Introduction
Renal cell cancer (RCC) accounts for 2-3% of all cancers (1). According to World Health Organisation Report 2014, RCC was the 9th and 14th most frequent malign tumor in men and women in 2012, respectively, and the 16th most common cause of cancer-related death worldwide with 143,000 deaths (2). The number of RCCs has increased due to the widespread use of ultrasonography and computed tomography (CT), and these tumors are frequently small and low grade. Although most of these tumors consist of small masses, the number of large masses is quite high.
Factors affecting prognosis in renal tumors can be classified as anatomical, histological, clinical and molecular. Tumor size is an important prognostic factor for RCCs in Tumar, nodes, metostases classification. Some cut-off values for tumor size determine the T stage, such that, 4 cm and 10 cm are threshold values for T1a and T1b tumors and T2a and T2b tumors, respectively. Some authors argue that these thresholds do not have prognostic values (3) or that the use of other tumor size thresholds is better (4). Tumor size can also be considered as a threshold value for the proposed cancer treatment as 4 cm and 3 cm are widely accepted threshold values for partial nephrectomy and ablative therapies (5). However, in the modern era, these thresholds are not strictly restrictive for experienced surgeons thanks to the development of technological equipment such as robotic surgery.
On the grounds that the prognosis of RCC is variable, many researchers are trying to find prognostic factors that affect RCC survival. As with many cancers, tumor progression and grade are considered to be the most important prognostic factors in RCC. However, it is still unclear which factor and how much it affects the prognosis. In this study, we analyzed the prognostic factors that affect cancer-specific survival (CSS) in kidney tumors larger than 10 cm and tried to identify the most effective factors.
Materials and Methods
Patient Selection, Data Collection and Follow-up of the patients one hundred and twenty-six patients who underwent radical nephrectomy due to ≥10 cm renal mass and whose pathology report was consistent with RCC between January 2010 and June 2016 were included in the study. Data was obtained from patient files. In localized disease, University of California, Los Angeles (UCLA) integrated staging system (UISS), which was developed by UCLA and combined TNM stage (I to IV), Eastern Cooperative Oncology Group (ECOG) performance status (PS) and Fuhrman degree, were used (6). The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic system, which combines Karnofsky performance status, the interval between diagnosis and treatment, lactate dehydrogenase, corrected calcium, and hemoglobin, was used to determine the risk of recurrence of metastatic disease (7). Tumor pathology, stage, renal vein invasion, perinephric fat invasion, tumor thrombus, lymph node, adrenal and distant organ metastasis status, and ECOG PS Grade of the patient were recorded. Tumor size was calculated from histopathological evaluations because it was more consistent. In order for the histopathological types to be statistically significant, a minimum of seven subjects were required. Therefore, histopathological types less than seven (n=13) were excluded from the study. Tumor staging and nuclear grading were performed according to 2017 TNM classification and Fuhrman’s nuclear grading system, respectively (8). Tumor staging and follow-up of patients were performed with enhanced thoracoabdominal CT or magnetic resonance imaging. Patients were subjected to regular controls and CSS rates were calculated. Patients identified as exitus by the hospital system and their exitus dates were also recorded. The present study was conducted in compliance with the Declaration of Helsinki and written informed consent was obtained from the patients. Because of the study was designed as a retrospective study, ethics committee approval was not obtained.
Statistical Analysis
Kaplan-Meier analysis or Cox regression was used to analyze the relationship between CSS and clinicopathological variables including gender, tumor size, side, location, pathological type, T stage, renal vein invasion, perinephric fat invasion, tumor thrombus, lymph node metastasis, adrenal metastasis, distant organ metastasis, and adjuvant treatment. Pairwise comparisons were evaluated using the Log-Rank test after Kaplan-Meier analysis. Forward stepwise (according to the method of likelihood ratio) multiple logistic regression analysis was used for RCC risk factor analysis. All statistical analyzes were performed using IBM SPSS version 23.0. A p-value <0.05 was considered statistically significant.
