Prognostic value of the systemic immune-inflammation index in patients with upper tract urothelial carcinoma after radical nephroureterectomy

Upper tract urothelial carcinoma (UTUC) accounts for 5–10% of urothelial carcinomas [1]. Though radical nephroureterectomy (RNU) with bladder cuff removal is the standard treatment of UTUC patients, the tumors were found to be invasive at diagnosis in 60% of cases [2]. The disease recurrence in the bladder or non-bladder sites is frequent [3]. Many studies have focused on the pre-, intra-, and postoperative prognostic factors of patients with UTUC after RNU [4‐7]. According to the European Association of Urology (EAU) Guidelines on UTUC, template lymphadenectomy, and perioperative platinum-based combination chemotherapy should be considered in patients with high-risk tumors [2]. Enhancing comprehension of prognostic factors and constructing a predictive model can facilitate the identification of patients at high risk of recurrence, thereby necessitating the implementation of more rigorous therapeutic and monitoring interventions.

Preoperative prognostic factors encompass various variables such as patient age, tobacco usage, tumor focality, tumor location, grade, hydronephrosis, and inflammation-related indicators, among others [6]. However, the accuracy of tumor pathological features obtained through uroscopy is limited [8]. Furthermore, preoperative ureteroscopy has been identified as a risk factor for intravesical recurrence (IVR) and has a negative impact on the prognosis of patients with UTUC after RNU [9, 10]. Additionally, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) pose challenges in detecting microscopic invasion and are inadequate for determining personalized treatment approaches [6, 11, 12].

Inflammation plays a contributing role in the initiation and advancement of various cancers [13]. Numerous inflammation- and immune-related factors have been identified as having prognostic value for oncological outcomes in patients with UTUC following RNU [7, 14], including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). Increased NLR, PLR, and LMR have been linked to a heightened risk of recurrence and poorer survival rates [15]. The systemic immune-inflammation index (SII), which is an integrated immune and inflammatory index derived from peripheral lymphocyte, neutrophil, and platelet counts, has been identified as an independent prognostic indicator in various cancer types such as gastric cancer, colorectal cancer, hepatocellular cancer, and lung cancer [16‐19]. A meta-analysis has demonstrated that a higher SII value is significantly associated with poorer survival outcomes in urological cancers, including prostate cancer and urothelial carcinoma [20].

The predictive efficacy of SII in patients with UTUC after RNU has been assessed in several studies. These studies have reported that a high SII is an independent predictor of poorer recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) [15, 21]. Additionally, an elevated SII is associated with an increased risk of muscle-invasive and non-organ-confined disease following RNU [15, 21]. Moreover, the SII has been shown to be a significant prognostic factor for bladder recurrence [11]. However, the prognostic significance of SII in relation to extra-urothelial recurrence (EUR) remains unexplored, and the potential correlation between tumor status and SII has not been thoroughly examined. This study aims to assess the predictive value of SII for survival outcomes and recurrence in patients with UTUC, investigate the association between tumor status and SII, and construct a predictive model based on significant prognostic factors.

Our study revealed that a high SII was a notable unfavorable prognostic determinant for OS and EUR in patients with UTUC after RNU. While certain factors such as tumor stage, tumor grade, and surgical margins have been associated with poor survival outcomes, these are typically assessed postoperatively using pathological specimens. In contrast, blood-based inflammation biomarkers can be conveniently obtained prior to surgery and aid urologists in making optimal clinical decisions for individual patients.

Inflammation and immune responses are critical components of tumor genesis, proliferation, invasion, and metastasis [22]. Inflammation-related indicators including SII, NLR, PLR, and LMR can reflect the situation of systemic inflammatory response and have been demonstrated to show prognostic value in in various malignancies [23‐26]. The inflammation, infection, and oncogene activation lead to the activation of transcription factors in tumors and stroma, which subsequently lead to the production of chemokines, cytokines, and prostaglandins and induce the recruitment of inflammatory cells [27]. The secretion of chemokines and cytokines in the circulation mediates alteration in distant sites and results in tumor-derived cytokines and growth factors secreted into the systemic circulation to mediate alteration in distant sites [13]. Through the production of growth factors (for example G-CSF and GM-CSF) and the production of inflammatory cytokines, including IL-6, IL-1β, and IL-17 (neutrophil diversity and plasticity in tumor progression and therapy), tumor cells and tumor niche regulate the development, maturation, and release from the bone marrow of neutrophils, which result in peripheral neutrophilia [28, 29].

