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Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma
EUROPEAN UROLOGY 56 (2009) 1006–1012
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Kidney Cancer
Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma Hyuk-Jin Cho a, Su Jin Kim a, U-Syn Ha a, Sung-Hoo Hong a, Joon Chul Kim a, Yeong-Jin Choi b, Tae-Kon Hwang a,* a
Department of Urology, Kangnam St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
b
Department of Pathology, Kangnam St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
Article info
Abstract
Article history: Accepted November 18, 2008 Published online ahead of print on November 28, 2008
Background: The impact of capsular invasion on the survival of patients undergoing surgery for renal cell carcinoma (RCC) has attracted little attention in the literature and remains controversial. Objectives: To evaluate the value of capsular invasion, without perirenal fat invasion, on the prognosis of patients with localized clear-cell RCC. Design, setting, and participants: Between 1984 and 2007, we retrospectively reviewed the records of 317 consecutive patients with localized clear-cell RCC (pT1–T2N0M0) who underwent radical nephrectomy or nephron-sparing surgery at our institution. Overall, 299 patients were eligible for the study. We analyzed clinical (presentation and body mass index [BMI]) and pathologic (tumor size, Fuhrman nuclear grade, collecting system invasion, microvascular invasion, and capsular involvement) parameters. Measurements: Recurrence-free survival (RFS) and cancer-specific survival (CSS) were investigated using the Kaplan-Meier method, and the Cox regression model was used to determine the significant prognostic factors based on multivariate analysis. Results and limitations: Renal capsular invasion was observed in 106 of 299 patients (35.5%). Capsular invasion had a statistically significant association with age, symptomatic presentation, tumor diameter, pathologic stage, collecting system invasion, and microvascular invasion. The mean follow-up was 60.5 mo (range: 1–249). The 5-yr RFS and CSS rates for tumors with capsular invasion were significantly lower compared with rates for tumors without invasion (77.7% vs 92.3% and 85.5% vs 95.7%, respectively; p = 0.0004). Multivariate analysis showed that BMI (hazard ratio [HR] = 0.19), stage (HR = 2.45), and capsular invasion (HR = 3.36) were independent prognostic factors of disease recurrence. With respect to CSS, BMI (HR = 0.20), tumor size (HR = 1.13), and capsular invasion (HR = 4.03) were the factors related to death. Nevertheless, we recognize that these findings may be limited by the study’s retrospective, single-institution design. Conclusions: Our findings suggest that capsular invasion is associated with poor survival in patients with localized clear-cell RCC. # 2009 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Capsule Prognosis Renal cell carcinoma Staging
* Corresponding author. Department of Urology, Kangnam St. Mary’s Hospital, 505, Banpo-dong, Seocho-gu, Seoul 150-713, Korea. Tel. +82 2 590 1386; Fax: +82 2 599 7839. E-mail address: [email protected] (T.-K. Hwang). 0302-2838/$ – see back matter # 2009 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eururo.2008.11.031
EUROPEAN UROLOGY 56 (2009) 1006–1012
1.
Introduction
The incidence of renal cell carcinoma (RCC) is on the rise, in part due to the more frequent use of abdominal imaging. Although the rate of metastatic RCC at initial presentation remains substantial, the incidence of asymptomatic, pathologically localized RCC has demonstrated the greatest increase [1–3]. Despite displaying a pathologically confined disease at the time of nephrectomy, 20–40% of patients demonstrate local recurrence or distant metastasis after nephrectomy [4,5]. This fact has led to research on the clinical behavior of the disease to identify the pathologic parameters of a worse prognosis and define groups of patients with more chances of disease recurrence. The 2002 TNM classification is based only on tumor size for predicting survival in localized tumors. Therefore, additional prognostic factors are needed that will predict high-risk patients. The impact of capsular invasion on the survival of patients undergoing surgery for RCC has attracted little attention in the literature and remains controversial [6–8], ranging from no influence on patient outcome [8] to being the most relevant prognostic factor influencing patient survival [7]. Two previous studies [6,8] clustered chromophobe, papillary, and clear-cell RCC subtypes into a single pathologic entity during analysis, despite the known histologic, genetic, and prognostic differences of these RCC subtypes. Therefore, we determined whether capsular invasion (without penetration) was an independent predictor of prognosis for patients with localized clear-cell RCC after surgical resection with curative intent.
2.
