Neutrophil-to-Lymphocyte Ratio Is Associated with Disease Progression in a Surveillance Cohort of Patients with Branch-Duct IPMN

1. Introduction

The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, with a 5-year overall survival rate of approximately 13% [1]. The incidence is rising at a rate of 0.5% to 1.0% per year, and PDAC is projected to become the second-leading cause of cancer-related mortality by 2030 [2]. The unfavorable prognosis of PDAC is largely driven by aggressive tumor biology and the asymptomatic nature of early disease, resulting in the majority of patients presenting with locally advanced or metastatic disease at diagnosis when curative surgical resection is no longer feasible [1,2]. Only 15–20% of patients present with resectable disease, underscoring the critical importance of identifying and monitoring precursor lesions before malignant transformation occurs [2,3].

Among the recognized precursors of PDAC, intraductal papillary mucinous neoplasms (IPMNs) represent the most common and clinically relevant entity. IPMNs are mucin-producing cystic neoplasms of the pancreatic ductal system, with a reported prevalence of 3–20% in the general population that increases with age [4]. The branch-duct subtype (BD-IPMN) is by far the most frequently encountered subtype, accounting for over 95% of IPMNs in clinical practice [5]. Although BD-IPMNs carry a lower risk of malignant transformation than main-duct IPMNs, the risk remains clinically relevant. Long-term surveillance studies have demonstrated cumulative incidences of high-grade dysplasia or invasive carcinoma of 3.3% at 5 years, 6.6% at 10 years, and up to 15% at 15 years [6]. Furthermore, patients with BD-IPMN have an approximately ninefold higher risk of developing pancreatic cancer than the age-matched general population [7]. With the increasing use of cross-sectional imaging, the incidental detection of BD-IPMNs has risen substantially, resulting in an increasing number of patients undergoing long-term surveillance [8,9]. Current management of BD-IPMN is guided by the 2024 revised International Association of Pancreatology (IAP) guidelines, known as the Kyoto guidelines [10,11]. These guidelines stratify patients according to the presence of worrisome features (WF) and high-risk stigmata (HRS). HRS, including obstructive jaundice, enhancing mural nodule ≥ 5 mm, main pancreatic duct (MPD) ≥ 10 mm, and suspicious or positive cytology, are considered indications for surgical resection [10,11]. WF such as cyst diameter ≥ 3 cm, MPD 5–9 mm, enhancing mural nodule < 5 mm, thickened cyst walls, abrupt change in MPD caliber with distal atrophy, lymphadenopathy, elevated CA 19-9, and cystic growth rate ≥ 2.5 mm/year, prompt further evaluation with endoscopic ultrasound and closer surveillance [10,12]. Despite these advances, the Kyoto guidelines have notable limitations. Their risk stratification relies predominantly on morphological imaging criteria, which are subject to interobserver variability and may not fully capture the biological behavior of individual lesions [13,14]. Validation studies have shown that the Kyoto model achieves only modest discrimination for high-grade dysplasia or invasive carcinoma, with reported AUC values as low as 0.62 in external cohorts [15]. Serum CA 19-9, the only routinely used serum biomarker incorporated in the guidelines, has limited sensitivity for early or low-volume disease [16,17]. Consequently, there is a recognized need for complementary, noninvasive, and readily accessible biomarkers that may improve risk stratification and inform surveillance strategies in patients with BD-IPMN [13,18].

The neutrophil-to-lymphocyte ratio (NLR) has emerged as one of the most extensively studied inflammation-based biomarkers in oncology. Derived from a routine complete blood count, NLR reflects the balance between pro-tumorigenic neutrophil-driven inflammation and anti-tumor lymphocyte-mediated immunity [19,20]. The biological rationale is well established: neutrophils promote tumor progression through angiogenesis, immune suppression, and extracellular matrix remodeling, while a relative lymphopenia reflects impaired adaptive anti-tumor immunity [21,22]. In the context of IPMN, several retrospective studies of surgically resected cohorts have demonstrated that elevated preoperative NLR is significantly associated with invasive carcinoma [23,24]. Additional studies have found that NLR can be used as a criterion to differentiate invasive from non-invasive IPMN [25,26]. However, the available studies have several important limitations, most notably their exclusive focus on surgically resected cohorts. This introduces an inherent selection bias toward higher-risk lesions, including main-duct or mixed-type IPMNs.

To date, no study has evaluated NLR in a dedicated surveillance cohort of patients with BD-IPMN. This study investigates whether NLR can serve as a dynamic biomarker of malignant progression and improve risk stratification during routine follow-up.

2. Materials and Methods

3. Results

4. Discussion

In this EUS-based surveillance cohort of patients with BD-IPMN, elevated NLR was significantly associated with disease progression, including the development of worrisome features (WF), high-risk stigmata (HRS), the need for pancreatic resection, and advanced histopathology. Moreover, NLR increased longitudinally in patients with progressive disease and was particularly associated with the development of cyst growth, cyst size ≥ 30 mm, and main pancreatic duct dilation. Patients with an NLR above the cohort median had a twofold increased risk of harboring progressive BD-IPMN, highlighting the potential value of NLR as a readily available biomarker for risk stratification during surveillance.

