The Predictive Value of the Preoperative Systemic Inflammatory Response Indices in Non–Organ-Confined Disease in Upper Urinary Tract Urothelial Carcinoma

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J Urol Oncol. 2023;21(2):174-180

Publication date (electronic) : 2023 July 31

doi : https://doi.org/10.22465/juo.224400580029

Sung Kyung Choi¹, Chan Hoon Gwak¹, Jungyo Suh^,1, Bumjin Lim¹, Cheryn Song¹, Dalsan You¹, In Gab Jeong¹, Jun Hyuk Hong¹, Bumsik Hong¹, Choung-Soo Kim², Hanjong Ahn¹

¹Department of Urology, Asian Medical Center, Ulsan University College of Medicine, Seoul, Korea

²Department of Urology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea

Corresponding author: Jungyo Suh Department of Urology, Asian Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Email: uro_jun@amc.seoul.kr

Received 2022 November 2; Revised 2022 November 4; Accepted 2022 November 5.

Abstract

INTRODUCTION

Upper tract urothelial carcinoma (UTUC) is a rare urologic malignancy that arises from the urothelium of the upper part of the urinary tract, from the renal calyx to the ureter [1]. Because the muscle layer of the renal pelvis and ureter is thin, UTUC has a relatively higher risk of muscle invasion. About 50% of patients with UTUC have non–organ-confined (non-OC) disease at diagnosis [2]. Current golden standard treatment of patients with UTUC consists of radical nephroureterectomy (RNU) with bladder cuffing [3]. RNU shows good oncologic outcomes and prognosis in patients with early-stage UTUC; however, it is less effective in patients with non-OC disease because these patients have lower survival rates and require additional treatment [2, 3]. The evidence from the perioperative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) trial, The adjuvant chemotherapy became standard treatment [4]. However, neoadjuvant chemotherapy still has benefit from results in pathologic downstaging, and patients receiving neoadjuvant treatment plus RNU have lower disease recurrence rates than patients treated with RNU alone [5]. For this reason, the proper identification of UTUC patients at highrisk for non-OC disease before RNU is important for better patient management.

Several preoperative clinical parameters are predictive of advanced pathologic stage and lymph node metastasis in patients with UTUC [6]. These factors include patient age [7], hydronephrosis [8], tumor multifocality [9], tumor location [9], and some blood-based biomarkers [10]. Because of the similarity of immune system responses to cancer and infection [11], systemic inflammatory response indices (SII) can be accurate and cost-effective blood-based predictors of disease severity or poor prognosis. Previously identified indices include the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio. In addition, the C-reactive protein-to-albumin ratio (CAR) has recently emerged as a systemic inflammatory biomarker for oncologic outcomes and disease severity in several malignancies [12, 13]. CAR may be indicative of acute and chronic activation of the immune system, as well as chronic malnutrition, suggesting that it may provide benefit not provided by other SII [14]. The present study therefore determined whether preoperative SII, especially in CAR, can predict locally advanced or node-positive disease UTUC.

MATERIALS AND METHODS

2. Patient Selection and Cohort Follow-up Protocols

The medical records of patients who underwent RNU due to UTUC at single tertiary referral center between March 2010 and December 2020 were retrospectively reviewed. Patients with non-UC on final pathological examination and those who received neoadjuvant chemotherapy were excluded (Fig. 1). Within 1 month prior to RNU, all included patients underwent routine laboratory testing, including complete blood count and albumin levels, as well as computed tomography (CT) scans to evaluate the urinary system. Ureteroscopy with or without biopsy was not performed routinely but was dependent on whether visible tumors were detected on CT scans. Patients underwent lymph node dissection if they were clinically suspected of having nodepositive disease on CT scans or there was a high suggestion of non-OC disease from preoperative images [3].

Fig. 1.

Flow chart of patient selection for the study population. AMC, Asan Medical Center; UTUC, upper tract urothelial carcinoma.

RESULTS

1. Patient Characteristics

A review of medical records identified 711 patients who underwent RNU due to UTUC, without undergoing neoadjuvant chemotherapy, at the Asan Medical Center between March 2010 and December 2020 (Table 1). These 711 patients included 507 men (71.3%) and 204 women (28.7%), with a mean age of 68.6±9.9 years. Of these patients, 262 (36.8%) had non-OC disease, including 255 (35.9%) with locally advanced and 51 (7.2%) with node-positive disease. Moreover, 380 (53.4%) had tumors of the ureter, 122 (17.2%) had multifocal tumors, and 372 (52.3%) had hydronephrosis. These patients had a mean±standard deviation NLR, PLR, and CAR of 2.56±1.84, 139±62.5, and 0.23±0.75, respectively.

Table 1.

Baseline characteristics of the study population

4. Factors Predictive of Non–Organ-Confined Disease

Univariate analyses showed that hydronephrosis (odds ratio [OR], 1.63; 95% CI, 1.20–2.22; p<0.01), high NLR (OR, 1.80; 95% CI: 1.32–2.47; p<0.01), high PLR (OR, 1.73; 95% CI, 1.27–2.37; p<0.01), and high CAR (OR, 2.88; 95% CI, 2.04–4.08; p<0.01) were significantly predictive of non-OC disease. Multivariable analyses showed that hydronephrosis (OR, 1.46; 95% CI, 1.06–2.01; p=0.02), high PLR (OR, 1.45; 95% CI, 1.05–2.01; p=0.03), and high CAR (OR, 2.56; 95% CI, 1.79–3.66; p<0.01) were independent predictive markers of non-OC UTUC (Table 2).

Table 2.

