In 2013, there were more than 350,000 patients with kidney cancer worldwide, and approximately 140,000 patients die of kidney cancer-specific causes annually. Kidney cancer has become the seventh most common cancer and its incidence rate is increasing each year.[1,2] In 2014, there were approximately 68,300 new cases of renal cancer in China, with an incidence rate of 4.99/100,000, which is also increasing annually. Localized renal cancer refers to renal cancer with TNM stage T1–2N0M0; this cancer is an important type of renal malignant tumor with relatively good clinical prognosis through treatment including radical nephrectomy or partial nephrectomy. Therefore, exploring the overall prognosis of renal cancer via local renal cancer has important guiding significance. Our previous research reported a localized renal carcinoma incidence rate of 97.9% (4,079/4,167) in a single center. The three main pathological types of renal cell carcinoma are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC type I and type II), and colorimetric cell renal cell carcinoma (chRCC). ccRCC is the most important pathological type and the prognosis of ccRCC is worse than those of pRCC and chRCC.[6–9] The present study focused on ccRCC and excluded the effects of other pathological subtypes to achieve high representativeness. Until now, studies screening for the prognostic risk factors for LCCRC in the Chinese population lacked large samples and long-term follow-up. Therefore, the present study included 1,376 patients with pathologically confirmed LCCRC after surgery who underwent surgical treatment at the Department of Urology of the General Hospital of the PLA between January 2008 and December 2012 and who were followed up for more than 5 years. This study analyzed the risk factors for CSM using Cox regression analysis and explored the scoring efficiency in predicting the prognosis of LCRCC.
MATERIALS AND METHODS
Inclusion and exclusion criteria
The clinical data of 4,167 patients with kidney cancer who were diagnosed and treated at the Department of Urology of the General Hospital of the PLA between January 2008 and September 2016 were collected for statistical analysis. The inclusion criteria [Figure 1] were (1) pathologically confirmed ccRCC with pathological stage T1–2M0N0 and (2) complete medical history, pathology, and follow-up data. The exclusion criteria were (1) imaging examination showing lymph node, local or distant metastasis, or venous tumor thrombus; (2) pathologically confirmed ccRCC combined with other pathological subtypes; or (3) combined with other malignant tumors in the same period; and (4) metastatic kidney cancer. The clinical data of 1,376 LCRCC patients with a median follow-up of 78.1 (60–105) months between January 2008 and December 2012 were further confirmed and collected. The patients were categorized into two groups as per whether CSM occurred (the end point of clinical observation) (CSM and non-CSM groups). This study was approved by the Ethics Committee of the First Medical Center of PLA General Hospital.
The data were mainly collected by consulting medical records for hospitalization and discharge diagnoses, doctors’ orders and course of disease, surgical records, and related complications/comorbidities. Postoperative follow-up data were obtained from the follow-up database of the Department of Urology of the General Hospital of the PLA. The pathological data included renal cancer pathological stage based on the 2010 American Joint Committee on Cancer–recommended TNM staging; the standards of renal cancer nuclear grade (G) included G1 (high differentiation: Fuhrman I and II), G2 (moderate differentiation: Fuhrman III), and G3 (poor differentiation: Fuhrman IV). Any combination of two Fuhrman grades was defined as G1.[11,12] The surgical strategies included nephron-sparing surgery and radical nephrectomy. The surgical methods included open surgery, laparoscopic surgery, and robot-assisted laparoscopic surgery. The surgical approaches included using retroperitoneal and transperitoneal approaches.
The patients were diagnosed and treated between January 1, 2008 and December 30, 2012. The median follow-up was 78.1 (60–105) months. Within 6 months after surgery, the follow-up frequency was once every 3 months; 6 months after the surgery, the follow-up frequency was once every 6 months. The follow-up period ended on December 30, 2017. The patients underwent regular abdominal ultrasound, lung computed tomography, liver/kidney function assessment, and bone scan if necessary. The follow-up included evaluations for local tumor recurrence, distant metastasis, and death. CSM was defined as the observation end point for follow-up.
