and specificity in detecting mucinous lesions to 78 and 87 %, respectively. Surgically treated high-grade dysplasia PCLs did not show worrisome mutations in cyst fluid, while 80 % of the malignant lesions had mutations typical for advanced lesions. The advanced neoplasias showed 95 % specificity for worrisome gene mutations, with the highest diagnostic accuracy observed for NGS mutations, achieving an AUC of 0.777 in the ROC curve analysis compared to 0.631 for CEA. Patients with worrisome gene mutations were offered surgical treatment. NGS results contributed to the decision to operate in 11 out of 23 cases. In 71 % of all cases, NGS supported the diagnosis, with 3 % false positives and 12 % false negatives.

Conclusions: NGS analysis of pancreatic cyst fluid demonstrates high specificity and may serve as an additional diagnostic tool to CEA. Combining cystic fluid CEA and NGS increases the accuracy in determining whether a lesion is mucinous and NGS showed a higher diagnostic accuracy in advanced lesions compared to CEA. While the absence of alarming NGS findings should not preclude surgical treatment, patients with alarming mutations should be considered for surgery.