Results
A total of 445 patients underwent radical nephrectomy with the diagnosis of renal parenchymal tumors during the study period. The tumor of 307 patients was smaller than 10 cm. Ewing sarcoma (n=1), spindle cell sarcoma (n=1), liposarcoma (n=1), mixed epithelium stromal tumor (n=1), mucinous tubular and spindle cell sarcomas (n=2), neuroectodermal tumors (n=1), neuroendocrine tumors (n=1), pleomorphic sarcomas (n=1), squamous cell carcinomas (n=1) and urothelial carcinomas (n=2) were not included in the study because the number of cases was insufficient to draw any statistical conclusions. The remaining 126 patients were included in the study. According to the ECOG performance status, 42 patients had grade 0, 40 had grade 1, 36 had grade 2, and eight had grade 3 performance status. There were no patients in the 4th grade. The majority of patients had good performance status. Therefore, the survival effect of ECOG status was insignificant. The mean age of the patients was 59.1 years. Most of the patients were male (88/126). The mean tumor size was 128.05 mm. The most common histopathological type and Fuhrman grade was clear cell grade 3 (29.4%). Tumors most commonly presented with T3a stage (35.7%), followed by T2b, T4 and T3b (31.7%, 24.6% and 8.0%, respectively). Renal vein invasion was detected in 32 patients (25.4%). Sixty-six patients (52.4%) had perinephric fat invasion. Twelve patients (9.5%) had tumor thrombus and 11 patients (8.7%) had adrenal metastasis. Twenty-eight patients (22.2%) had distant organ metastases. The mean disease-specific survival was 39.2 (range, 1-168) months. The majority of patients with localized disease was in the UCLA integrated staging system intermediate risk group and the majority of the metastatic patients were in the intermediate group according to the MSKCC prognostic system (54.0% and 53.6%, respectively). Patient and tumor characteristics are summarized in Table 1. A total of 87 patients received adjuvant treatment. The multidisciplinary urooncology council determined which treatment should be administered to which patient. Thirty eight of 66 patients with perinephric fat invasion received immunotherapy, seven of 12 patients with tumor thrombosis received targeted therapy, eight of 11 patients with adrenal metastasis received immunotherapy and one of them received targeted therapy, and 20 of 28 patients with distant organ metastasis received immunotherapy and four received targeted therapy. A total of nine patients received adjuvant temsirolimus treatment. Indications and distribution of adjuvant therapy are shown in Table 2.
Although not statistically significant, age negatively affected survival (p=0.091). Fifty-two (59.1%) men and 22 (57.9%) women died during the follow-up period. Twenty-two patients died due to myocardial infarction, 21 patients due to multiple organ failure as a result of generalized impairment, 19 patients due to acute respiratory distress syndrome and 12 patients due to cerebrovascular disease. The one-year CSS rate was 62.5% and 5-year CSS rate was 41.4% in men. In women, these rates were 75% and 45.9%, respectively. Mean CSS was 65.7 months for men and 61.3 months for women (p=0.753). Mean CSS was 60.6 months for right-sided tumors and 67.1 months for left-sided tumors (p=0.900). Mean CSS was 68.9 months for lower pole tumors, 52.6 months for middle pole tumors and 42.2 months for upper pole tumors (p=0.124). Renal vein invasion, perinephric fat invasion, tumor thrombus, lymph node metastasis, adrenal metastasis and distant organ metastasis negatively affected mean CSS (p<0.001, p<0.001, p<0.001, p<0.001, p=0.013, and p<0.001, respectively). Tumor size negatively affected CSS although the relationship was not statistically significant (p=0.058, OR: 1.007, 95.0% CI: 1.000-1.014). When survival rates were evaluated according to tumor histopathology, the 1-year CSS rate was 91.7%, 77.4%, 44.4%, 75%, and 83.3%, for clear cell grade 2, clear cell grade 3, clear cell grade 4, chromophobe, and papillary, respectively. Pairwise comparisons of tumor stages were shown in Table 3. Presence of renal vein invasion significantly affected survival (p<0.001). Perinephric fat tissue invasion was also a negative prognostic factor (p<0.001). Tumor thrombosis negatively affected survival (p<0.001) and lymph node metastasis was also a prognostic factor negatively affecting CSS (p<0.001). Estimated CSS in terms of renal vein invasion, perinephric fat tissue, tumor thrombus status and lymph node metastasis status is shown in Figure 1 2-3-4.
Five and 10-year estimated CSS rates according to the variables are shown in Table 4. The result of the reduced model of Cox regression analysis is given in Table 5, and it revealed that stage T2b, stage T3a, stage T3b, tumor thrombus, lymph node metastasis and adjuvant therapy were the most effective factors for CSS (HR=6.644, 2.358, 8.164, 3.149, 5.143, 6.188, and 2.014, respectively).
