Introduction
Pancreatic neuroendocrine neoplasms (pNENs) represent a heterogeneous group of malignancies characterized by diverse pathological features and clinical behaviors. The annual incidence is less than 1 per 100,000 individuals (1). PNENs predominantly arise sporadically; however, they may also develop in association with hereditary syndromes such as multiple endocrine neoplasia type I (MEN1) and von Hippel-Lindau (VHL) disease (2). PNENs account for approximately 2%-5% of all pancreatic neoplasms. These tumors originate from multifunctional pancreatic neuroendocrine stem cells (1, 3). The biological behavior, histological characteristics and clinical manifestations of PNENs are highly heterogeneous. These tumors can grow independently or aggressively and even metastasize at an early stage. Their biological characteristics may also change as the disease progresses (4).
Patients with G1 and G2 grade have a 10-year overall survival rate of 60-70%. Owing to the possibility of recurrence or metastasis of pNENs, the median survival of G3 patients is less than 2 years (5). Surgery is the main treatment for pNENs. The incidence of lymph node metastasis (LNM) in patients with nonfunctional pNENs with a maximum diameter ≤2 cm ranges from 17% to 27.3% (6, 7). The TNM stage of the tumor is correlated with LNM. In patients without distant metastases, tumor size and LNM strongly affect the prognosis and surgical approach (8). The routine dissection of lymph nodes increases the difficulty of surgery, prolongs the operation time and increases postoperative complications (9). To reduce patient pain and postoperative complications, it is necessary to fully evaluate LNM before surgery. Some researchers have reported that the tumor size, T stage and tumor grade are related to LNM (10).
Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) are noninvasive, rapid, easy-to-obtain and inexpensive indicators, that can reflect the balance of inflammation and immune activity in the body. They have been proven to be important indicators of prognosis and disease severity in a variety of tumors. These parameters have promising clinical applications (11–13).
MLR, an emerging biomarker that integrates the opposing roles of monocytes and lymphocytes, has garnered significant attention in oncology research. By quantifying the balance between these two key immune cell populations, MLR provides a dynamic reflection of the host’s immune status and its interaction with tumor biology. This biomarker has demonstrated significant predictive and prognostic value across a range of malignancies, including hepatocellular carcinoma, gastrointestinal stromal tumors, endometrial cancer, bladder cancer, and breast cancer (14). Notably, studies have shown that MLR not only serves as a baseline indicator of disease aggressiveness but also reflects changes in immune dynamics during treatment. For instance, in patients with hepatocellular carcinoma receiving locoregional therapy, elevated MLR levels at both baseline and relapse have been strongly associated with adverse outcomes, underscoring its utility in guiding therapeutic decisions and monitoring disease progression (15). As a noninvasive and cost-effective marker, MLR holds promise as a complementary tool in personalized cancer management. Further validation in large-scale prospective studies is warranted to fully establish its clinical utility across diverse cancer types and treatment modalities.
Some researchers have shown that hepatocellular carcinoma patients with a low MLR have longer recurrence-free survival (RFS) (15). MLR in adult lymphoma patients with peripheral lymph node enlargement is significantly greater than that in nonlymphoma patients. MLR is a good diagnostic marker for lymphoma (16).
When neuroendocrine cells are overactivated by chronic inflammation, they may develop atypical or neoplastic lesions (17).
NLR and PLR are independent factors that affect the prognosis of pNEN patients. A high NLR is often associated with poor prognosis (10, 13, 18, 19).
LNM is related to the prognosis of patients and influences the mode of surgery. Owing to the heterogeneity of pNENs, predicting LNM before surgery is valuable for guiding clinical treatment. Patients with the potential for LNM are screened, and lymph node dissection is recommended during tumor resection. However, there are limitations in deciding whether to perform lymph node dissection on the basis of only tumor size. More risk factors need to be revealed to comprehensively evaluate LNM to determine the appropriate timing for lymph node dissection.
Hence, we performed this retrospective study to explore the risk factors associated with LNM in patients with resectable pNENs in our center by analyzing clinical data, inflammatory markers, and pathological features.
Discussion
The incidence of pNENs is low, ranging from 0.1/100,000 to 0.48/100,000 (20). However, with improvements in diagnostic equipment, pathological classification systems, and physician knowledge, the incidence of pNENs in Europe, America, Japan, and China is increasing yearly (21), and an increasing number of studies have investigated the factors affecting the prognosis of pNENs. A previous literature review revealed that age, sex, race, tumor size, tumor marker levels, histological pathology, LNM and tumor stage are associated with the prognosis of pNENs. At present, LNM is considered one of the most important factors for poor prognosis (8, 22). Multiple studies based on the SEER database have shown that tumor location (pancreatic head), tumor grade, tumor size, T stage, Ki-67, vascular invasion and nerve invasion are associated with LNM. Patients with a higher risk of LNM have a worse prognosis (23, 24). Our study also revealed that tumor grade, tumor size, vascular invasion, nerve invasion, and bilirubin level were associated with LNM, and that tumor size was an independent risk factor for LNM, which was consistent with the results of previous studies based on databases. In our study, the level of bilirubin was associated with LNM. We speculate that tumors located in the head of the pancreas are more likely to compress the bile duct and cause increased bilirubin levels.