Importantly, the discriminatory performance of baseline NLR should be interpreted in the context of its modest magnitude. When analyzed as a continuous variable, baseline NLR showed limited and non-significant discrimination for subsequent disease progression in our analysis. Thus, although an NLR > 2.36 was associated with an approximately twofold increased risk of disease progression, the non-significant AUC indicates that NLR should not be regarded as a standalone predictive or diagnostic marker. Rather, our findings support its potential role as a complementary biomarker that may provide additional biological information alongside established imaging and clinical parameters. Prospective studies incorporating NLR into multivariable prediction models are required to determine whether it provides incremental prognostic value beyond established risk factors.

Neutrophils are the most abundant circulating leukocytes and have traditionally been regarded as short-lived effectors of innate immunity. However, it is now well established that neutrophils recruited into the tumor microenvironment, termed tumor-associated neutrophils (TANs), undergo functional reprogramming and can adopt a protumorigenic phenotype (N2) that actively promotes cancer development and progression [27,28,29]. In the context of pancreatic neoplasia specifically, TANs have been shown to facilitate tumor progression through several interconnected mechanisms: secretion of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), which drive angiogenesis and extracellular matrix remodeling; release of neutrophil elastase, which directly stimulates tumor cell proliferation; production of reactive oxygen species (ROS) that induce DNA damage and genomic instability; and suppression of cytotoxic CD8+ T-cell responses through arginase-1 secretion and upregulation of immune checkpoint molecules such as Nectin2 [30,31,32]. Furthermore, neutrophil extracellular traps (NETs), web-like chromatin structures released by activated neutrophils, have been shown to be substantially enriched within the PDAC tumor microenvironment, where they promote angiogenesis, stromal remodeling, and immune evasion [33,34]. A schematic overview of the underlying pathogenesis is shown in Figure 5.

Critically, these protumorigenic mechanisms involving neutrophils are not restricted to established invasive carcinoma but may already be active during the early stages of pancreatic neoplastic transformation. Myeloid cell infiltration, including neutrophils and myeloid-derived suppressor cells, has been observed surrounding early PanIN-I lesions, suggesting that an inflammatory microenvironment may develop well before the onset of invasive disease [32].

The NLR, as a peripheral blood marker, is thought to reflect this tumor-immune dynamic at the systemic level. The neutrophil count serves as a surrogate for the protumorigenic, proangiogenic, and immunosuppressive inflammatory response, while the lymphocyte count reflects the adaptive antitumor immune surveillance capacity [35]. An elevated NLR therefore captures a systemic immunological imbalance that favors tumor promotion over tumor suppression. This interpretation is supported by the observation in the present study that NLR increased longitudinally in patients with progressive disease, mirroring the temporal evolution of the local inflammatory microenvironment during the dysplasia-carcinoma sequence. Sugimachi et al. similarly reported that NLR was significantly higher in patients with high-grade or invasive IPMN during the year preceding surgery, suggesting that changes in NLR may accompany disease progression and could potentially provide a dynamic marker during surveillance [36]. The associations observed in the present study between elevated NLR and the development of cyst growth, cyst size ≥30 mm, and main pancreatic duct dilation are biologically plausible and align with current concepts of inflammation-driven pancreatic tumorigenesis. Neutrophil-derived mediators, including VEGF and MMP-9, promote angiogenesis, vascular permeability, and extracellular matrix remodeling, processes that may facilitate cyst expansion and progressive structural changes within the pancreatic parenchyma, including fibrosis, ductal remodeling, and alterations of the cyst wall and epithelial architecture.

Concurrently, the inflammatory microenvironment shaped by tumor-associated neutrophils and neutrophil extracellular traps can alter ductal epithelial homeostasis, promote mucin production, and contribute to ductal remodeling and dilation [31,33]. Importantly, these morphological alterations constitute established WF according to the Kyoto guidelines. Our findings therefore suggest that NLR may reflect the biological processes driving disease progression rather than simply serving as a marker of its radiographic manifestations.

In this context, NLR may represent a systemic surrogate marker of the inflammatory and immunological changes that precede the emergence of guideline-defined risk features. These observations may have important implications for clinical practice. Current surveillance strategies for BD-IPMN are largely driven by structural changes detected on imaging, with the appearance of WF frequently triggering intensified surveillance and invasive diagnostic procedures such as EUS. The present data suggest that longitudinal assessment of NLR could complement existing imaging-based approaches by providing a readily available measure of disease biology. In particular, a persistently increasing NLR may identify patients at heightened risk of progression before overt morphological changes become apparent. Such an approach would acknowledge that biological progression may precede radiographic progression and could enable earlier identification of high-risk lesions. Conversely, stable NLR values over prolonged follow-up may indicate biological stability and help identify patients at lower risk of progression. If validated in prospective studies, incorporation of NLR into surveillance algorithms could refine patient selection for EUS and other invasive diagnostic procedures, thereby improving individualized risk stratification while potentially reducing unnecessary interventions in selected low-risk patients.