1007
Methods
The records of 317 consecutive patients surgically treated for localized (pT1-2/N0/M0), unilateral, sporadic clear-cell RCC at our institution between 1984 and 2007 were reviewed retrospectively. Patients with insufficient pathologic data (n = 2) or inadequate follow-up (n = 16) were excluded, leaving 299 patients available for analysis. Associations with outcome were evaluated for patients with clearcell RCC only, given the documented differences in outcome and associations with outcome by RCC histologic subtype. The surgical procedures included open radical nephrectomy in 126 cases (42.1%), laparoscopic radical nephrectomy in 141 cases (47.2%), open partial nephrectomy in 4 cases (1.3%), and laparoscopic partial nephrectomy in 28 cases (9.4%). Initial pathologic evaluation was performed by 1 of 10 pathologists and later confirmed by a single pathologist. All histologic sections were fixed with buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin (H&E). All of the resected tumors were macroscopically and microscopically examined for tumor diameter, pathologic tumor stage (pT1 vs pT2), tumor grade (1 and 2 [low-grade], 3 and 4 [high-grade]), microvascular tumor invasion, collecting system invasion, and cell type. Capsular invasion was defined as either infiltrative invasion with the tumor protruding into the capsule or when the tumor cell nest was observed in the capsule or when the renal capsule was invaded via tumor expansion (Fig. 1). Prognosis according to depth of capsule invasion was also studied. However, because the tumors were located in different areas, the thickness of the capsules varied as well. Therefore, we took an inverse approach in which we measured from the border between the perirenal fat and capsule to the tumor (in millimeters). Tumors were staged according to the 2002 TNM criteria [9] for pathologic staging and Fuhrman’s criteria [10] for tumor grading. All clinical charts of the
Fig. 1 – Photomicrograph of renal capsule invasion; (a) expansile invasion—renal cell carcinoma with overlying attenuated renal capsule (arrow) with expanding tumor invasion; (b) infiltrative capsule invasion—renal cell carcinoma showing protruding tumor cell invasion (arrow); (c) infiltrative capsule invasion—a separate tumor cell nests in the renal capsule (arrow).
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EUROPEAN UROLOGY 56 (2009) 1006–1012
clinical presentation (symptomatic and incidental), and BMI. The BMI
Table 1 – Characteristics in 299 patients with T1–T2N0M0 clearcell renal tumors
was categorized based on the cut-off points for Asians, as recommended
Variable
patients were reviewed for clinical variables, including age, gender,
by the World Health Organization (<23, 23–25, and >25 kg/m2) [11]. Continuous variables are shown as the mean standard deviation (SD) or range, and categoric data are shown as the absolute and relative frequencies. Patients were evaluated every 3 mo for the first 2 yr after treatment,
Median age (range) Follow-up (mo) Mean SD Median (range) Mean tumor diameter (cm) (range)
Value 56 (25–86) 60.5 55.3 52.3 (1–249) 4.7 (0.8–20)
every 6 mo for the next 3 yr, and yearly thereafter with chest x-ray, abdominal ultrasonography or computed tomography (CT), and serum
n (%)
chemistries.
Gender Male Female Clinical presentation Incidental Symptomatic Surgery Radical Nephron-sparing pT stage (TNM 2002) T1a T1b T2 Fuhrman grade I II III IV Microvascular invasion Collecting system invasion Capsular invasion
The main end points were the correlation between the presence of capsular invasion and other pathologic findings, and the correlation between rates of recurrence-free survival (RFS) and rates of cancerspecific survival (CSS) with pathologic outcomes. For the statistical analysis, we used the chi-square test or student t test to evaluate the associations among the listed variables. The Kaplan-Meier method was used to determine CSS and RFS rates, and the differences among the CSS and RFS rates were analyzed using the log-rank test. Univariate and multivariate analyses were assessed with the Cox proportional hazards model. For each prognostic factor, the hazard ratio (HR) in the univariate analysis and the adjusted HR in the multivariate analysis are given, including the 95% confidence interval (CI). The k statistic, which is a measure of agreement between observers that corrects for chance agreement, was used to evaluate the concordance between original and reviewed capsular invasion. Concordance was considered to be fair, 0.00–0.20; moderate, 0.21–0.45; substantial, 0.46–0.75; almost perfect, 0.76–0.99; or perfect, 1.00 [12]. To evaluate the prognostic value of capsular invasion, the authors also constructed an additional multivariate model adjusting for the Mayo Clinic SSIGN score, which is a
195 (65.2) 104 (34.8) 213 (71.2) 86 (28.8) 267 (89.3) 32 (10.7) 163 (54.5) 89 (29.8) 47 (15.7) 60 193 44 2 24 42 106
(20.1) (64.5) (14.7) (0.7) (8.0) (14.0) (35.5)
SD = standard deviation.
composite scoring system that was developed specifically for patients with clear-cell RCC [13]. In all tests, p < 0.05 was considered to be statistically significant.
invasion was analyzed simply as being either ‘‘present’’ or ‘‘absent’’ as a prognostic pathologic feature of RCC.
3.
Results
3.2.
3.1.
Patient characteristics
Treatment failure in the form of local tumor recurrence and/ or metastasis was encountered in 33 (11.0%) patients. Kaplan-Meier curves revealed a much better RFS in patients without capsular invasion ( p = 0.004, Fig. 2a). The 5- and 10-yr RFS rates of patients with capsular invasion (77.7% and 69.1%, respectively) were significantly worse than rates in those without invasion (92.3% and 85.9%, respectively). In addition to capsular invasion, the following five clinical and pathologic variables were associated with RFS (Table 3): symptoms, microvascular invasion, pT stage, tumor size, and BMI. The risk of recurrence from RCC for patients with a BMI of 25 kg/m2 was reduced to about 31% of that in patients with a BMI of <23 kg/m2. Patient gender, age, and tumor grade had no statistically significant impact on RFS, while collecting system invasion was of marginal significance ( p = 0.051). On multivariate analysis, capsular invasion, pT stage, and BMI were important prognostic factors for RFS (Table 3). Patients with capsular invasion were at approximately 3.3 times the risk of recurrence compared with patients without capsular invasion.