All data were analyzed using SPSS version 13.0 and MedCalc 188.8.131.52 software. The measurement data are expressed as means ± standard deviation and were assessed using t-tests and one-way analysis of variance. The count data are expressed as rates or percentages, and intergroup comparisons were performed using the χ2 test or Fisher’s exact test. Cox regression was used to correct for 13 factors, including age, sex, body mass index (BMI), surgical method, surgical strategy, surgical approach, surgical time, and nuclear grade to evaluate the risk of CSM. Receiver operating characteristic curves (ROCs) were constructed as per the screened risk factors, and the optimal criticality judgment value of CSM in LCRCC patients was used as the scoring standard to construct the prediction model for the prognosis of these patients. P <.05 was considered significant.
Comparisons of general clinical data
This study included a total of 1,376 LCRCC patients, aged 52.2 ± 11.9 years; of these, 1,019 (74.1%) were male and 357 (25.9%) were female, with a male: female ratio of 2.9:1. There were 707 cases of right renal tumor (51.4%) and 669 cases (48.6%) of left renal tumor, with a side-to-side ratio of 1.1:1. Of the 1,376 selected patients, 77 had CSM, corresponding to an incidence rate of 5.6%. Comparisons between the groups with or without CSM, as shown in Table 1, revealed no significant differences in sex, BMI, tumor location, surgical time, and pre/postoperative blood creatinine (P >.05, Table 1) between the CSM and non-CSM groups. Compared with the non-CSM group, the CSM group had a significantly higher average age, larger average tumor diameter, and higher nuclear grade level (P <.05, P <.01, Table 1). Meanwhile, the CSM group had significantly more cases of radical resection, robot-assisted laparoscopy via the retroperitoneal approach, and more bleeding than the non-CSM group (P <.05, P <.01, Table 1).
The median follow-up time was 78.1 (60–105) months. Overall, 141 patients died (7.3%, 141/1,376 cases); CSM occurred in 77 cases, corresponding to an incidence rate of 5.6% (77/1,376 cases). A total of 81 patients were lost to follow-up, corresponding to a loss rate of 5.89%.
Risk factors for CSM
Multivariate Cox regression analysis was performed to screen for correlations between the dependent variable (CSM) and 13 independent variables (age, sex, BMI, tumor location, tumor diameter, surgical approach, surgical strategy, surgical method, surgical time, intraoperative blood loss, pre/postoperative creatinine level, and pathological nuclear grade). The results showed that age, tumor diameter, and pathological nuclear grade highly correlated with the risk factors for CSM (P <.05, P <.01, Table 2) and were risk factors in LCRCC patients.
Evaluation of the optimal cutoff points for tumor diameter and age for CSM
ROC curve analysis showed that the optimal cutoff point for tumor diameter for the prediction of CSM was 5.8 cm, with an area under the ROC curve (AUC) of 0.687 (95% confidence interval [CI]: 0.62–0.75), specificity of 83.8%, and sensitivity of 46.8% (P <.0001) [Figure 2].
ROC curve analysis also showed that the optimal cutoff point for age for the prediction of CSM was 53 years, with an AUC of 0.763 (95% CI: 0.739–0.785), specificity of 81.8%, and sensitivity of 60.5% (P <.0001) [Figure 3].
Construction of a prognostic model for LCRCC
The three risk factors identified above (age, tumor diameter, and nuclear grade) were scored as follows. Age: > 53 years = 1 point, ≤ 53 years = 0 points; tumor diameter: diameter > 5.8 cm = 1 point, ≤ 5.8 cm = 0 point; and nuclear grade: I = 1 point, II = 2 points, and III = 3 points. The patients were then grouped per their total score into the low-risk (LR, ≤ 2 points,) intermediate-risk (IR, 3–4 points), and high-risk (HR, 5 points) groups. The CSM rates in the LR, IR, and HR groups were 3.8% (45/1,188 cases), 13.8% (24/1,188 cases), and 58.3% (8/14 cases), respectively [Table 3 and Figure 4]. The differences among these groups were significant (χ2 = 96.581, P <.001).