Discussion
RCC constitutes approximately 85% of primary renal cancers. As with all cancers, predicting prognosis in RCC is important for treatment management. In RCC patients, TNM stage, tumor nuclear grade and RCC subtype provide important prognostic information. Prognostic factors in renal cancers can be classified as anatomical, histological, clinical and molecular. Accurate staging is very important in order to decide the treatment of these tumors and to predict prognosis and response to treatment. Pathological staging determines the anatomic spread of the tumor and its relationship with the surrounding tissues. Tumor size in the TNM system used for the staging of renal tumors is one of the most important prognostic factors. Tumor size is not only a prognostic marker; it is also a determining factor for the type (partial/radical) and method of operation (open/laparoscopic). In the literature, the prognostic factors for T1 (≤7 cm) and T2 (≤10 cm) tumors are well established and there are many studies in this regard. However, there is uncertainty about the prognosis and surgical methods of renal masses larger than 10 cm. For this reason, in the present study, we performed a survival analysis by evaluating prognostic factors in renal tumors larger than 10 cm that underwent surgical treatment in our clinic and we aimed to evaluate the prognostic factors for these masses. In our study, we used the current TNM classification system for staging purpose (8). Prognostic systems and nomograms may predict survival better than TNM classification or Fuhrman’s grading system alone in localized and metastatic diseases in patients with RCC. We used the UISS developed by UCLA for localized disease. In metastatic disease, classification systems such as the MSKCC prognostic system and Hang’s model are available. We used MSKCC prognostic system to assess recurrence risk in metastatic patients.
Tumor size has been addressed in many studies. In a study of 360 patients, Kunkle et al. (9) showed that every 1 cm increase in all tumor sizes increased the incidence of metastatic disease by 22%. In another study, it was shown that the life expectancy was dependent on tumor size and the survival rate was 84% in <5 cm tumors and 0% in >10 cm tumors (10). Similarly, although the relationship was not significant, tumor size and survival were inversely proportional in our study (p=0.058). The Fuhrman grade is the most widely accepted grading system in RCC grading and is an independent prognostic factor (11). Fuhrman grade was also an important factor affecting CSS in our cohort.
T stage is one of the important prognostic factors for RCC. Amin et al. (12) defined T stage as an independent predictor of aggressive clinical phenotype, defined as local recurrence, metastasis development and death from disease in chromophobe RCC. It is a well-established data that T1 stage causes higher CSS than T2-4. Bianchi et al. (4) reported a 5-year CSS rate of 80.7-86.2% for the 4,963 T2-stage RCC cases undergoing surgical treatment. Kopp et al. (13) also reported a 5-year CSS rate of 82.5-86.7% in 202 T2-stage RCC treated at multiple centers. In our results, the 5-year survival rate for stage T2 was 93%. The reason that this result is more optimistic may be due to the fact that the patients in the above studies are collected from different centers and that the patient groups were not homogeneously distributed. Laird et al. (14) found a 5-year survival rate of 64.4-67.3% for 252 stage T3 RCC cases from the British medical center. In two other studies, the 5-year CSS rate for T3 stage RCC was reported to be 46-51.1% (15,16). In our cohort, the 5-year CSS rate for stage T3a was 26% and 16% for T3b. Probably; the reason why these rates were lower than other studies are that we often have to operate these patients with cardiovascular surgeons. However, sometimes we have difficulties to organize together and the surgical procedure may be delayed.
Many drugs have shown clinical benefit in metastatic RCC. Recently, the efficacy of the immune-checkpoint inhibitors has been shown, as well as immunotherapy and targeted therapy. A recurrence rate of 35% despite surgical resection underlines the importance of these treatments (17). Prior to the use of tyrosine kinase inhibitors (TKIs), INF-α and IL-2 were the standard treatment of metastatic RCC. In the analysis of six prospective studies, Motzer et al. (18) showed a 13-month overall survival advantage in patients treated with INF-α. Identification of the von Hippel-Lindau gene has shed light on the understanding of RCC pathogenesis. However, targeting of angiogenesis and Mammalian terget of Rapamycin (mTOR) pathway has provided benefit in clinical outcomes. These agents include vascular endothelial growth factor receptor TKIs (sunitinib, pazopanib, axitinib, sorafenib) and mTOR inhibitors (temsirolimus and everolimus) (19,20). In our study, 87 patients received adjuvant therapy and adjuvant therapy was an important factor affecting CSS. This result also supports the efficacy of adjuvant therapy in tumors larger than 10 cm.