Of the 299 patients, 252 (84.3%) and 47 (15.7%) patients were classified as T1 or T2, respectively. Capsular invasion was seen in 106 (35.5%) patients. Interobserver variability regarding capsular invasion showed almost perfect agreement (k = 0.79), demonstrating high reliability. The mean age was 56 yr (range: 25–86) and the mean follow-up in all patients was 60.5 55.3 mo (median: 52.3; range: 1–249). All 32 patients (10.7%) who underwent nephron-sparing surgery had negative margins. Table 1 lists the clinical and pathologic features of the 299 patients. We observed a statistically significant association of capsular involvement with age, symptoms, pathologic stage, tumor size, microvasular invasion, and collecting system invasion (Table 2). High-grade tumors had a greater tendency to be associated with capsular invasion (12.4% vs 20.8%; p = 0.056). The mean distance from the borderline between perirenal fat and capsule to the tumor was 0.136 mm (range: 0.00–1.50), and this depth of invasion was shown by Cox proportional hazard models not to have a statistically significant correlation with RFS and CSS (HR = 6.02; 95% CI, 0.59–61.51; p = 0.13 and HR 5.09; 95% CI, 0.18–136.39; p = 0.33, respectively). Therefore, in our study, capsular
3.3.
Recurrence-free survival
Cancer-specific survival
Cancer-related death occurred in 22 patients (7.4%) during follow-up. Capsular invasion was also associated with a
EUROPEAN UROLOGY 56 (2009) 1006–1012
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Table 2 – Association between different variables and capsular invasion Variable Age (yr) <50 50 Tumor diameter SD (cm) Gender Male Female Clinical presentation Incidental Symptomatic pT stage (TNM 2002) T1a T1b T2 Grade Low (1–2) High (3–4) Microvascular invasion Absent Present Collecting system invasion Absent Present
Negative invasion
Positive invasion
p value
77 (33.9) 116 (60.1) 4.1 2.1
25 (23.6) 81 (76.4) 5.7 3.6
121 (62.7) 72 (37.3)
74 (69.8) 32 (30.2)
– 0.216
145 (75.1) 48 (24.9)
68 (64.2) 38 (35.8)
– 0.045
119 (61.7) 56 (29.0) 18 (9.3)
44 (41.5) 33 (31.1) 29 (27.4)
– – <0.001
169 (87.6) 24 (12.4)
84 (79.2) 22 (20.8)
– 0.056
183 (94.8) 10 (5.2)
92 (86.8) 14 (13.2)
– 0.015
177 (91.7) 16 (8.3)
80 (75.5) 26 (24.5)
– <0.001
– 0.004 <0.001
SD = standard deviation.
poor CSS rate: the 5- and 10-yr survival rates were 85.5% and 69.5% for patients with capsular invasion and 95.7% and 90.6% for those without capsular invasion, respectively ( p = 0.004, Fig. 2b). Among other variables, pT stage, tumor size, and BMI were associated with the CSS rate in the univariate analysis. Multivariate analysis showed that capsular invasion, tumor size, and BMI were independent factors for CSS (Table 4). Capsular invasion remained significantly associated with RFS (HR = 2.71; 95% CI, 1.30– 5.66; p = 0.008) and CSS (HR = 4.39; 95% CI, 1.78–10.81; p = 0.001) after adjusting for the SSIGN score. Taken together, capsular invasion was associated with a risk of disease recurrence and death in patients with localized clear-cell RCC.
Because the majority of the patients in this study were pT1 (84.3%), Kaplan-Meier curves for the RFS and CSS were analyzed separately for this subgroup. The 5-yr RFS rate for the presence or absence of capsular invasion was estimated at 82% and 92% ( p = 0.006), while the 5-yr CSS rate was 89% and 96% ( p = 0.005), respectively. 4.
Discussion
It has been recently reported that the incidence of RCC, especially early-stage, small, incidentally discovered tumors is on the rise, suggesting diagnosis at an earlier stage as a result of earlier detection [1–3]. This might be explained, in part, by the increased number of early stage
Fig. 2 – (a) Recurrence-free and (b) cancer-specific survival curves for capsular invasion.