Renal cancer is the second largest tumor of the urinary system (second to bladder cancer) and has a 5-year survival rate of only 71%. In Europe and the United States, the reported CSM rate for LCRCC is 20%–40% owing to local tumor recurrence and distant metastases after surgery. The present study enrolled 1,376 LCRCC cases from the Department of Urology of the General Hospital of the PLA, as research subjects and excluded potential interferences by other pathological subtypes, local infiltration, and local/distant metastases. The median follow-up period was 78.1 (60–105) months, during which 77 died, corresponding to a CSM rate of 5.6%.
Studies have shown that many factors affect the prognosis of renal cancer, including clinical and pathological factors, such as patient age at surgery, preoperative status, laboratory test results, tumor pathological stage, nuclear grade, tumor necrosis, and tumor pathological subtype. The results of the present study further confirmed age, tumor stage, tumor diameter, nuclear grade, pathological typing, tumor necrosis, and sarcomatoid differentiation as prognostic factors for clinical nonmetastatic renal cancer. Furthermore, these results also confirmed that age, tumor diameter, and nuclear grading are risk factors for CSM in a patient population with renal carcinoma and excluded the effects of sex, BMI, surgery-related factors, and serum creatinine. These findings are similar to those of previous studies. Tobias reviewed the literature on the prognostic factors and prognostic models of RCC, in which most studies concluded that the prognostic risk factors in patients with localized RCC (LRCC) were closely related to tumor stage, nuclear grade, pathological subtype, clinical features, or clinical status. Van der Mijn used a Cox proportional hazard model to retrospectively analyze the risk factors for tumor recurrence in 873 patients undergoing RCC surgery between 2000 and 2015 and confirmed that a high pathological T stage and nuclear grade are independent risk factors for RCC recurrence after nephrectomy; moreover, they also found that diabetes was associated with an increased risk of recurrence in patients with early-stage disease.
Age is not only related to the occurrence of renal cancer but is also closely related to its progression and prognosis. Hupe et al. investigated 1,538 patients with renal cancer from 1991 to 2010 and reported the correlation between age and renal cancer prognosis. The study found that the rate of tumor stage progression and tumor metastasis in elderly patients was higher, age was an independent prognostic factor for cancer-specific survival and metastasis, the risk of metastasis was increased by 30%, and the cancer-specific survival time was shortened by 50% in the population aged >63 years. The multivariate Cox results in the present study showed that age (95% CI: 1.058–1.105, P <.001) was closely related to CSM due to LCRCC in a Chinese population. The best clinical judgment value of age was 53 years, with an AUC of 0.763 (95% CI: 0.739–0.785), specificity of 81.8%, and sensitivity of 60.5% (P <.0001). That is, with age of 53 years as the threshold, renal cancer patients of different ages can be stratified to preliminarily predict the incidence of renal cancer CSM. Different studies reported differed optimal cutoff points of age, which reflect differences among different ethnic groups and countries.
