Introduction

Kidney cancers have histological subtypes with different characteristics, account for approximately 3% of adult cancers, and are in the third rank among urogenital cancers (1). Renal cell carcinoma (RCC) comprises 85%-90% of primary renal malignant tumors originating from the renal tubular epithelium and has different genetic characteristics (2). RCCs, highly angio-invasive tumors, tend to metastasize to the lungs, bones, liver, and brain by hematogenous and lymphatic spread. Survival in RCC is poor, especially in the clear cell subtype, which is prone to diagnosis at an advanced stage, and 20%-30% of patients are also in the metastatic stage during this period (3,4). Therefore, the management of these patients is very challenging. The 5-year survival rate is less than 20%, even if the metastatic tumor is removed, the survival is between 25 and 50% (5). However, the incidence of renal tumors, which are often incidentally diagnosed as smaller and low-grade tumors, is increasing because of the widespread use of non-invasive imaging tools. The histological subtype, grade, size, extracapsular spread, and lymphovascular invasion status can be considered among the main factors affecting the prognosis of renal tumors (6).

Positron emission tomography integrated with computed tomography (PET/CT) imaging has become a key modality for imaging patients with cancer and is frequently used in renal cancers, particularly to detect recurrence and evaluate treatment response. Cancer staging with ¹⁸F-fluorodeoxyglucose (FDG) PET imaging is since malignant tumoral cells have higher glucose metabolism than normal cells (7). However, renal cancers are prone to exhibit low tracer uptake (8,9).

Whilst there is a wealth of literature addressing the use of ¹⁸F-FDG PET/CT in renal tumors, the relationship between PET metabolic measurements obtained from the pre-treatment initial staging examination and patients’ survival after long-term follow-up has not been well investigated. Therefore, we investigated the potential predictive role of ¹⁸F-FDG PET/CT and metabolic data in the analysis of survival in patients with RCC.

Materials and Methods

Patients

A total of 100 patients [66 men and 34 women; mean age 58.1±11.7 (range: 34-82 years)] with RCC were examined between August 2013 and March 2022 on ¹⁸F-FDG PET/CT scans were retrospectively enrolled in the analyses at the initial staging before surgical or oncological treatments.

The University of Health Sciences Turkey, Istanbul Training and Research Hospital Clinical Research Ethics Committee approved the study protocol (number: 88, date: 02.03.2022) and the Declaration of Helsinki rules were followed to conduct this study.

¹⁸F-FDG PET/CT Scan and Interpretation of Images

¹⁸F-FDG doses according to patient weight (3.7 mBq/kg) were injected into the patients when their blood glucose values were <140 mg/dL. Initially, CT (n=68 with contrast-enhanced, n=32 without contrast-enhanced) data followed by PET scan were received 60 min after ¹⁸F-FDG injection between the vertex-proximal thigh in an mCT 20 PET/CT scanner (Siemens Molecular Imaging, Hoffman Estates, IL) and all images were examined first visually and then semi-quantitatively. Regions with increased ¹⁸F-FDG uptake than background and nearby structures in primary tumors, nodal and distant metastases were recorded. Maximum standardized uptake value (SUV_max) was measured automatically by drawing an elliptical volume of interest to include the pathological tumoral lesions in the three planes in ¹⁸F-FDG PET/CT. The review process was carried out by combining the metabolic findings from the PET component with anatomical information obtained from the CT component. Initial staging images were evaluated to determine whether primary tumor SUV_max (SUV_max-T) predicted patient survival. According to the 8^th edition of the American Joint Committee on Cancer 2018 tumor, node, and metastasis (TNM) staging system, the disease stage was determined, and the patients were followed up for at least 5 years or until death to evaluate their survival outcomes (10).

Statistical Analysis

Study data were evaluated by SPSS 25.0 software (IBM, Armonk, NY, USA) and p<0.05 was considered statistically significant. Numbers and percentages were used to indicate the categorical data. Median and mean with standard deviation values were used to express the quantitative calculations. The relationship between survival and categorical variables was assessed by Pearson chi-squared. Time from PET/CT to death or final analysis of the study was calculated to determine overall survival (OS) and survival curves were performed and compared using the Kaplan-Meier method and Mantel-Cox Log-rank test. Receiver operating characteristic curve (ROC) analysis was used to express the cut-off values for OS. Univariate analyses of SUV_max on survival outcomes were measured using the Cox regression analysis. Independent variables related to OS were determined by significant factors by using multivariate logistic regression analysis. The data were expressed at a 95% confidence interval (CI).