Neutrophils have complex roles in tumor development and progression. The pro-tumor phenotype of tumor-associated neutrophils can support tumor growth via different mechanisms, including the promotion of genetic instability, tumor cell proliferation, angiogenesis, metastasis, and immunosuppression [30, 31]. High infiltration of tumor-associated neutrophils and peripheral neutrophilia has been reported to be associated with poor prognosis in many human tumors [32, 33]. It has also been reported that high NLR and increased peripheral blood neutrophil counts may be associated with a higher frequency of tumor-infiltrating neutrophils [34]. Peripheral neutrophils also contribute to tumor development, progression, and metastasis through a variety of mechanisms, including the promotion of angiogenesis, production of matrix metalloproteinases, and escorting of circulating tumor cells [35‐37].

Platelets play an important role in tumor progression. Paracrine secretion of IL-6 from tumor cells stimulates the production of thrombopoietin (TPO), resulting in megakaryopoiesis and platelet genesis and leading to a status of thrombocytosis and hypercoagulability known as Trousseau’s syndrome [38, 39]. Platelets can directly or indirectly interact with tumor cells and increase tumor progression by promoting proliferation, resisting cell death, inducing angiogenesis, activating invasion, establishing pre-metastatic microhabitats, and evading immune detection [40]. Elevated platelet counts have been reported to be associated with increased cancer risk at several sites [41].

Numerous studies have reported associations between elevated platelet counts and decreased disease-specific survival rates across various types of cancer [42]. In the context of cancer immune surveillance and resistance, lymphocytes play a crucial role in impeding the proliferation and growth of tumor cells through cytotoxic cell death. Conversely, the presence of T lymphocytes within the tumor microenvironment has been consistently linked to improved prognoses, highlighting their significant anti-tumor functionality [43, 44]. Lymphocytes inhibit the proliferation and growth of tumor cells by cytotoxic cell death in cancer immune surveillance and resistance. In contrast, lymphocytes have an important anti-tumor function, and infiltration of T lymphocytes in the tumor microenvironment was known to be correlated with better prognosis [43, 44]. CD8 + T cells contribute to direct tumor cell lysis and the production of cytotoxic cytokines. CD4 + Th1 cells assist cytotoxic T lymphocytes and impress tumor progression by the production of cytokines (for example, IFN-γ), Th17 cells, and Treg cells function in the anti-tumor process by activating cytotoxic lymphocytes or suppression of inflammation [45]. To summarize, neutrophils, platelets, and lymphocytes are crucial components in inflammation and immunity related to cancer. In UTUC, multiple system inflammation and immune-related indexes based on these factors have been developed to predict the prognosis of patients after RNU, including NLR, PLR, and LMR[7, 46‐48]. The SII, which incorporates the counts of neutrophils, platelets, and lymphocytes, offers a more comprehensive assessment of the host’s immune and inflammatory status compared to the aforementioned indicators [49].

For patients with UTUC after RNU, IVR and EUR can significantly decrease survival time. Therefore, the relative prediction model also aroused a great interest in recent years. To our knowledge, the present study is the first proposal to confirm that SII possesses predictive value for EUR among UTUC patients and construct a prediction model with SII included. In accordance with prior research, our findings indicated that urine cytology, eGFR, and tumor stage were independent prognostic factors for IVR [48]. Interestingly, SII was not associated with IVR from our results. Although Chen et al. reported elevated SII can predict bladder recurrence, some patients with a history of bladder cancer were included in their study [11]. We hypothesize that the observed disparity may be attributed to the heterogeneity of the study population, variations in baseline characteristics, inclusion of different variables, inadequate sample size, or statistical noise. Undoubtedly, further investigations involving larger sample sizes are imperative to establish reliable conclusions.

In addition, an examination was conducted to investigate the correlation between preoperative SII levels and invasion sites. The outcomes revealed a significant association between elevated SII levels and high tumor grade, as well as invasion in various anatomical locations including the mucosa, muscle, adipose tissue, and neural and vascular structures. These findings suggested a heightened invasiveness of tumors exhibiting elevated SII levels. Plausible mechanistic explanations for these observations involve tumor-induced inflammation and subsequent cytokine production, particularly IL-6 and IL-8, which are known to play a pivotal role in the epithelial-mesenchymal transition (EMT). Furthermore, the induction and maintenance of tumor EMT are facilitated by the presence of inflammation, thereby facilitating the advancement towards metastasis [50].

There are several limitations to the present study that should be acknowledged. Firstly, it is imperative to note that this study is retrospective and conducted within a single center, thus potentially limiting the generalizability of the findings due to the relatively small sample size. Secondly, the inclusion of only 11 patients with low-grade tumor grade necessitates further validation of the predictive capabilities of the models for clinical outcomes in patients with low tumor grade. Lastly, it is crucial to develop a more universally applicable threshold for SII, as the cutoff employed in this study may not be applicable across other studies.

Our study suggested that a high level of preoperative SII is associated with both worse OS and shorter EURFS in UTUC patients after RNU. We developed nomogram models for predicting the OS, IVR, and EUR of patients, respectively, and their discrimination, calibration, and clinical use were proved through internal validation.