Univariate and multivariate logistic regression analyses of factors associated with non–organ-confined disease

5. Factors Predictive of Locally Advanced Disease

Univariate analyses showed that hydronephrosis (OR, 1.67; 95% CI, 1.22–2.27; p< 0.01), high NLR (OR, 1.89; 95% CI, 1.38–2.59; p<0.01), high PLR (OR, 1.77; 95% CI, 1.29–2.42; p<0.01), and high CAR (OR, 2.79; 95% CI, 1.97–3.96; p<0.01) were significantly predictive of locally advanced disease. Multivariate model analysis found that hydronephrosis (OR, 1.50; 95% CI, 1.09–2.07; p=0.01), high PLR (OR, 1.49; 95% CI, 1.08–2.07; p=0.02), and high CAR (OR, 2.46; 95% CI, 1.72–3.52; p<0.01) were independent predictive markers of locally advanced disease (Table 3).

Table 3.

Multivariate logistic regression analyses of factors associated with locally advanced disease and node-positive disease

DISCUSSION

This study aimed to evaluate the predictive value of SII for non-OC disease in patients with UTUC. Univariate analyses showed level of SII and the preoperative hydronephrosis were significantly higher in patients with non-OC UTUC. The multivariate analysis showing that hydronephrosis, high PLR, and high CAR were independent predictive markers of non-OC disease. Moreover, sub-analyses showed that high CAR was predictive of both of locally advanced and node-positive disease.

Although POUT trial data confirmed the clinical role of adjuvant chemotherapy [4], decreased renal function after RNU affected on eligibility or regimen of adjuvant treatment [17]. Neoadjuvant chemotherapy has potential benefit than adjuvant chemotherapy, in the patients who has risks of renal function decline after RNU [18]. The prediction of the non-OC disease before RNU is clinically important, because these patients can benefit from neoadjuvant chemotherapy [19]. Many clinical, pathologic, and molecular biomarkers have been found to predict advanced stage and non-OC disease [6]. For example, older age was shown to be predictive of non-OC UTUC 7, as well as being prognostic of poor oncological outcomes. Although older age at diagnosis is associated with a higher incidence of advanced stage disease [2], the ability of age to predict non-OC UTUC remains uncertain. In this study, we also founded that patient age was not predictive factor for non-OC disease.

Recent technological advances in preoperative imaging have altered the clinical role of CT scanning for the diagnosis of UTUC and determining treatment plans [20]. A recent meta-analysis reported that the diagnostic performance of multidetector CT urography was excellent, with a pooled sensitivity of 92% (95% CI, 85%–96%) and a pooled specificity of 95% (95% CI, 88%–98%) [21]. Moreover, CT urography revealed specific tumor characteristics, including local invasiveness [22], hydronephrosis [8], and tumor location [20]. In this study, we founded hydronephrosis on CT scans was predictive factor of non-OC disease and locally advanced (pT3-4) disease.

The present study also found that tumor multifocality was predictive of node-positive disease. Tumor multifocality in pathologic specimen was associated with poor oncological outcome in organ confined UTUC [23]. Chromecki et al. [23] reported tumor multifocality, which defined by the presence of tumors in both of the ureter and pelvis, is associated with high grade tumor, tumor stage, lymph node metastasis, and survival. However, most studies defined tumor multifocality using pathologic specimens; thus, this definition is not suitable for the preoperative evaluation of disease aggressiveness. In this study, we defined the multifocality of tumors from preoperative CT scan based on anatomical landmark. Although the present study found that multifocal tumors did not predictive for locally advanced disease, it can use for prediction of node-positive disease in UTUC.

Although genetic and molecular biomarkers show potential benefit for prediction of stage or oncological outcome of UTUC [24], SII are still clinically useful because these assays are easy to perform, rapid, and inexpensive [25]. However, previous inflammatory markers such as NLR or PLR, have a potential association with cancer-related cachexia, which can have potential confounding effects [26]. Despite of other SII, CAR reflect both of systemic inflammatory responses and status of malnutrition [27], which can be both the cause and effect of tumorigenesis, and has been associated with reduced patient survival and response to treatment [28]. CAR has shown promising results in other malignancies [12, 13] and urothelial carcinomas [29]. The present study found that CAR was a better predictor of non-OC disease, both of locally advanced or node-positive UTUC than other SII.

This study had several limitations, including its retrospective design and inclusion of patients from a single center, which may have resulted in an inevitable risk of bias. Negligible number (n=44) of overlapping populations of locally advanced disease (N=499) and node-positive disease (N=51); thus, the actual role of CAR on node-positive disease should be needed to investigate in large number of node-positive patient cohort. Moreover, this study included only Asian patients, and these findings might differ in other ethnicities. Despite these limitations, to the best of our knowledge, this is the first and largest study showing that CAR is a predictive marker of non-OC UTUC, and it constantly showing that CAR was predictive of locally advanced and node-positive disease. And the minor point, we founded tumor multifocality in preoperative CT scan can be predictive factor for node-positive disease in UTUC. Large scaled, prospective, multicenter studies are needed to validate the predictive role of preoperative CAR and determine its cutoff value for patients with UTUC.

CONCLUSIONS

Hydronephrosis, high PLR, and high CAR were independent predictive markers of non-OC UTUC and of locally advanced disease, whereas high CAR and tumor multifocality were predictive of node-positive disease. Taken together, these findings show that CAR is a novel predictor of any subtype of non-OC disease. Prospective, large scale, multicenter studies are needed to validate the clinical role and determine the optimal cutoff value of CAR in patients with UTUC.

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