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Table 3 – Cox regression analysis for recurrence-free survival
Table 4 – Cox regression analysis for cancer-specific survival
Variable
Variable
Univariate model Presentation (symptoms/incidental) MVI Stage (pT2/pT1) Tumor size (cm)a BMI (kg/m2) (23–25/23) (25/23) Capsular invasion Grade (3 and 4 or 1 and 2) Collecting system invasion Multivariate model Capsular invasion BMI (kg/m2) (23–25/23) (25/23) Stage (pT2/pT1)
HR
95% CI
p value
2.024 3.444 2.522 1.222
1.017–4.148 1.411–8.409 1.200–5.304 1.120–1.334
0.044 0.006 0.014 0.001
0.491 0.314 3.069 1.982 2.239
0.215–1.125 0.117–0.843 1.514–6.222 0.934–4.204 0.995–5.034
0.092 0.021 0.001 0.074 0.051
3.366
1.573–7.201
0.001
0.336 0.197 2.458
0.134–0.846 0.058–0.668 1.117–5.409
0.062 0.009 0.025
Univariate model Presentation (symptoms/incidental) MVI Stage (pT2/pT1) Tumor size (cm)a BMI (kg/m2) (23–25/23) (25/23) Capsular invasion Grade (3 and 4 or 1 and 2) Collecting system invasion Multivariate model Capsular invasion BMI (kg/m2) (23–25/23) (25/23) Tumor size (cm)a
HR
95% CI
p value
1.261 1.091 2.502 1.155
0.538–2.953 0.254–4.673 1.019–6.142 1.035–1.288
0.593 0.906 0.045 0.009
0.502 0.173 4.391 1.193 1.547
0.192–1.305 0.039–0.764 1.783–10.821 0.438–3.251 0.569–4.198
0.159 0.021 0.001 0.729 0.391
4.039
1.634–9.983
0.002
0.510 0.200 1.135
0.195–1.329 0.045–0.884 1.008–1.278
0.168 0.033 0.036
HR = hazard ratio; CI = confidence interval; MVI = microvascular invasion; BMI = body mass index. a Continuous variable.
HR = hazard ratio; CI = confidence interval; MVI = microvascular invasion; BMI = body mass index. a Continuous variable.
RCC now being detected as a result of widespread use of imaging modalities for evaluating a wide variety of abdominal and pelvic symptoms. Predicting the risk of recurrence after nephrectomy for low-stage RCC is crucial because a higher risk status requires closer postoperative surveillance, and earlier detection of disease recurrence may provide the most favorable outcomes. The prognosis for patients with RCC is primarily dependent on disease stage. Localized disease (pathologic stage pT1-2) confers the best prognosis, with 5-yr CSS rates after nephrectomy ranging from 71% to 97% [14,15]. Currently, tumor size (in particular, greatest tumor dimension) is the only prognostic indicator used by the TNM classification system for localized tumors. Tumor size as a single prognostic factor may be considered insufficient for describing the biological heterogeneity of renal tumors, even when localized. It then seems reasonable to introduce new variables within the T1 and T2 stages that would help define prognostic factors within this increasingly important cohort of patients. Capsular invasion has been evaluated as a prognostic indicator in localized RCC. To the best of our knowledge, there are only three retrospective studies dealing with the prognostic value of capsular invasion in RCC [6–8]. Early studies suggested that patients with this histological finding had a poor prognosis with a greater chance of disease progression [6,7]. In contrast, one study indicated no association between capsular invasion and prognosis [8]. The observed rate of capsular invasion in our study was 35.5%, equivalent to that reported by Jeong et al [7] and Su¨er et al [8]. At a mean follow-up of 60.5 mo, we clearly demonstrated the discriminating role of capsular invasion as a prognostic factor for RCC. The 5-yr RFS and CSS rates were 92.3% and 95.7% for negative capsular invasion, respectively, in contrast to 77.7% and 85.5% for positive capsular invasion. This result is in accordance with other studies. Klatte et al [6] evaluated 519 patients with localized RCC and observed RFS
in 75.6% and 86.9% of patients with or without capsular invasion, respectively, at a median follow-up of 49 mo. In their multivariate analysis, capsular invasion, collecting system involvement, Eastern Cooperative Oncology Group (ECOG) performance status, tumor grade, and tumor size affected RFS. Interestingly, they reported that patients with capsular involvement had the same RFS as patients with stage pT3aN0M0 RCC. As in the present study, tumor grade and size were associated with an incidence of capsular invasion. In addition, Jeong et al [7] analyzed 288 patients with clear-cell RCC who underwent a radical nephrectomy. They demonstrated the independent prognostic role of capsular invasion, with a marked difference in the CSS rate for stage pT2. They showed that capsular invasion was associated with a more advanced pT stage. A recent study conducted by Su¨er et al [8] did not identify capsular invasion as an independent factor. The 5-yr CSS rates in patients with or without capsular invasion were 92.68% and 90.4%, respectively. Unfortunately that study had some important limitations. The authors were unable to show that Fuhrman grade and tumor size—the most widely recognized prognostic factors for RCC—were independent prognostic factors for these patients. The mean follow-up was also relatively short (40.7 mo). These investigators suggested that capsular invasion is not an indicator of aggressive biological behavior but merely reflects that a tumor had a peripheral origin. They did not evaluate the association between capsular invasion and tumor location, but they did report a relation between capsular invasion for higher Fuhrman grade and pathologic tumor stage. From our study, patients with capsular invasion had a substantially higher risk of progression of RCC. Moreover, the risk of recurrence and death increased by 3.36 and 4.03 times, respectively. We herein report that patients with RCC tumors invading the renal capsule remain at significant risk of recurrence and death, even after adjusting for the SSIGN score. It is difficult to provide a scientifically sound
EUROPEAN UROLOGY 56 (2009) 1006–1012
