Endoscopic Ultrasound-Guided Pancreatic Cystic Fluid Biochemical and Genetic Analysis for the Differentiation Between Mucinous and Non-Mucinous Pancreatic Cystic Lesions
Angelo Bruni et al.
Abstract
Pancreatic cystic lesions (PCLs) are increasingly identified via computerized tomography (CT) and magnetic resonance (MR), with a prevalence of 2–45%. Distinguishing mucinous PCLs (M-PCLs), which include intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) that can progress to pancreatic ductal adenocarcinoma, from non-mucinous PCLs (NM-PCLs) is essential. Carcinoembryonic antigen (CEA) remains widely used but often demonstrates limited sensitivity and specificity. In contrast, endoscopic ultrasound-guided measurement of intracystic glucose more accurately differentiates PCL subtypes, as tumor-related metabolic changes lower cyst fluid glucose in mucinous lesions. Numerous prospective and retrospective studies suggest a glucose cut-off between 30 and 50 mg/dL, yielding a sensitivity of 88–95% and specificity of 76–91%, frequently outperforming CEA. Additional benefits include immediate point-of-care assessment via standard glucometers and minimal interference from blood contamination. DNA-based biomarkers, including KRAS and GNAS mutations, enhance specificity (up to 99%) but exhibit moderate sensitivity (61–71%) and necessitate specialized, expensive platforms. Molecular analyses can be crucial in high-risk lesions, yet their uptake is constrained by technical challenges. In practice, combining glucose assessment with targeted molecular assays refines risk stratification and informs the choice between surgical resection or active surveillance. Future investigations should establish standardized glucose thresholds, improve the cost-effectiveness of genetic testing, and integrate advanced biomarkers into routine protocols. Ultimately, these strategies aim to optimize patient management, limit unnecessary interventions for benign lesions, and ensure timely therapy for lesions at risk of malignant transformation.
1. Introduction
Pancreatic cystic lesions (PCLs) are increasingly identified due to the widespread application of advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), with an estimated prevalence ranging between 2 and 45% of the general population [1]. These lesions exhibit a wide spectrum ranging from benign lesions, such as serous cystadenomas with minimal malignant potential, to premalignant and malignant entities, including mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) [2]. The accurate characterization of PCLs is clinically relevant due to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC), which has a reported five-year mortality rate of 89% [3,4]. Discriminating between lesions devoid of malignant potential and those that are premalignant or malignant remains critical to avoid overtreatment of benign cysts and to identify patients who require active surveillance or surgical resection [5,6]. A major challenge in this context is distinguishing between mucinous PCLs (M-PCLs) and non-mucinous PCLs (NM-PCLs), as most premalignant PCLs are mucinous [1,7,8]. Although, certain NM-PCLs, including cystic neuroendocrine tumors, solid pseudopapillary neoplasms, cystic metastatic epithelial neoplasms, and cystic ductal adenocarcinomas, also carry a substantial risk of malignant transformation [1,9,10,11].
Benign pancreatic lesions, such as pseudocysts and serous cystadenomas (SCNs), constitute 16–39% of all pancreatic cysts, with SCNs being almost universally benign [12]. Their prevalence increases when lesions are discovered incidentally during imaging performed for unrelated conditions [13,14].
Among the premalignant PCLs, MCNs and IPMNs are the most frequent diagnoses. MCNs demonstrate a malignancy risk ranging from 1–34%, whereas IPMNs show variable malignant potential depending on subtype: branch-duct IPMNs carry a 12–47% risk, and main-duct IPMNs present a higher risk of 38–68% [14,15]. Although malignant progression remains infrequent in the broader population of PCLs, the 5–10-year risk is estimated at approximately 5–8%, with the risk increasing for main-duct IPMNs and lesions exhibiting worrisome features such as mural nodules or a cyst size greater than 3 cm [3]. Current guidelines recommend endoscopic ultrasound (EUS) evaluation for PCLs that exhibit worrisome features on cross-sectional imaging, with fine-needle aspiration (FNA) for cyst fluid analysis, cytological assessment, and biochemical marker evaluation (Figure 1) [2,16].
Figure 1. Illustration of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of a pancreatic cyst with biochemical markers (CEA, CA19-9, and glucose) and DNA-based markers (KRAS, GNAS, VHL, CDKN2A, PIK3CA, SMAD4, and TP53).
