Upper tract urothelial carcinoma (UTUC) is a rare and highly heterogeneous disease which accounts for approximately 5% of all urothelial malignancies (1, 2). In China, the figure may be even higher, accounting for 17.9% of urothelial cancers (3). The incidence of this disease varies in different regions. UTUC is more likely to invade surrounding tissues and metastasize due to the thin ureteral wall and abundant periductal lymph. Because of this, it has a poor prognosis and often has more aggressive biological characteristics, and its five-year survival rate is about only 60% (4). Radical nephroureterectomy (RNU) has been the main treatment option because of the absence of standardized clinical diagnosis and treatment guidelines. Despite timely completion of standard radical surgery, the outlook remains grim, as 22% to 47% of patients experience intravesical recurrence postoperatively (5). Thus, it is necessary to investigate biomarkers that can be monitored after RNU.

An increasing amount of studies have concentrated on the involvement of the immune system in every stage of cancer progression (6). Inflammation may lead to alterations in the levels of different cells associated with inflammation in the body, including leukocytes, erythrocytes, and thrombocytes. Blood markers of inflammation like platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR) have been utilized for assessing inflammation levels in the body and predicting the likelihood of recurrence and prognosis in urinary system cancers (7–10). The systemic immune-inflammation Index (SII), a novel inflammatory marker, has gained increasing recognition and acceptance in recent times. It is determined by the formula SII = platelet count × neutrophil count/lymphocyte count. It has more excellent clinical value than previous inflammatory indicators because it simultaneously contains three kinds of peripheral blood cells. To date, there have been no published meta-analyses examining the effects of SII on the prognosis of UTUC. Hence, the objective of this research was to methodically examine the predictive importance of SII in individuals diagnosed with this condition.

Carcinogenesis is increasingly regarded as a function of the interaction between the tumor and the surrounding tumor microenvironment (TME) (19, 20). Increasing evidence suggests that the development of a tumor frequently signifies an imbalance in the body’s inflammatory immune response, with inflammation being intricately linked to the tumor. The presence of immune cells is crucial for speeding up the growth of tumors, the formation of new blood vessels, and the spread of cancer to other parts of the body through the stimulation of different cytokines. There has been emerging evidence that neutrophils are involved in cancer-related inflammation. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by neutrophil toxicity can lead to DNA damage and genetic instability (21), while neutrophils can further advance tumor growth through enzyme release (22–24). Much literature has shown that platelets promote tumor progression and metastasis (25–27). By identifying tumor-associated antigens, T lymphocytes that infiltrate tumors can initiate immune responses against the tumor (28). Research has demonstrated that tumors with T cell inflammation are more responsive to immunotherapy (29).

The SII provides a more comprehensive measure of inflammation in the body than the previous indexes like PLR, NLR, and LMR. The body’s red blood cell, platelet, and lymphocyte levels are included in it. In the research on hepatocellular carcinoma, SII has been identified as a valuable prognostic marker for the first time (30). Subsequently, it has been verified that it has prognostic value in various tumors, and it is a novel marker with the advantages of simplicity and low price. Numerous past meta-analyses have indicated a correlation between SII and the outcome of cancerous growths, including tumors in the digestive system, urogenital system, lung, pancreas, breasts, and more (31–36). The initial meta-analysis of SII in individuals with UTUC examines its predictive value by pooling information from six studies involving 3911 participants. Despite the limited number of studies included, it is considered adequate considering the rare occurrence of UTUC. Furthermore, all the specimens analyzed in this research consisted of over 100 instances in order to minimize any potential disruptions. Our analysis systematically assessed the potential usefulness of SII in predicting clinicopathological characteristics and prognosis in patients with urinary cancer undergoing treatment with RUN. Our statistical analysis indicated that elevated levels of SII before surgery were more reliable indicators of worse survival results, such as reduced OS, CSS, and RFS, along with negative pathological characteristics like LVI (present vs absent), pT stage (pT≥3 vs < 3), and pN stage (N+ vs N0). Previous articles of the same type have reached similar conclusions (37).