A large multicenter study analyzed 291 chromophobe-cell RCCs and suggested that gender was an independent predictor of CSS, and reported that female patients had a significantly lower risk of dying from the disease (21). In our study, on the contrary, the mean CSS rate was higher in males (65.7 vs 61.3), but the difference was not significant (p=0.753).
The relationship between tumor histopathology and survival has been examined in many studies and conflicting results have emerged. There are single-center studies reporting that the survival of chromophobe RCC is better than that of conventional RCC (22,23). However, in large, multicenter series, tumor histology has not been identified as an independent prognostic factor (24,25). Our results revealed that the histological type was an important prognostic factor and affected survival significantly.
In a single-center survival analysis of 1326 patients from China, the tumor thrombus [renal vein or inferior vena cava (IVC)] was a prognostic factor, but the level of IVC involvement was not associated with prognosis (26). Previously, controversial results have been reported about the relationship between IVC thrombus level and tumor prognosis. In our study, we did not stratify the level of thrombus, but tumor thrombus was an important prognostic factor for survival and one of the most important factors affecting CSS in multivariate analysis.
Siddiqui et al. (27) evaluated the prognostic value of perinephric fat invasion and concluded that it was a negative prognostic factor in all tumor sizes and that it was unnecessary to utilize the tumor size for grouping the T3a stage. On the other hand, Yoo et al. (28) found that >7 cm pT3a tumors had a worse prognosis than ≤7 cm pT3a tumors and concluded that tumor size should be included for more accurate staging for patients with perinephric fat tissue invasion. Murphy et al. (29) compared stage T2 and T3a patients according to clinicopathological features and pointed out that tumor size was a more significant prognostic factor than perinephric fat invasion. Gofrit et al. (30) also advocated that perinephric fat invasion was an insignificant prognostic factor, and in the new TNM staging system that they proposed, they excluded perinephric fat invasion and included tumor size and venous involvement. Our results, similar to the last two studies, confirmed that perinephric fat invasion was an important prognostic factor for survival alone, but not an independent factor in Cox regression analysis.
Tumor size is very important in the T staging of renal tumors and provides important information about prognosis, treatment method and survival. There are many studies mentioned above in which T1 and T2 stage renal tumors were stratified and the relationship between tumor size and other important prognostic factors was analyzed. In this study, we focused on T2b-stage tumors and evaluated the relationship between prognostic factors and survival. In the light of our study, perhaps further stages between T2b and T3 may be identified in the future with prospective, randomized, large patient group studies.
Our study is unique since it was the first study to evaluate prognostic factors in kidney tumors over 10 cm in diameter. The evaluation of pathologic specimens by an experienced, single genitourinary pathologist is a significant advantage of our study. Our study also had some limitations. Although the patient data were carefully reviewed from the files, the retrospective nature of the study and relatively small patient group were the main drawbacks. A total of 87 patients out of 126 received adjuvant treatment and this was a confounding variable that might affect the result. Another important limitation was the absence of a comparison group and that might have generated a selection bias.
Conclusion
Tumor size is an important factor affecting the treatment modalities, technique and prognosis in T1 and T2 stage tumors. However, our results showed that this effect was minimal and other clinicopathological features were important in T2b and higher stage tumors. Adjuvant therapy was also found to be a significant factor affecting CSS. Prospective studies are needed for a higher level of evidence.
Ethics
Ethics Committee Approval: Because of the study was designed as a retrospective study, ethics committee approval was not obtained.
Informed Consent: Written informed consent was taken from all patients in order to be able to use their data in scientific studies without revealing their private information.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: F.K., A.Ş., E.A., S.K., S.Ş., B.S., Ç.Ç., İ.C., Concept: F.K., A.Ş., Design: F.K., A.Ş., Data Collection or Processing: F.K., A.Ş., E.A., S.K., S.Ş., B.S., Analysis or Interpretation: F.K., A.Ş., E.A., S.K., S.Ş., B.S., Ç.Ç., İ.C., Literature Search: F.K., Writing: F.K.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.