Abstract
Aim: To evaluate the prognostic value of tumor size in patients with pathological T3aN0M0 renal cell carcinoma (RCC) postoperatively. Patients and Methods: We retrospectively reviewed charts of patients with pathological T2N0M0 and T3aN0M0 RCC undergoing radical or partial nephrectomy at our Institution from 2000-2020. Survival analysis using Kaplan–Meier analysis and multivariate Cox regression was performed. Results: A total of 165 patients were included and analyzed. We found that patients with pT3a RCC >7 cm experienced worse 5-year recurrence-free survival (43.8% versus 77.3%, p=0.006) and cancer-specific survival (67.6 versus 94%, p=0.003) compared with those with pT3a RCC ≤7 cm. However, there was no significant difference in recurrence-free and cancer-specific survival between patients with pT2 and pT3a RCC ≤7 cm. Based on multivariate analysis, tumor size >7 cm was an independent factor for tumor recurrence and cancer-related death [hazard ratio(HR)=2.654, p=0.005; and HR=5.016, p=0.005, respectively]. Renal vein invasion was associated with poorer 5-year recurrence-free survival than fat invasion (48.1% versus 70.9%, p=0.032) and was a predictor for tumor recurrence (HR=1.987, p=0.043). Conclusion: Tumor size has a significant impact on prognosis for patients with pathological T3aN0M0 RCC and should be taken into consideration when staging disease and predicting outcomes for these patients.
The tumor, node and metastasis (TNM) staging system is a standard and useful method for risk stratification and for predicting prognosis of patients with malignancy. According to the recent eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system, T-staging for renal cell carcinoma (RCC) is defined by tumor size and extrarenal extension (1). The staging system defines stage pathological (p) T1 and pT2 on the basis of tumor size alone, whereas pT3a is classified based on anatomic tumor invasion regardless of tumor size. Such invasion includes perirenal fat invasion (FI), renal sinus FI, renal vein invasion (RVI) and pelvicalyceal system invasion. Prognosis for patients with stage pT3a RCC is heterogeneous and whether different sites of invasion carry similar prognostic values remains controversial (2–8). Furthermore, several studies also reported that tumor size has an impact on the oncological outcomes for patients with stage pT3a RCC (9–15). Herein, we aimed to first evaluate the impact of tumor size on the prognosis for patients with pT3a RCC, and subsequently to compare oncological outcomes between pT3a RCC and pT2 RCC. In addition, we analyzed the prognostic significance of different invasion sites for pT3a RCC.
Patients and Methods
After approval by the Institutional Review Board (CE13240A-3), we retrospectively analyzed data of 655 patients who underwent surgery for RCC at our hospital over a 20-year period, from 2000 to 2020. According to the 2017 AJCC TNM system (1), we identified a total of 165 patients with stage pT2N0M0 and with pT3aN0M0 RCC for analysis.
Image study using computed tomography or magnetic resonance imaging was performed preoperatively for the clinical staging of renal tumors. Pathological review was conducted by our experienced pathologists to determine tumor stages and histopathological features. All patients underwent postoperative follow-up using computed tomography or magnetic resonance imaging at 3- to 6-month intervals.
Patient demographics, clinicopathological features and surgical characteristics were extracted for evaluation. Continuous variables are expressed as medians and interquartile ranges (IQRs). The Kruskal–Wallis test was used to compare the means of continuous variables, while the Pearson chi-square test was used to compare categorical variables. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using the Kaplan–Meier method and a log-rank test was applied to compare survival curves. The duration of survival analysis was calculated from the date of surgery to the date of diagnosis of metastasis (RFS), the date of death from cancer (CSS), or last follow-up. Univariable and multivariable Cox proportional hazard regression models were used to assess prognostic values of clinical and pathologic factors. Statistical significance was set at p≤0.05. All analyses were performed using SPSS software (version 19.0; SPSS Inc., Chicago, IL, USA).
Results
We identified 165 patients who underwent partial or radical nephrectomy for stage pT2N0M0 and pT3aN0M0 RCC. According to the pathological tumor stage and tumor size, patients were divided into three groups: pT2, pT3a ≤7 cm and pT3a >7 cm. Their clinical and pathological characteristics are listed in Table I.
Patient demographics, pathological characteristics and outcomes.