While NLR is simple, inexpensive, universally available, and reproducible, making it an attractive candidate for integration into clinical risk stratification models [20,37], several inherent limitations must be acknowledged when interpreting its clinical significance in the context of BD-IPMN surveillance. First, NLR is a nonspecific marker of systemic inflammation and is influenced by a wide range of physiological, demographic, and environmental factors independent of the underlying pancreatic pathology. A large population-based analysis of 48,023 adults from the National Health and Nutrition Examination Survey demonstrated that sex, age, race/ethnicity, body mass index, marital status, physical activity, smoking history, and alcohol consumption are all independently associated with NLR magnitude [38]. In particular, smoking has a well-documented dose-dependent effect on NLR: cigarette smoking disproportionately increases neutrophil counts relative to lymphocytes, and NLR rises in a linear fashion with cumulative pack-years [39]. Importantly, smoking cessation has been shown to significantly reduce NLR in tandem with other inflammatory and oxidative stress markers [40]. Given that smoking is also an established risk factor for pancreatic malignancy, this represents a potential confounding pathway that is difficult to fully disentangle. Owing to the retrospective nature of the study, data on patients’ smoking status and the timing of their last cigarette prior to blood collection were not available.

Second, NLR is acutely elevated by intercurrent infections, sepsis, and any systemic inflammatory condition, all of which may be present incidentally at the time of routine blood sampling during surveillance [41,42]. Corticosteroid use, whether exogenous or endogenous, markedly alters NLR by simultaneously increasing neutrophil release from the bone marrow and marginated pool while inducing lymphocyte apoptosis and redistribution; even a single dose of moderate-dose corticosteroids can double the NLR within 24 h [43,44]. Furthermore, chronic comorbidities prevalent in the BD-IPMN surveillance population, including obesity, diabetes mellitus, cardiovascular disease, and chronic obstructive pulmonary disease, are each independently associated with elevated NLR through distinct inflammatory mechanisms [45,46,47].

Third, NLR shows significant circadian variation. Neutrophil counts in peripheral blood peak during the late afternoon, while lymphocytes reach their highest levels around midnight, driven by rhythmic cortisol and epinephrine release [48,49,50]. This diurnal fluctuation means that the timing of blood sampling can meaningfully influence NLR values, a variable that is rarely standardized in retrospective studies or routine clinical practice.

Further limitations should be considered as well. The relatively small patient cohort limits statistical power, particularly for analyses of NLR in specific WF, HRS, or histopathological subgroups. Additionally, the observed associations between NLR and disease progression were unadjusted. Due to the retrospective nature of the study and the lack of sufficiently complete information on relevant potential confounders, including smoking status, alcohol consumption, comorbidities, and medication use, multivariable analysis was not performed. Therefore, an independent association between NLR and disease progression cannot be established, and residual confounding cannot be excluded. Furthermore, the retrospective design introduces variability in surveillance intervals, clinical decision-making, and timing of laboratory assessments. Moreover, the development of a new WF does not necessarily reflect true malignant progression, especially given the very low number of patients who developed carcinoma. One possible explanation for these findings is the unusually high frequency of EUS surveillance in our cohort, with patients undergoing examinations on average every 7.5 months, even in the absence of WFs or HRS. Notably, the cohort also showed a high incidence of WFs, with 22.1% of patients developing at least one during follow-up. Given that only two cases of carcinoma occurred in the entire cohort, these data raise the question of whether the current definition of WFs should be reconsidered, or whether certain WFs should be weighted differently in risk assessment.

Consequently, while elevated NLR appears associated with disease progression, prospective studies are needed to validate its role in risk stratification and clinical management.

5. Conclusions

In this large EUS surveillance cohort of patients with BD-IPMN, elevated NLR was significantly associated with disease progression, including the development of worrisome features, high-risk stigmata, the treatment-indication of pancreatic resection, and advanced histopathology. Moreover, NLR increased over time in patients with progressive disease, suggesting that longitudinal NLR assessment may provide complementary information on disease activity during BD-IPMN surveillance.

Author Contributions

Conceptualization, F.J.H. and A.E.; formal analysis, F.J.H. and L.S.; investigation, F.J.H. and L.S.; writing—original draft preparation, F.J.H. and A.E.; writing—review and editing, P.E., D.R.Q., M.S., C.T.R., R.S., C.Z., M.A., B.K., A.K., S.S. and L.W.; supervision, O.C. and A.E. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the Medical Association Westfalen-Lippe (2026-067-f-S; 10 March 2026).

Informed Consent Statement

Any informed consent was waived by the institutional ethics committee due to the retrospective nature of the study and the exclusive use of previously collected, anonymized patient data.

Data Availability Statement

For all data requests, please contact the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research received no external funding.