Results

Overall, 65 patients had clear cell RCC, 21 had chromophobe RCC, nine had papillary RCC, and five had unclassified RCC. The clinicopathological TNM staging was stage 1 in 40 patients, stage 2 in 14 patients, stage 3 in 9 patients, and stage 4 in 37 patients. Distant metastases were visualized in 34 patients on ¹⁸F-FDG PET/CT, and the lungs and bones were the most common sites of distant metastasis (Figure 1). Information on the characteristics of the patients is presented in Table 1. The median follow-up time was 5.61 years (range, 0.01-8.7 years; 0.78 years for deceased patients, 7.78 years for living patients). Fifty-two RCC-related deaths occurred; the remaining 48 patients were alive at the last check.

SUV_max-T levels in the patients ranged from 2.1 to 48.9 (median 5.9, mean 9.0±7.9). In our study, there were significant differences according to the PET metabolic parameters of the primary tumor. SUV_max-T was significantly higher in patients with distant metastases than in the negative ones (p<0.001). Also, SUV_max-T was significantly higher in the RCC-related death group than in the other group (p<0.001). There was statistical significance in OS between groups for tumor and cancer staging (p<0.001). However, there was no statistical significance for gender and histological subtypes on patients’ survival outcomes (p=0.264 and p=0.784) (Figure 2).

The time-dependent ROC curves were generated to analyze the efficacy of SUV_max-T to predict OS (Figure 3). High SUV_max-T was associated with a shorter OS and the highest SUV_max-T value to predict OS was a cut-off level of 5.4, which retained 81% and 75% sensitivity and specificity, respectively. Considering 1-year, 3-year, and 5-year survival, the best clinical performance of SUV_max-T was achieved at a cut-off level of 7.4, 5.5, and 5.5, which indicated the highest sensitivity and specificity, respectively (Table 2). These results suggest that SUV_max-T is a reliable parameter for predicting OS. The patients’ 1-year, 3-year, and 5-year OS rates were 71%, 61%, and 57%, respectively. Furthermore, OS rates were 52% vs. 48% in patients with SUV_max ≤5.4 vs. >5.4 on ¹⁸F-FDG PET/CT. Also, univariate Cox regression analysis identified the values of SUV_max-T as a significant prognostic marker for OS (p<0.001, Odds ratio: 1.135, 95% CI: 1.098-1.173).

The effect of SUV_max on OS was compared with that of possible prognostic markers and the SUV_max levels exhibiting statistical significance in univariate analysis were included in the multivariate analysis. The findings of the multivariate analysis are indicated in Table 3. Analysis of SUV_max in association with patients’ gender, histological tumor subtypes, and tumor staging at the initial pretreatment period revealed that SUV_max-T was a significant independent prognostic factor of OS in patients with RCC (p<0.001). However, cancer staging remained independent significance for OS (p<0.001). Regardless of the tumor stage and the histopathological subgroups, patients with a higher SUV_max had a shorter OS than patients with a lower SUV_max (Figure 4). In this study, the mean OS for 48 patients with SUV_max ≤5.4 was 7.4 years (95% CI: 6.623-8.181), while in 52 patients with SUV_max >5.4, the mean OS was 3.3 years (95% CI: 2.349-4.170). Differences in OS among these patients were statistically significant (SUV_max ≤5.4 vs. >5.4, p<0.001).

Discussion

Oncological PET/CT imaging has proven its importance in diagnosis, staging, evaluation of treatment response, and recurrence detection in most cancer types and is an indispensable modality in this field. Since RCC exhibits low glucose metabolism and tumoral ¹⁸F-FDG uptake, PET/CT is more limitedly preferred as an imaging tool in the initial staging (11,12). However, several researchers have examined the efficacy of ¹⁸F-FDG PET in determining the metabolic and molecular characterization of renal tumors (13,14). In a retrospective study investigating the impact of SUV_max levels on patient mortality in renal tumors, it was determined that patients with metastasis lived shorter, liver metastases showed shorter survival, and the lung metastases had higher SUV_max levels (15).