According to the 2020 EAU guidelines, patients with UTUC should be divided into low-risk and high-risk groups according to whether the tumor is solitary, tumor size, tumor pathological grade, and whether there is metastasis on preoperative examination (2). In cases of high-risk UTUC, RNU with bladder excision remains the standard treatment (38). There are still some controversial problems in the clinical diagnosis and treatment of UTUC. Clinically, we usually perform lymph node dissection (LND) for patients with possible lymph node metastasis suggested by preoperative imaging or suspected lymph node metastasis found during surgery. Due to the lack of solid evidence and prospective randomized controlled studies, LND is still controversial. Some studies have shown that LND improves survival, even in patients with clinicopathological negative lymph nodes (39, 40). Some relevant studies have proved that ureteroscopic biopsy before radical nephroureterectomy may increase the risk of postoperative bladder recurrence (41–43). Due to this, computed tomography urography (CTU) has become a first-line examination method to diagnose UTUC, due to its high sensitivity and specificity (44, 45). However, for some atypical advanced UTUC, accurate preoperative diagnosis and clinical staging still face challenges.

Preoperative neoadjuvant chemotherapy and postoperative adjuvant therapy are hot topics in this field. Adjuvant chemotherapy (AC) is chemotherapeutic therapy commonly used to reduce tumor recurrence or metastasis after surgery in patients with malignant tumors. Neoadjuvant chemotherapy (NAC) is systemic chemotherapy before local treatment, such as surgery or radiation. For high-risk upper tract urothelial carcinoma, a growing body of data shows that patients receiving neoadjuvant chemotherapy (NAC) prior to RNU may benefit more (46, 47). A study based on National Cancer Database (NCDB) data from the United States shows that preoperative determination of the depth of a primary upper urinary tract tumor remains to be addressed and is a key factor in determining whether to implement NAC in patients with high-grade UTUC (48). Based on a meta-analysis, NAC was associated with statistically significant OS and CSS in all patients and in patients with locally advanced UTUC. AC was associated with improved metastasis-free survival and CSS patients with locally advanced UTUC. In contrast, the association between AC and OS was significant only patients with locally advanced UTUC (49).

In particular, this study further examined the relationship between SII and clinicopathological characteristics, and found that SII was associated with LVI (present vs absent), pT stage (pT ≥ 3 vs<3) and pN stage (N+ vs N0), indicating the potential value of SII in determining preoperative clinical staging and risk stratification. SII can be included in the prognostic model to increase the accuracy and provide more accurate clinical evidence support for NAC and AC treatment. We advocate that SII can be used as a clinical decision aid until a patient’s treatment is determined. Asian patients had more severe and graded diseases than other ethnic groups (49, 50). However, subgroup analysis in this study showed that race was not yet an independent predictor of survival.

This article still has the following limitations. First, this study included a small number of articles, only 7 cohorts of 6 studies, including 3911 patients. Second, among the six included studies, only one was from Europe and the United States, while the remaining five were from Asia, including Japan, China and Taiwan. Additionally, all included studies were retrospective. The above factors suggest that there may have been publication bias in this meta-analysis. We look forward to further improving the meta-analysis in more large-scale clinical studies.

According to a comprehensive analysis of all included articles, higher preoperative SII was independently associated with poorer survival outcomes and pathological changes. To some extent, SII can be used as a convenient, cheap and reliable prognostic marker for UTUC patients.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

ZY: Writing – original draft, Writing – review & editing. ZX: Writing – original draft, Writing – review & editing. JM: Writing – original draft, Writing – review & editing. PD: Funding acquisition, Project administration, Resources, Writing – review & editing. SW: Writing – review & editing. JL: Validation, Investigation, Writing – review & editing. YC: Writing – review & editing. YY: Conceptualization, Resources, Writing – review & editing.