explanation for this finding. Significantly greater proportions of patients with capsular invasion were symptomatic at diagnosis, had a higher tumor stage, had microvascular invasion, and had collecting system invasion. Mean tumor size was greater in capsular invading tumors. There was also a tendency for an association between capsular involvement and high-grade tumor. We believe that the association of capsular invasion with other poor prognostic pathologic findings reflects the overall aggressive biology of these tumors. Generally, worse tumor grades have been shown to be associated with an increased incidence of recurrence and poor survival [16,17]. However, an association with grade was not established in our series. Most of the literature to date has reported survival differences between low-grade (including both grades 1 and 2) and high-grade (including both grades 3 and 4) tumors, and we used such groupings as well. However, a key anomaly in our Fuhrman grade distribution must be noted: only 0.7% (4) grade IV tumors were included, and low-grade tumors made up 84.6% of the study population. As a result of such bias, the Fuhrman grade was inappropriately found not to be a prognostic factor. A comparison among the various studies of capsular invasion is difficult because of variations in inclusion criteria, nonstandardized therapeutic procedures, duration of follow-up, and definition of end points (RFS, CSS, and overall survival). Moreover, all of the studies, including the current study, were limited by the retrospective design. In the current study, we restricted our analysis to patients with localized, clear-cell RCC. We believe that we minimized the potential for confounding bias that might emanate from combining localized and advanced RCC patients into one group or combining all RCC histologic subtypes into one pathologic entity. Our findings suggest that including capsular invasion in future RCC staging systems is warranted because of the relative frequency in low-stage tumors and the independent effect of this factor on recurrence and death. By adding capsular invasion in estimating prognosis in patients with pT1-2 tumors, the predictive value of the TNM staging system can be improved considerably with regard to survival. It is important to confirm these findings prospectively by using multicentric studies to obtain more significant statistics.
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Study concept and design: Cho. Acquisition of data: Kim. Analysis and interpretation of data: Ha, Kim. Drafting of the manuscript: Cho. Critical revision of the manuscript for important intellectual content: Kim, Hwang. Statistical analysis: Hong. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Choi, Hwang. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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5.
Conclusions
Capsular invasion is associated with specific clinical findings, as well as poor prognostic variables, and it is an important independent predictor of survival for patients with localized clear-cell RCC. If corroborated at other large centers, the addition of capsular invasion will add additional prognostic information to the TNM system, which currently is based only on tumor size.
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Author contributions: Tae-Kon Hwang had full access to all the data in
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the study and takes responsibility for the integrity of the data and the
stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168:
accuracy of the data analysis.
2395–400.
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[14] Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H.
[16] Dall’Oglio MF, Ribeiro-Filho LA, Antunes AA, et al. Microvascular
Independent validation of the 2002 American Joint Committee
tumor invasion, tumor size and Fuhrman grade: a pathological triad
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using a large, single institution cohort. J Urol 2005;173: 1889–92. [15] Bedke J, Pritsch M, Buse S, et al. Prognostic stratification of localized renal cell carcinoma by tumor size. J Urol 2008;180:62–7.
Editorial Comment on: Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma Alessandro Volpe Division of Urology, Maggiore della Carita` Hospital, University of Eastern Piedmont, Corso Mazzini, 18, 28100, Novara, Italy [email protected] Renal cell carcinoma (RCC) is characterized by very heterogeneous biological and clinical behavior. Despite timely and technically correct surgical treatment, some patients with localized RCC develop unexpected recurrence. Accurate prognostic factors are needed to identify low-stage tumors at higher risk of recurrence that should be followed with stricter postoperative surveillance protocols. Pathologic features such as tumor size, nuclear grade, and microvascular and collecting system invasion were already found to have prognostic implications for organ-confined RCCs. The presence of a fibrous pseudocapsule in renal tumors has been described since the late 1940s. Minervini et al recently presented a detailed histopathologic analysis of tumoral pseudocapsule in patients who underwent enucleation of RCC, confirming the presence of a continuous, nonfenestrated layer of dense connective tissue completely surrounding the tumor in all cases [1]. The potential prognostic role of RCC capsular invasion has attracted little attention until recently [2–4]. In this issue of European Urology, Cho et al investigate the impact of capsular invasion on disease recurrence and survival in a series of 299 patients who underwent radical nephrectomy or nephron-sparing surgery for pT1-T2 N0 M0 clear-cell RCC at their institution [5]. The authors observed that capsular invasion without perirenal fat infiltration is a frequent finding in localized tumors (35.5%) and significantly correlates with age, symptomatic presentation, tumor size, pathologic stage, collecting system invasion, and microvascular invasion. At multivariate analysis, capsular invasion was found to be an independent prognostic factor of recurrence and of cancer-related death. This study is limited by a relatively small sample size and by its retrospective nature, but it suggests that capsular involvement may be a marker of aggressive biology in RCC, reflecting a tumor with invasive and perhaps metastatic potential. If larger prospective multicentric studies will confirm these findings, capsular invasion may be incorporated into future staging systems
178:425–8. [17] Minervini A, Lilas L, Minervini R, Selli C. Prognostic value of nuclear grading in patients with intracapsular (pT1-pT2) renal cell carcinoma. Long-term analysis in 213 patients. Cancer 2002;94:2590–5.
