The Role of Genetic, Metabolic, Inflammatory, and Immunologic Mediators in the Progression of Intraductal Papillary Mucinous Neoplasms to Pancreatic Adenocarcinoma

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TL;DR

Intraductal papillary mucinous neoplasms (IPMN) are benign pancreatic cysts that can progress to pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer-related mortality. This review summarizes the genetic (KRAS, GNAS, RNF43, TP53, CDKN2A, SMAD4), metabolic (altered glucose and lipid metabolism, Warburg effect), inflammatory (elevated NLR, CAR, PGE2), and immunologic (Treg infiltration, CAF activation, immune evasion) changes driving IPMN-to-PDAC progression. Clinically, these findings may enable better risk stratification to reduce the nearly 50% rate of unnecessary surgical resection for low-grade IPMNs.

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**Background:** Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the US and is projected to become the second most common cause of cancer death by 2030. Early PDAC constitutes <15% of new diagnoses and is surgically resectable with better outcomes, but most patients present with advanced disease. Intraductal papillary mucinous neoplasms (IPMN) are the most prevalent cystic precursor lesions to PDAC. IPMNs are mucin-producing cysts arising from main pancreatic duct (MD-IPMN) or branch ducts (BD-IPMN); MD-IPMN carries higher malignant risk. Four histopathological subtypes exist: gastric (49–63%), intestinal (18–36%), pancreaticobiliary (7–18%), and oncocytic (1–8%). Gastric is most common but rarely progresses, while pancreaticobiliary is associated with aggressive PDAC. Current management relies on surgical resection of high-risk lesions based on imaging and clinical features, but nearly 50% of resected IPMNs have only low-grade dysplasia, indicating substantial overtreatment. This review examines genetic, metabolic, inflammatory, and immunologic mechanisms underlying IPMN progression to PDAC.

**Methods:** The authors conducted a narrative review of the literature, synthesizing findings from whole exome sequencing studies, metabolomic analyses (nuclear magnetic resonance, liquid chromatography mass spectrometry, gas chromatography mass spectrometry), immunohistochemical studies, and clinical biomarker investigations. Key studies reviewed include Noe et al.'s whole exome sequencing of IPMNs and MCNs, Hong et al.'s methylation-specific droplet-digital PCR panel, and multiple studies on cyst fluid and serum biomarkers.

**Key Results:** Genetic alterations: KRAS mutations occur in 50–80% of IPMNs (most commonly G12D), and GNAS mutations in 40–70% of lesions (most commonly R201H or R201C). KRAS and/or GNAS mutations are found in >90% of IPMNs. RNF43 mutations occur in 10–75% of IPMNs. TP53, CDKN2A, and SMAD4 mutations occur at lower rates in low-grade dysplasia but increase with advanced neoplasia. Novel mutations identified by whole exome sequencing include ATM (17% of lesions) and GLI3 (8% of samples). Aberrant CpG island methylation occurs in >80% of IPMNs, with increasing methylation levels correlating with dysplasia grade. A seven-gene methylation panel (SOX17, BNIP3, FOXE1, PTCHD2, SLIT2, EYA4, SFRP1) stratified high-grade vs. low-grade cystic lesions with 79.8% to 83.6% accuracy. Metabolic alterations: GLUT-1 expression was absent in low-grade dysplasia but detected in 60% of high-grade IPMNs. Lipidomic pathway activity (phospholipid biosynthesis, beta-oxidation, fatty acid metabolism) was markedly elevated in IPMN cyst fluid compared to benign serous cystic neoplasms. Triacylglycerol classes differed significantly between high-grade and low-grade dysplasia in both plasma and cyst fluid. ApoA2 outperformed CA19-9 in differentiating low- from high-grade dysplasia. PGE2 concentrations in cyst fluid correlated with dysplasia grade independent of NSAID use, diabetes, pancreatitis, or cyst size. Inflammatory markers: Elevated neutrophil-lymphocyte ratio (NLR) differentiated IPMN-associated invasive carcinoma from noninvasive disease but was suboptimal for differentiating dysplasia grades. CRP-to-albumin ratio (CAR) was an independent predictor of advanced neoplasia. Serum ferritin showed similar predictivity to CA19-9. Immune modulation: CD8+ lymphocytes are sequestered in peritumoral compartments while Tregs infiltrate the neoplasm. Th1-polarized CD4+ cells decrease relative to Th2-polarized cells with advanced dysplasia. Cancer-associated fibroblasts (CAFs) increase from low-grade to high-grade IPMN. Inflammatory CAFs (iCAFs) were identified only in invasive carcinoma, while myofibroblastic CAFs (myCAFs) were present even in low-grade lesions. Activated pancreatic stellate cells (PSCs) show increased alphaSMA, periostin, and galectin-1 expression in high-grade vs. low-grade dysplasia.

**Clinical Implications:** Current risk stratification using imaging characteristics, EUS morphology, and cyst fluid CEA/cytology has <50% accuracy. Novel technologies including EUS-guided needle-based confocal endomicroscopy (EUS-nCLE), cyst fluid next-generation sequencing (NGS), and through-the-needle biopsy (TTNB) offer improved diagnostic accuracy. Liquid biopsy approaches—circulating cell-free DNA analysis detecting KRAS and GNAS mutations, and extracellular vesicle MUC5AC levels—show promise for non-invasive risk stratification. The immune phenotype of low-grade IPMNs that had already progressed at resection was similar to advanced neoplasia, suggesting immune surveillance attenuation occurs early and may enable clinical interception before progression to advanced neoplasia requires surgical resection.