There were 53 patients in the pT2a group, 65 patients in the pT3a ≤7 cm group, and 47 patients in the pT3a >7 cm group. Their median (IQR) tumor size was 9 (7.7-10) cm, 5.2 (3.9-6.0) cm and 9.0 (7.7-10) cm, respectively. Patients with pT3a ≤7 cm tumors were older (p=0.03) and had more clear-cell RCC (p<0.001). More cases with partial nephrectomy were in the pT3a RCC ≤7 cm group (p=0.019). During a median follow-up period of 51 (IQR=19.5-86) months, 51 patients (30.9%) overall experienced disease recurrence, with patients in the pT3a >7 cm group having significantly more disease recurrence (22%, p=0.015). Nineteen patients (11.5%) died from disease progression and patients in the pT3a >7 cm group had significantly lower CSS (at the end of follow-up: 74.5% versus 93.8%, p=0.002).
Results of survival analyses using the Kaplan–Meier method are shown in Figure 1. Patients with pT3a tumor >7 cm experienced significantly worse 5-year RFS than those with pT3a tumor ≤7 cm (43.8% versus 77.3%, p=0.003). Furthermore, pT3a tumor >7 cm was associated with worse 5-year CSS when compared with pT3a tumor ≤7 cm (67.6% versus 94.0%, p=0.03). RFS and CSS for patients with pT3a tumor ≤7 cm were similar to those for patients with pT2a tumors (p=0.721 and p=0.831, respectively). Figure 2 shows the comparison of survival between patients with pT2, pT3a with FI and pT3a with RVI (with/without FI). Patients with pT3a RVI/FI experienced significantly worse 5-year RFS compared with patients with FI alone (48.1% versus 70.9%, p=0.032). Patients with FI had higher 5-year CSS than those with RVI/FI, but this did not reach statistical significance (85.6% versus 77.7%, p=0.28).
Recurrence-free (A) and cancer-specific (B) survival among three groups of patients with renal cell carcinoma: pT2, pT3a ≤7 cm, and pT3a >7 cm. Having pT3a tumor >7 cm group was associated with poor recurrence-free and cancer-specific survival.
Comparison of recurrence-free (A) and cancer-specific (B) survival for patients with pT2 renal cell carcinoma, pT3a with fat invasion (FI) and pT3a with renal vein invasion (RVI) (with or without FI). Patients with pT3a with RVI/FI had significantly poorer recurrence-free survival.
Based on univariate analyses, tumor size >7 cm (HR=2.634, 95% CI=1.345-5.16, p=0.005), RVI (HR=2.002, 95% CI=1.045-3.904, p=0.037) and high Fuhrman grade (HR=2.321, 95% CI=1.138-4.735, p=0.021) were significantly associated with poorer RFS. Multivariate analyses also showed that tumor size >7 cm (HR=2.654, 95% CI=1.341-5.251, p=0.005), RVI (HR=1.987, 95% CI=1.022-3.863, p=0.043) and high Fuhrman grade (HR=2.682, 95% CI=1.299-5.535, p=0.008) were independent prognostic factors for tumor recurrence (Table II). Regarding CSS, tumor size >7 cm (HR=4.828, 95% CI=1.554-14.996, p=0.006) and high Fuhrman grade (HR=7.402, 95% CI=1.673-22.757, p=0.008) were both predictors for poor survival based on univariate analyses. Multivariate analyses confirmed that tumor size >7 cm (HR=5.016, 95% CI=1.611-15.617, p=0.05) and high Fuhrman grade (HR=7.695, 95% CI=1.734-34.142, p=0.007) were both associated with poor CSS (Table III).
Univariate and multivariate analyses of prognostic factors for recurrence-free survival of patients with renal cell carcinoma.
Univariate and multivariate analyses of prognostic factors for cancer-specific survival of patients with renal cell carcinoma.
Discussion
TNM staging system is a useful tool for risk stratification of patients, and for predicting their disease outcomes. The latest TNM system classifies pT1 and pT2 RCC based on tumor size only, with pT3 RCC subdivided according to characteristics of tumor invasion without considering tumor size. Therefore, stage pT3a RCC includes renal tumors of different sizes, with the possibility of heterogeneous prognosis for these patients (1). Our previous report indicated RVI was associated with poor oncological outcomes when compared with invasion of perirenal or sinus fat for patients with pT3a RCC (8). In the present study, we divided patients with pT3a RCC into two groups based on their tumor sizes at a cutoff value of 7 cm. We found that patients with pT3a renal tumors >7 cm experienced worse RFS and CSS than those with pT3a ≤7 cm, and that pT3a tumor >7 cm is an independent predictor.