According to the National Cancer Database (NCDB) (2004-2014), in a retrospective study of 2664 patients with pNENs, 2132 patients underwent lymph node dissection, 28% of whom had lymph node metastases, and the overall survival time of patients with and without lymph node dissection was 152.8 and 147.3 months, respectively (p = 0.61) (25). Krampitz et al. reported no significant difference in 10-year overall survival between patients with and without LNM (26), however, neither study suggested that lymph node dissection should be routinely avoided in all pNEN patients. Obtaining an adequate and consistent nodal yield during surgery and pathology is essential for accurate staging.
Although well-differentiated, low-grade pNENs are often considered relatively indolent tumors, patients with LNM have a recurrence rate as high as 40% to 50% (27). The recurrence rate of patients with liver metastases after surgery is as high as 95% (28). Therefore, we should be cautious about detecting LNM.
Inflammatory molecular markers have been widely used in the diagnosis and prognosis of various tumors. Long-term inflammation can promote tumorigenesis, and various cells in the tumor microenvironment can also secrete a variety of inflammatory factors. The systemic inflammatory response is closely related to the occurrence, development and metastasis of tumors (29).
Lymphocyte infiltration within the tumor microenvironment serves as a prognostic indicator of robust antitumor immune responses. Accumulating evidence has demonstrated that tumors with dense lymphocyte infiltration are often associated with heightened immune surveillance and more effective immune-mediated tumor control. Low lymphocyte counts are associated with adverse clinical outcomes, suggesting a weakened immune response in the host. This may be explained by reduced numbers of CD4+ T cells, which are vital for tumor suppression and defence (30). Elevated lymphocyte counts in peripheral blood or tumor tissue are consistently correlated with improved overall survival and better clinical outcomes in patients with various malignancies. This relationship highlights the critical role of lymphocytes in orchestrating adaptive immune responses against cancer and their potential as biomarkers for stratifying patients on the basis of prognosis (13).
Monocytes, key components of the mononuclear phagocyte system during the innate immune response, have emerged as critical regulators in cancer initiation and progression (31). These cells exert immunosuppressive effects through the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and the secretion of key regulatory cytokines, such as interleukin-10 (IL-10), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-β (TGF-β), which collectively disrupt T-cell metabolism and function (32). By targeting critical metabolic pathways in T-cells, these signals not only suppress T-cell proliferation and activation but also induce a state of T-cell exhaustion or dysfunction, thereby undermining antitumor immunity. The accumulation of monocyte-derived macrophages and their immunosuppressive activity within the tumor microenvironment thus represent critical drivers of immune evasion and disease progression, highlighting their potential as therapeutic targets for restoring effective antitumor immune responses (33).
Increased monocyte numbers and decreased lymphocyte numbers in inflammatory diseases lead to an imbalanced MLR. Some studies have also shown that pNEN patients with a low MLR at baseline have a better prognosis, and that their MLR is an independent predictor of tumor recurrence (34, 35). Few studies have investigated the relationships between NLR, PLR, MLR and LNM. A study involving 95 patients with resectable pNENs revealed that RFS was greater in patients without LNM. The preoperative NLR level was an independent risk factor for LNM. A higher the NLR resulted in a higher the risk of LNM. PLR and MLR were not included (10). In our study, NLR and PLR were not associated with LNM, whereas MLR was a risk factor for LNM and had a predictive effect on LNM. The ability to predict the risk of LNM from tumor size alone was weaker than that of the multivariate combination.
The depletion of intratumoral lymphocytes compromises immune surveillance, directly contributing to enhanced tumor progression, recurrence, and metastasis. Conversely, monocyte-derived tumor-associated macrophages (TAMs) play a critical role in oncogenesis by promoting tumor invasion, angiogenesis, and immunosuppression, primarily through their polarization into M2 phenotype. A high MLR may be closely associated with postoperative recurrence. Therefore, MLR may help optimize treatment strategies, such as more aggressive early intervention or intensive follow-up (34).
The combination of the four significant factors—NEN grade, tumor size, monocyte-to-lymphocyte ratio (MLR), and vascular invasion—demonstrated superior predictive performance compared with any individual factor alone. Specifically, the AUC of the combined model was 0.898 (95% CI 0.815–0.981, P < 0.05), indicating that the integration of these factors significantly enhanced the ability of the model to discriminate between outcomes. While models with moderate AUC values may exhibit limited standalone predictive power, their clinical utility can be significantly amplified when they are integrated with established clinical indicators such as imaging findings or biomarkers. The results highlight the value of multimodal approaches in refining risk stratification and guiding personalized patient management.
Our study had several limitations. First, some selection biases may exist since our study was a retrospective single-center study. In the future, a multicenter study could be performed to verify our findings. Second, because of the low incidence of pNEN, the number of samples included in our study that met the inclusion criteria was limited. Lymph node dissection extent was based on surgeon judgment and preoperative assessment.