Urothelial carcinomas are identified as malignant tumours that arise from the urothelial epithelium and may involve the bladder and upper urinary tract. As the most common malignancy of the urinary tract, BC accounts for 90%–95% of all urothelial carcinomas characterised by multiple, multifocal recurrences throughout the genitourinary tract. In China, the incidence of BC is increasing in men, although mortality is decreasing in both genders [16]. According to distinct clinical recurrence, progression and prognosis, BC is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Recently, most patients with BC have been diagnosed with NMIBC [4], and approximately 53% experience progression to life-threatening MIBC [17]. Given the very high recurrence rate, the prediction of recurrence is particularly important in NMIBC. According to the probabilities of recurrence and progression defined in the European Organisation for Research and Treatment of Cancer Genitourinary Cancer Group risk scoring system, patients were divided into low-, intermediate- and high-risk groups [4]. Given the extremely high recurrence and progression risk in NMIBC patients, the clinical management of high-risk NMIBC is identified to be challenging. Early detection of recurrences and accurate identification and prediction of the likely progression of tumours are especially vital. BCG followed by maintenance therapy remains the golden standard of care for high-risk patients [18].
Generally, tumour-related pathological factors such as tissue type, grade, stage and LVI have been used to predict recurrence, progression, metastasis and prognosis in a majority of cancer cases. However, this standard evaluation system ignores demographic and other clinical features, such as immune and inflammatory status, which may contribute to its heterogeneity. Malnutrition is a common comorbidity and a consequence of the increase in inflammatory cytokines associated with cancer and metabolic alterations in most patients with malignant tumours [19]. Cancer malnutrition or cachexia, reflected by hypoalbuminemia and hyperlymphocytosis, is associated with increasing morbidity and mortality in patients with cancer [20,21]. In addition, several studies have shown that malnutrition is associated with recurrence and interferes with the patient’s response to cancer treatment [22, 23]. Albumin concentration and lymphocyte count, which are the common indicators of nutritional status, are important predictors of nutritional risk and postoperative complications. PNI, which is calculated using serum albumin concentration and absolute lymphocyte count, is considered an essential predictive indicator of different types of human cancers [24,25,26]. As a hallmark of cancer that fosters recurrence, progression and metastasis, tumour-associated systemic inflammation has been extensively reviewed in recent years [27]. Systemic inflammatory response (SIR) markers such as lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and derived neutrophil-to-lymphocyte ratio have been used to evaluate inflammatory responses and predict tumour prognosis in several types of malignancies, including urological cancer [28,29]. However, these inflammation-based markers integrated only two types of inflammatory cells. SII, which is based on neutrophil, platelet and lymphocyte counts, was first used in hepatocellular carcinoma and was considered a predictor of several types of solid tumours [12,13,30]. In this study, we investigated the preoperative nutrition- and inflammation-based factors, PNI and SII, in high-risk NMIBC patients who received intravesical instillation of BCG after TURBT. To the best of our knowledge, this is the first study to investigate the predictive values of PNI and SII for long-term RFS and the relationships of these indices, gender, age, smoking status, BMI, smoking status and pathological parameters with the RFS outcomes of high-risk NMIBC.
The optimal cut-off values of PNI and SII for predicting RFS outcomes vary across studies. Lee et al. [31] reported a PNI of 45 for follicular lymphoma, whereas Car et al. [32] reported a PNI of 46 as the optimum cut-off value for OS in patients with metastatic colorectal cancer. Additionally, Tang et al. [33] reported an SII of 463.56 for BC with total cystectomy. However, Akan et al. [34] determined an SII of 672.75 as cut-off value for high-risk NMIBC with intravesical instillation of BCG after surgery. Our PNI value was slightly higher than those in previous studies, whereas the SII value was similar to that of Tang et al. [33]. The difference could have been influenced by the different types of tumours, differences in risk group stratification and clinicopathological stages for BC, heterogeneous patient status and different statistical methods.