for RCC. Patients with localized pT1-2 RCCs and capsular invasion may have similar outcomes compared to patients with perirenal fat invasion and may be therefore incorporated in the pT3a category in a future update of the TNM classification [4]. Capsular invasion may be also integrated with other pathologic and molecular prognostic markers in designing better prognostic nomograms for localized RCC. Further research is needed on the topic of RCC capsular invasion. Standardized and reproducible definitions for histologic assessment of capsular infiltration after radical and partial nephrectomy are required. Furthermore, several questions have to be answered: Does the depth of tumor penetration in the pseudocapsule correlate with the oncologic outcomes? Does the pattern of capsular invasion (tumor infiltration, tumor cell nests within the pseudocapsule, tumor expansion in the pseudocapsule) indicate a different ability of the tumor to progress and to infiltrate? Does invasion of the pseudocapsule on the parenchymal side and on the perirenal side have the same prognostic significance? This information is expected to further define the role of capsular invasion as a valuable prognostic factor for risk stratification of localized RCC.
References [1] Minervini A, di Cristofano C, Lapini A, et al. Histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. Eur Urol 2009; 55:1410–8. [2] Jeong IG, Jeong CW, Hong SK, Kwak C, Lee E, Lee SE. Prognostic implication of capsular invasion without perinephric fat infiltration in localized renal cell carcinoma. Urology 2006;67:709–12. [3] Suer E, Ergun G, Baltaci S, Beduk Y. Does renal capsular invasion have any prognostic value in localized renal cell carcinoma? J Urol 2008;180:68–71. [4] Klatte T, Chung JS, Leppert JT, et al. Prognostic relevance of capsular involvement and collecting system invasion in stage I and II renal cell carcinoma. BJU Int 2007;99:821–4. [5] Cho H-J, Kim SJ, Ha U-S, et al. Prognostic value of capsular invasion for localized clear-cell renal cell carcinoma. Eur Urol 2009; 56:1006–12.
DOI: 10.1016/j.eururo.2008.11.032 DOI of original article: 10.1016/j.eururo.2008.11.031
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Kidney Cancer
Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma Hyuk-Jin Cho a, Su Jin Kim a, U-Syn Ha a, Sung-Hoo Hong a, Joon Chul Kim a, Yeong-Jin Choi b, Tae-Kon Hwang a,* a
Department of Urology, Kangnam St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
b
Department of Pathology, Kangnam St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
Article info
Abstract
Article history: Accepted November 18, 2008 Published online ahead of print on November 28, 2008
Background: The impact of capsular invasion on the survival of patients undergoing surgery for renal cell carcinoma (RCC) has attracted little attention in the literature and remains controversial. Objectives: To evaluate the value of capsular invasion, without perirenal fat invasion, on the prognosis of patients with localized clear-cell RCC. Design, setting, and participants: Between 1984 and 2007, we retrospectively reviewed the records of 317 consecutive patients with localized clear-cell RCC (pT1–T2N0M0) who underwent radical nephrectomy or nephron-sparing surgery at our institution. Overall, 299 patients were eligible for the study. We analyzed clinical (presentation and body mass index [BMI]) and pathologic (tumor size, Fuhrman nuclear grade, collecting system invasion, microvascular invasion, and capsular involvement) parameters. Measurements: Recurrence-free survival (RFS) and cancer-specific survival (CSS) were investigated using the Kaplan-Meier method, and the Cox regression model was used to determine the significant prognostic factors based on multivariate analysis. Results and limitations: Renal capsular invasion was observed in 106 of 299 patients (35.5%). Capsular invasion had a statistically significant association with age, symptomatic presentation, tumor diameter, pathologic stage, collecting system invasion, and microvascular invasion. The mean follow-up was 60.5 mo (range: 1–249). The 5-yr RFS and CSS rates for tumors with capsular invasion were significantly lower compared with rates for tumors without invasion (77.7% vs 92.3% and 85.5% vs 95.7%, respectively; p = 0.0004). Multivariate analysis showed that BMI (hazard ratio [HR] = 0.19), stage (HR = 2.45), and capsular invasion (HR = 3.36) were independent prognostic factors of disease recurrence. With respect to CSS, BMI (HR = 0.20), tumor size (HR = 1.13), and capsular invasion (HR = 4.03) were the factors related to death. Nevertheless, we recognize that these findings may be limited by the study’s retrospective, single-institution design. Conclusions: Our findings suggest that capsular invasion is associated with poor survival in patients with localized clear-cell RCC. # 2009 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Capsule Prognosis Renal cell carcinoma Staging
* Corresponding author. Department of Urology, Kangnam St. Mary’s Hospital, 505, Banpo-dong, Seocho-gu, Seoul 150-713, Korea. Tel. +82 2 590 1386; Fax: +82 2 599 7839. E-mail address: [email protected] (T.-K. Hwang). 0302-2838/$ – see back matter # 2009 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eururo.2008.11.031
EUROPEAN UROLOGY 56 (2009) 1006–1012
1.