Histological factors include tumor pathological staging, tumor size, nuclear grade, RCC subtype, sarcomatoid features, microvascular invasion, tumor necrosis, or collective system invasion, all of which are closely related to the prognosis of renal cancer.[2,21,22] Nuclear grading plays an important role in predicting RCC prognosis[2,15] and is an independent risk factor for the prognosis of RCC; a relationship also observed in the present study. Nuclear grade (95% CI: 1.176–2.384, P =0.004) was associated with CSM, that is, the worse the nuclear grade, the worse the patient prognosis. This study included only LCCRC patients; thus, tumor diameter was the only stage criterion. Multivariate Cox analysis showed that tumor diameter (95% CI: 1.130–1.287, P <.001) was closely related to RCC prognosis. As the tumor volume increased, the prognosis of LCRCC worsened. This study also used ROC analysis to confirm 5.8 cm as the optimal cutoff point for tumor diameter to predict the CSM rate after radical or partial resection (AUC = 0.68, 95% CI: 0.62–0.75; specificity = 83.8%, sensitivity = 46.8%, P <.0001), that is, the tumor diameter of 5.8 cm showed good prognostic stratification for the LCRCC patients enrolled in the present study who had a single pathological type and a median follow-up time exceeding 5 years. These results are similar to those of previous clinical studies. For example, Zisman et al. analyzed data from the University of California, Los Angeles Kidney Cancer Registry and found a tumor diameter cutoff of 4.5 cm significantly increased the resolution between stages T1 and T2, indicating that a cutoff of 7 cm for differentiation between T1 and T2 tumors may be exceedingly high. Elmore et al. showed that a tumor diameter of 5 cm best distinguished the prognostic risk of LRCC. Furthermore, the study also recommended a tumor diameter of 4–5 cm as the standard for nephron-sparing surgery.
As a heterogeneous and complex disease, the natural course of RCC is highly complicated. The combination of existing clinical characteristics with clear prognostic variables to explore models for the prediction of renal cancer prognosis has become a primary research focus. Yaycioglu et al. and Cindolo et al. established two prediction models based on tumor size and clinical symptom scores. These two models are mainly used to predict cancer-specific survival and tumor recurrence rates for LCRCC. In these studies, the 5-year cancer-specific survival rates in the HR and LR groups were 57% (with a tumor recurrence rate of 32%) and 92% (with a tumor recurrence rate of 7%). In 2001, researchers at the University of California, Los Angeles constructed the University of California, Los Angeles Integrated Staging System (UISS), which considered TNM stage, tumor pathological grade, and Eastern Cooperative Oncology Group quality of life score for renal cancer to divide LCRCC into LR, IR, and HR stratifications. The 5-year survival rates were 91%, 67%, and 44%, respectively. The tumor stage, size, grade, and necrosis scoring system developed by Mayo Medical Center in 2002 was based on 1,801 patients with CRCC who underwent radical nephrectomy between 1970 and 1998 and combined tumor staging, tumor size, nuclear grade, and tissue necrosis into a scoring system to estimate the 1-10–year survival rates of CRCC. In 2017, Parker et al. investigated 3,600 CRCC patients and divided them into three subgroups with the median postoperative follow-up times of 20 years, 9.2 years, and 7.6 years, respectively. Their results showed that the stage, size, grade, and necrosis scoring system continued to demonstrate a very strong predictive ability for the prognosis of modern CRCC and could help guide the clinical monitoring of ccRCC patients receiving radical or partial nephrectomy. The present study applied ROC analysis to screen age and tumor diameter to determine the optimal critical value for prognosis. The values were then combined with the pathological nuclear grade as a scoring standard to categorize LCRCC prognosis as LR (≤2 points), IR (3–4 points), and HR (5 points), in which the CSM rates of patients with more than 5 years of follow-up were 3.8%, 13.8%, and 58.3%, respectively. In this study, the prognosis of LCRCC in the Chinese population was well stratified. The scoring standard is also an important supplement to the prognostic model of RCC and can provide hypotheses for further clinical research.
This study has several limitations. First, longer clinical follow-up observations are needed to confirm these results. Second, our conclusions are based on a single-center follow-up retrospective analysis of renal cancer patients undergoing surgical treatment, which require verification and support by further multicenter or other large prospective studies.
This study was approved by the Ethics Committee of the First Medical Center of PLA General Hospital.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
This work was supported by the National Natural Science Foundation of China (82070765); Open project of the Key Laboratory of Proteomics (SKLPO202009).
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