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Prognostic significance of the albumin-to-globulin ratio for upper tract urothelial carcinoma

Background Although the albumin-to-globulin ratio (AGR) is a promising biomarker for various malignancies, few studies have investigated its prognostic significance for upper tract urothelial carcinoma (UTUC). Methods This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline. We reviewed 179 patients with UTUC who underwent radical nephroureterectomy at our institution between 2008 and 2018. Associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS) were assessed. The Cox proportional hazards model was used for univariate and multivariable analyses. AGR was dichotomized as < 1.25 and ≥ 1.25, according to the most discriminatory cutoff determined from the receiver operating characteristic curve analysis. Results During a median follow-up of 34 months after surgery, 37 patients died from UTUC and 13 died of other causes. The preoperative AGR significantly correlated with pathological T stage, pathological N stage, and adjuvant chemotherapy. Multivariate analyses demonstrated that a decreased (< 1.25) preoperative AGR was an independent poor prognostic factor for both CSS (hazard ratio [HR] = 2.81, P <  0.01) and OS (HR = 2.09, P <  0.05). Conclusions Preoperative AGR < 1.25 might serve as a useful prognostic marker for patients with UTUC undergoing radical nephroureterectomy.


Background
Upper tract urothelial carcinoma (UTUC) is a relatively rare malignancy that accounts for 5-10% of urothelial carcinomas and generally has a poor prognosis [1,2]. Radical nephroureterectomy with bladder cuff excision is the gold standard treatment for nonmetastatic UTUC [3], whereas up to 19% of patients with UTUC have metastasis upon initial presentation [4].

Methods
This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline [27] (Supplementary Table 1 shows the REMARK checklist of the present study). This study was approved by the internal institutional review board of Kyorin University School of Medicine (approval number: 1154).

Patients
We retrospectively reviewed 185 consecutive patients who underwent radical nephroureterectomy with curative intent at Kyorin University Hospital between 2008 and 2018. We excluded six patients because of pathological diagnoses of urothelial dysplasia (n = 3), renal cell carcinoma (n = 2), and squamous cell carcinoma (n = 1), which left 179 available for analysis.

Preoperative AGR
Routine preoperative blood tests including serum total protein and albumin levels (g/dl) were performed within 1 month before surgery. The AGR was calculated using the following formula: AGR = [albumin / (total proteinalbumin)]. No patient had active infectious disorders during the blood tests.

Endpoints and follow-up
We assessed the associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS). The follow-up period started on the day of surgery. Follow-up information was obtained as of October 2018.

Statistical analysis
Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value of the AGR. Sensitivity, specificity and area under the curve (AUC) were calculated using a 2 × 2 contingency table for different cutoff values of the AGR. The optimal cutoff value of the AGR was determined by maximization of the Youden's index [Sensitivity − (1 − Specificity)]. Relations of the AGR to other variables were evaluated using the χ 2 test or Spearman's rank correlation coefficient. Survival curves were generated using the Kaplan-Meier method and compared using log-rank tests. The Cox proportional hazard regression model was used for univariate and multivariate analyses. All statistical analyses were performed using JMP Pro version 14.0.0 (SAS Institute, Cary, NC, USA). P < 0.05 was considered to indicate a significant difference.

Discussion
The present study demonstrates that a decreased (< 1.25) preoperative AGR was an independent indicator of poor prognosis for CSS and OS of patients with UTUC treated with radical nephroureterectomy.
The association between a low AGR and poor outcome of patients with cancer requires further research. However, the available data show that poor nutritional status or hypoalbuminemia is a negative prognostic factor for certain malignancies [13,15,16]. Chronic inflammation involving serum globulins plays a crucial  [16]. A low AGR may thus reflect the degree of poor nutritional status (hypoalbuminemia) and tumor progression (hyperglobulinemia) in a more sensitive manner than either measure alone and may therefore serve as a highly significant prognostic biomarker. Based on a similar concept as AGR (i.e. use of a ratio), several systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio [11,12,28], platelet-to-lymphocyte ratio [28], and lymphocyte-to-    Abbreviations: HR hazard ratio, CI confidence interval, AGR albumin-to-globulin ratio *Statistically significant monocyte ratio [28], have been established and wellinvestigated in the field of oncology, including urothelial carcinoma.
The major limitations of this study are its retrospective, single-institutional design and the limited number of patients. Further studies with larger populations are needed to confirm our results.

Conclusions
Given the significant prognostic associations of the AGR with CSS and OS, AGRs are easy to determine in routine clinical practice, and a preoperative AGR < 1.25 might serve as a useful prognostic biomarker of patients with UTUC treated with radical nephroureterectomy.
Additional file 1: Table S1. The REporting recommendations for tumour MARKer prognostic studies (REMARK) checklist of the present study (based on the original guideline [27]).