Diagnostic values of PET/CT at different SUV_max cut-off values in survival analysis are available for RCC in the literature (16,17). Komek et al. (18) investigated the relationship between the mortality results of 21 patients with RCC and showed that SUV_max values of ≥4.5, obtained from pre-treatment ¹⁸F-FDG PET/CT imaging, resulted in increased mortality. Furthermore, a cut-off value of 8.8 and SUV_max values higher than this have been reported as predictors of survival for advanced RCC (19). In this study, we evaluated the patient outcomes and mortality rates according to different SUV_max values, which refer to 1-year, 3-year, and 5-year results and we determined the patients’ mortality rates as 29%, 39%, and 43%, respectively (Figure 5). Nakaigawa et al. (20) evaluated 101 patients with RCC during the pretreatment or follow-up period and classified study patients into three subgroups based on their highest SUV_max levels and reported significant differences in OS for RCC. Subjects were followed for a median of 18 months and the median OS of patients with SUV_max <7.0, ≥7.0, and <12.0, and ≥12.0 was found as 41.9, 20.6, and 4.2 months, respectively. In this study, the median follow-up time of our patients was 5.61 years, and we observed the mean OS as 7.4 and 3.3 years, respectively, for SUV_max ≤5.4 vs. >5.4 levels, with sensitivity and specificity results of 81% and 75%. Additionally, the SUV_max threshold of 7.4 was significant in distinguishing patient mortality and survival within 1 year after PET/CT evaluation (Figure 6).

The use of volumetric measures such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) provided a correlation with prognosis in published studies (21). Nakajima et al. (22) showed that MTV and TLG calculated from PET data are also important prognostic markers in the survival analysis of RCC patients. Further pre-treatment TLG was found to be an independent indicator of the prognosis of OS in another study (23). Besides PET measurements, the prognostic value of pathological subtypes was investigated, and the clear cell variant was more prone to metastasis than the other two variants and exhibited a poor prognosis, but we did not observe any significant difference between the survival times of the histological subgroups (24). Tumor size, grading system, various other markers, and different radiopharmaceuticals used in hybrid molecular imaging have been reported in several articles as potential predictors of the prognosis of patients with RCC (25,26,27).

Study Limitations

This study had some limitations. First, our retrospective study showed a heterogeneous distribution among pathological subgroups and tumor stages. Also, the differences in the patients’ treatment protocols and follow-up strategies may have affected the survival analyses. Therefore, well-designed prospective studies are required to validate our findings.

Conclusion

Patients with high primary tumor SUV_max had increased mortality rates and shorter survival. SUV_max and the high-cancer stage were demonstrated as the significant prognostic predictors in patients with RCC. We think that SUV_max can act as a potential biomarker and reflect the disease prognosis. Evaluation of ¹⁸F-FDG accumulation using PET/CT may help plan treatment strategies and predict survival outcomes of these patients at diagnosis.

Ethics

Ethics Committee Approval: The University of Health Sciences Turkey, Istanbul Training and Research Hospital Clinical Research Ethics Committee approved the study protocol (number: 88, date: 02.03.2022) and the Declaration of Helsinki rules were followed to conduct this study

Informed Consent: Externally peer-reviewed.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: G.T., C.G., Ö.F.Ş., E.A., N.E., T.F.Ç., Concept: G.T., C.G., Ö.F.Ş., E.A., N.E., T.F.Ç., Design: G.T., C.G., Ö.F.Ş., E.A., N.E., T.F.Ç., Data Collection or Processing: G.T., C.G., Ö.F.Ş., E.A., N.E., T.F.Ç., Analysis or Interpretation: G.T., C.G., Ö.F.Ş., E.A., N.E., T.F.Ç., Literature Search: G.T., C.G., Ö.F.Ş., E.A., Writing: G.T., T.F.Ç.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.