Introduction
The incidence of renal cell carcinoma (RCC) is on the rise, in part due to the more frequent use of abdominal imaging. Although the rate of metastatic RCC at initial presentation remains substantial, the incidence of asymptomatic, pathologically localized RCC has demonstrated the greatest increase [1–3]. Despite displaying a pathologically confined disease at the time of nephrectomy, 20–40% of patients demonstrate local recurrence or distant metastasis after nephrectomy [4,5]. This fact has led to research on the clinical behavior of the disease to identify the pathologic parameters of a worse prognosis and define groups of patients with more chances of disease recurrence. The 2002 TNM classification is based only on tumor size for predicting survival in localized tumors. Therefore, additional prognostic factors are needed that will predict high-risk patients. The impact of capsular invasion on the survival of patients undergoing surgery for RCC has attracted little attention in the literature and remains controversial [6–8], ranging from no influence on patient outcome [8] to being the most relevant prognostic factor influencing patient survival [7]. Two previous studies [6,8] clustered chromophobe, papillary, and clear-cell RCC subtypes into a single pathologic entity during analysis, despite the known histologic, genetic, and prognostic differences of these RCC subtypes. Therefore, we determined whether capsular invasion (without penetration) was an independent predictor of prognosis for patients with localized clear-cell RCC after surgical resection with curative intent.
2.
1007
Methods
The records of 317 consecutive patients surgically treated for localized (pT1-2/N0/M0), unilateral, sporadic clear-cell RCC at our institution between 1984 and 2007 were reviewed retrospectively. Patients with insufficient pathologic data (n = 2) or inadequate follow-up (n = 16) were excluded, leaving 299 patients available for analysis. Associations with outcome were evaluated for patients with clearcell RCC only, given the documented differences in outcome and associations with outcome by RCC histologic subtype. The surgical procedures included open radical nephrectomy in 126 cases (42.1%), laparoscopic radical nephrectomy in 141 cases (47.2%), open partial nephrectomy in 4 cases (1.3%), and laparoscopic partial nephrectomy in 28 cases (9.4%). Initial pathologic evaluation was performed by 1 of 10 pathologists and later confirmed by a single pathologist. All histologic sections were fixed with buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin (H&E). All of the resected tumors were macroscopically and microscopically examined for tumor diameter, pathologic tumor stage (pT1 vs pT2), tumor grade (1 and 2 [low-grade], 3 and 4 [high-grade]), microvascular tumor invasion, collecting system invasion, and cell type. Capsular invasion was defined as either infiltrative invasion with the tumor protruding into the capsule or when the tumor cell nest was observed in the capsule or when the renal capsule was invaded via tumor expansion (Fig. 1). Prognosis according to depth of capsule invasion was also studied. However, because the tumors were located in different areas, the thickness of the capsules varied as well. Therefore, we took an inverse approach in which we measured from the border between the perirenal fat and capsule to the tumor (in millimeters). Tumors were staged according to the 2002 TNM criteria [9] for pathologic staging and Fuhrman’s criteria [10] for tumor grading. All clinical charts of the
Fig. 1 – Photomicrograph of renal capsule invasion; (a) expansile invasion—renal cell carcinoma with overlying attenuated renal capsule (arrow) with expanding tumor invasion; (b) infiltrative capsule invasion—renal cell carcinoma showing protruding tumor cell invasion (arrow); (c) infiltrative capsule invasion—a separate tumor cell nests in the renal capsule (arrow).
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clinical presentation (symptomatic and incidental), and BMI. The BMI
Table 1 – Characteristics in 299 patients with T1–T2N0M0 clearcell renal tumors
was categorized based on the cut-off points for Asians, as recommended
Variable
patients were reviewed for clinical variables, including age, gender,
by the World Health Organization (<23, 23–25, and >25 kg/m2) [11]. Continuous variables are shown as the mean standard deviation (SD) or range, and categoric data are shown as the absolute and relative frequencies. Patients were evaluated every 3 mo for the first 2 yr after treatment,
Median age (range) Follow-up (mo) Mean SD Median (range) Mean tumor diameter (cm) (range)
Value 56 (25–86) 60.5 55.3 52.3 (1–249) 4.7 (0.8–20)
every 6 mo for the next 3 yr, and yearly thereafter with chest x-ray, abdominal ultrasonography or computed tomography (CT), and serum
n (%)
chemistries.