Preoperative nutrition- and inflammation-based indicators are reported to be associated with postoperative complication and tumour prognosis [35]. In our study, low PNI and high SII were to be associated with lower BMI, higher recurrence frequency, higher tumour number, larger tumour size, higher tumour grade, more advanced T stage, more common LVI and concomitant CIS, all indicating more aggressive tumour phenotypes. The results of our study were consistent with those of previously published reports [36,37,38]. However, no associations were found between PNI and gender or smoking status. Furthermore, no relationships between SII and gender, age or smoking status were found. These findings may have been affected by certain influential factors, such as the limited number of patients, a bias resulting from patient selection, differences in patients in terms of risk stratification and pathological stages of BC.
Our study identified several noteworthy findings. Significant correlations were made between PNI or SII and RFS in all 387 patients in this study. Lower PNI and higher SII were found to be related to worse RFS, whereas elevated PNI and decreased SII were independently associated with better RFS. In addition, univariate analysis demonstrated that PNI, SII, age, BMI, tumour number, tumour size, tumour grade, T stage, LVI and concomitant CIS were significantly associated with RFS. However, some results obtained varied from those of previous studies. No relationship between gender or smoking status and RFS was found in univariate analysis. Moreover, PNI, SII, tumour number, tumour size, tumour grade, T stage, LVI and concomitant CIS were significantly associated with RFS in multivariate analysis. Incidentally, we found that older age, which is significantly associated with BC, was not an independent predictor of RFS, which was inconsistent with previous studies [37,39]. From a mechanistic view, lower BMI may be related to the patients’ low nutritional status and decreased immune response. However, in this study, BMI was not an effective predictor of RFS. Contradictory results have been reported as to whether BMI can predict clinical outcomes for BC [40,41]. These results may be due to biases related to the limited patient pool, varying clinicopathological stages of patients and risk stratification.
According to the EAU Guidelines 2020, sub-stratifying high-risk group patients and identifying those who are at highest risk of disease progression based on prognostic factors are necessary. An analysis of the highest-risk NMIBC subgroup showed that low PNI and elevated SII were significantly associated with poorer RFS. Unfortunately, due to the limited number of patients who met the highest-risk NMIBC group criteria, evaluating the relative predictive factors by univariate and multivariate analyses was insufficient.
The mechanism by which low nutritional status and increased SIR influence the biological features of tumours was not sufficiently understood and thus need further study. The association between low PNI or elevated SII and poor RFS in high-risk NMIBC patients could be elucidated at the physiological level. Patients with low PNI and high SII often have hypoalbuminemia, lymphopenia, neutrophilia and thrombocytosis. Malnutrition, reflected by hypoalbuminemia, creates a favourable microenvironment for tumour recurrence [42]. In addition, a poor nutritional status leads to tumour progression through the suppression of adaptive immunity against cancer cells [43]. Although the causes of tumour-induced lymphocytopenia remain to be elucidated in detail, one potential reason is the enhanced lymphocyte apoptosis and impaired lymphocyte homeostasis in cancer [44]. As part of the inflammatory response, neutrophils play a fundamental role in generating high levels of reactive oxygen species, tumour necrosis factor-α and macrophage migration inhibitory factor [45]. It can also cause the secretion of large amounts of arginase, and nitric oxide, which results in the disorder of T cell activation and the production of vascular endothelial growth factor [46,47]. Elevated platelet counts could also stimulate tumour angiogenesis and protect tumour-related cells from cytolysis, which contributes to tumour recurrence and progression. Evidence suggests that circulating platelet–tumour cell aggregates may favour cancer metastasis development [48]. Furthermore, platelets induce tumour cells to form cytoskeletal connections, thereby promoting cancer migration [49].
This present study had several limitations. First, it was based on retrospective data from a single institution representing one region. Second, this study has a retrospective cohort design, which may have promoted selection bias during patient selection and data collection. Third, the assessment of other reported inflammation- and nutrition-based indicators, such as Glasgow Prognostic Score, Naples Prognostic Score, Controlling Nutritional Status score, Carlson Comorbidity Index, mid-upper arm muscle area, Dietary Inflammatory Index and C-reactive protein/albumin ratio were not included in this study. Fourth, although laboratory data were all collected before surgery, the timing of blood withdrawal was variable. Finally, the specificities of PNI and SII may not be high. Therefore, further prospective studies with external validation are needed to confirm the findings of this study.