Background
Clinical presentation, imaging, and endoscopic ultrasound (EUS) findings, as well as fluid analysis possess prognostic features for intraductal papillary mucinous neoplasms (IPMN); however, classification of IPMN-risk remains challenging^1,2. As a means for further distinguishing high-risk IPMNs, next-generation sequencing (NGS) allows for validation of cyst subtype and prognostic mutation analysis³.
The KRAS and GNAS pathways are often present in IPMNs when compared with non-mucinous cysts. Other changes, such as SMAD4 and TP53, portend higher-risk IPMN. However, the BRAF mutation, a Raf isoform involved in the Ras oncogene signaling, is a lesser-known entity in IPMNs^4,5. In this study, we evaluated features of BRAF positive (BRAF+) when compared to BRAF negative (BRAF-) IPMNs. We predicted BRAF+ IPMNs would possess variable features compared to BRAF- IPMNs.
Methods
A multicenter prospective cohort study at two tertiary care centers in the United States in which subject data was gathered into a data repository. Initial demographics, radiologic parameters, location, and high-risk features were obtained. All subjects underwent EUS-guided aspiration or biopsy (EUS-FNA/FNB) for cyst fluid analysis, NGS, and cytology.
Subject data was separated by BRAF+ v. BRAF- mutations, and continuous variables were analyzed using student's t-test, categorical variables, a one-tailed Fischer’s exact testing using SPSS software.
Results
From 2018-2023, 134 IPMNs, were identified (24 BRAF+, 110 BRAF-). The mean age of the BRAF+ group was 71.3 years, and 45.5% were women, no different than the BRAF- group. The baseline size of the BRAF+ was no different than the BRAF- [22.8 millimeters (mm) by 14.4 mm versus (v.) 24.3 mm by 18.1 mm], nor was the distribution of cyst location (Table 1).
Morphologically, there was a higher proportion of IPMNs with septae in the BRAF- v. BRAF+ group (47.3% v. 16.7%, p=0.008) and wall enhancement (26.4% v. 4.2%, p=0.02). More BRAF- subjects had pancreatic ductal (PD) dilation compared to BRAF+ patients (28.2% v. 8.3%, p=0.03). The BRAF- group was also more likely to present with weight loss (17.3%, p=0.02), worsening glycemic control (30.9%, p=0.007), and pain (38.2%, p=0.02), v. BRAF+ subjects. There was a difference in mean amylase levels detected within cyst fluid (p=0.03) and glucose (p=0.0001), but not CEA levels. There was no significant difference seen in high-grade IPMN or cancer in the BRAF- v. BRAF+ groups. GNAS was seen more often in BRAF+ subjects (p=0.02), KRAS less often (p=0.01)(Table 2).
Conclusions
BRAF+ IPMNs possess a lower proportion of symptoms, including weight loss, worsening glycemic control, and pain. Morphologically, BRAF+ IPMNs have lower proportions of septae, wall enhancement, and PD dilation, with lower amylase levels and KRAS+; however, the significance of these findings requires further investigation.

Jason Denbo

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