Several previous studies have demonstrated the prognostic value of tumor size for patients with pT3a renal tumor. These studies reached similar conclusions: tumor size at the cutoff value of 7 cm should be considered for staging pT3a RCC (9–11). Nevertheless, previous studies had adopted an older version of the AJCC TNM system (sixth), which defined renal tumors with adrenal extension as stage pT3a, and those with renal vein invasion as pT3b. The discrepancy between staging versions may lead to some bias. Recently, several studies investigated the importance of tumor size on prognosis when using the 2010 or 2017 AJCC TNM system. Their finding was that pT3a renal tumor >7 cm is associated with lower RFS or CSS, and tumor size is an independent predictive factor of such outcomes (12–15). Furthermore, Brookman-May et al. (12) and Sugiyama et al. (14) both reported prognostic similarities between smaller pT3a renal tumors and their pT1 or pT2 counterparts. Our findings are consistent with the results of those studies: patients with pT3a renal tumor ≤7 cm and pT2 experienced similar oncological outcomes. Hence, both tumor size and invasion site should be considered when staging such patients.
Adjuvant therapy with the vascular endothelial growth factor receptor tyrosine kinase inhibitor for high-risk locally advanced RCC has been investigated in several studies. Results from the Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) study showed that adjuvant sunitinib for patients with locoregional high-risk RCC improved disease-free survival, while the Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma (AUUURE) and Pazopanib as Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy (PROTECT) trials reported no survival benefit (16–18). Sun et al., in a pooled analysis, concluded that adjuvant targeted therapy is not associated with consistent improvement in RFS or overall survival, and may even result in significant side-effects (19). Furthermore, several trials are investigating the use of adjuvant immune checkpoint inhibitors for patients with high risk RCC [reviewed in (20)], and tumor size is not typically considered when subdividing these patients for outcome prediction. Our present study found that pT3a RCC >7 cm was associated with worse RFS and CSS. Thus, tumor size might be taken into consideration when risk stratification either in the setting of clinical trials or real-world practice.
According to the eighth AJCC TNM staging system (1), stage T3a RCC is defined by various patterns of extrarenal extension, including RVI, perirenal FI, renal sinus FI, and pelvicalyceal system invasion. Previous studies reported that the prognostic value of different sites of extrarenal extension is heterogeneous, and it remains a subject of debate. Baccos et al. (6) and Shah et al. (7) found that tumors with RVI and FI carried similar prognosis. On the contrary, Jung et al. (3) and Park et al. (5) reported that patients with RVI experienced poor RFS and CSS. Our previous study also found that patients with RVI have poorer prognosis when compared with those with FI (8). In the present study, we found that RCC with RVI was associated with worse RFS and that it was a factor for higher recurrence rates based on multivariate analysis but did not reach statistical significance for CSS on multivariate analysis. The difference may be related to patient selection, as our previous study included patients with lymph node involvement. Such patients were excluded from the present study.
Several limitations exist for this study: Firstly, due to the retrospective design and relatively small sample size, there was inevitably inherent bias. Secondly, given the data collected spanned a 20-year period, from 2000 to 2020, the temporal difference across pathologists, surgical methods and systemic treatment likely affected the accuracy of our analysis. Despite such limitations, the present study enrolled patients with pT2aN0M0 and pT3aN0M0 renal tumors undergoing surgery at a single institution, therefore avoiding inter-institutional bias.
In conclusion, tumor size had a significant impact on the prognosis for patients with pT3aN0M0 RCC. The prognosis for patients with pT3a RCC >7 cm was worse than those with pT2 or pT3a RCC ≤7 cm. Patients with pT3a RCC ≤7 cm experienced similar outcomes to patients with pT2 RCC. In addition, RVI negatively influenced the prognosis in patients with pT3a RCC. Thus, tumor size and sites of invasion should be considered when evaluating patients with pT3a RCC and further investigation is warranted to determine better their prognostic significance.
Footnotes
Authors’ Contributions
The study was designed by GSL. Data were provided and analyzed by JRL, SSW, CSC, CKY, SCH, CLC, YCO and KYC. The article was drafted by GSL. All Authors read and approved the article for publication.
Conflicts of Interest
There are no conflicts of interest.
- Received February 4, 2022.
- Revision received February 26, 2022.
- Accepted March 3, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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