Gender Male Female Clinical presentation Incidental Symptomatic Surgery Radical Nephron-sparing pT stage (TNM 2002) T1a T1b T2 Fuhrman grade I II III IV Microvascular invasion Collecting system invasion Capsular invasion
The main end points were the correlation between the presence of capsular invasion and other pathologic findings, and the correlation between rates of recurrence-free survival (RFS) and rates of cancerspecific survival (CSS) with pathologic outcomes. For the statistical analysis, we used the chi-square test or student t test to evaluate the associations among the listed variables. The Kaplan-Meier method was used to determine CSS and RFS rates, and the differences among the CSS and RFS rates were analyzed using the log-rank test. Univariate and multivariate analyses were assessed with the Cox proportional hazards model. For each prognostic factor, the hazard ratio (HR) in the univariate analysis and the adjusted HR in the multivariate analysis are given, including the 95% confidence interval (CI). The k statistic, which is a measure of agreement between observers that corrects for chance agreement, was used to evaluate the concordance between original and reviewed capsular invasion. Concordance was considered to be fair, 0.00–0.20; moderate, 0.21–0.45; substantial, 0.46–0.75; almost perfect, 0.76–0.99; or perfect, 1.00 [12]. To evaluate the prognostic value of capsular invasion, the authors also constructed an additional multivariate model adjusting for the Mayo Clinic SSIGN score, which is a
195 (65.2) 104 (34.8) 213 (71.2) 86 (28.8) 267 (89.3) 32 (10.7) 163 (54.5) 89 (29.8) 47 (15.7) 60 193 44 2 24 42 106
(20.1) (64.5) (14.7) (0.7) (8.0) (14.0) (35.5)
SD = standard deviation.
composite scoring system that was developed specifically for patients with clear-cell RCC [13]. In all tests, p < 0.05 was considered to be statistically significant.
invasion was analyzed simply as being either ‘‘present’’ or ‘‘absent’’ as a prognostic pathologic feature of RCC.
3.
Results
3.2.
3.1.
Patient characteristics
Treatment failure in the form of local tumor recurrence and/ or metastasis was encountered in 33 (11.0%) patients. Kaplan-Meier curves revealed a much better RFS in patients without capsular invasion ( p = 0.004, Fig. 2a). The 5- and 10-yr RFS rates of patients with capsular invasion (77.7% and 69.1%, respectively) were significantly worse than rates in those without invasion (92.3% and 85.9%, respectively). In addition to capsular invasion, the following five clinical and pathologic variables were associated with RFS (Table 3): symptoms, microvascular invasion, pT stage, tumor size, and BMI. The risk of recurrence from RCC for patients with a BMI of 25 kg/m2 was reduced to about 31% of that in patients with a BMI of <23 kg/m2. Patient gender, age, and tumor grade had no statistically significant impact on RFS, while collecting system invasion was of marginal significance ( p = 0.051). On multivariate analysis, capsular invasion, pT stage, and BMI were important prognostic factors for RFS (Table 3). Patients with capsular invasion were at approximately 3.3 times the risk of recurrence compared with patients without capsular invasion.
Of the 299 patients, 252 (84.3%) and 47 (15.7%) patients were classified as T1 or T2, respectively. Capsular invasion was seen in 106 (35.5%) patients. Interobserver variability regarding capsular invasion showed almost perfect agreement (k = 0.79), demonstrating high reliability. The mean age was 56 yr (range: 25–86) and the mean follow-up in all patients was 60.5 55.3 mo (median: 52.3; range: 1–249). All 32 patients (10.7%) who underwent nephron-sparing surgery had negative margins. Table 1 lists the clinical and pathologic features of the 299 patients. We observed a statistically significant association of capsular involvement with age, symptoms, pathologic stage, tumor size, microvasular invasion, and collecting system invasion (Table 2). High-grade tumors had a greater tendency to be associated with capsular invasion (12.4% vs 20.8%; p = 0.056). The mean distance from the borderline between perirenal fat and capsule to the tumor was 0.136 mm (range: 0.00–1.50), and this depth of invasion was shown by Cox proportional hazard models not to have a statistically significant correlation with RFS and CSS (HR = 6.02; 95% CI, 0.59–61.51; p = 0.13 and HR 5.09; 95% CI, 0.18–136.39; p = 0.33, respectively). Therefore, in our study, capsular
3.3.
Recurrence-free survival
Cancer-specific survival
Cancer-related death occurred in 22 patients (7.4%) during follow-up. Capsular invasion was also associated with a
EUROPEAN UROLOGY 56 (2009) 1006–1012
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Table 2 – Association between different variables and capsular invasion Variable Age (yr) <50 50 Tumor diameter SD (cm) Gender Male Female Clinical presentation Incidental Symptomatic pT stage (TNM 2002) T1a T1b T2 Grade Low (1–2) High (3–4) Microvascular invasion Absent Present Collecting system invasion Absent Present
Negative invasion
Positive invasion
p value
77 (33.9) 116 (60.1) 4.1 2.1
25 (23.6) 81 (76.4) 5.7 3.6
121 (62.7) 72 (37.3)
74 (69.8) 32 (30.2)
– 0.216
145 (75.1) 48 (24.9)
68 (64.2) 38 (35.8)
– 0.045
119 (61.7) 56 (29.0) 18 (9.3)
44 (41.5) 33 (31.1) 29 (27.4)
– – <0.001
169 (87.6) 24 (12.4)
84 (79.2) 22 (20.8)
– 0.056
183 (94.8) 10 (5.2)
92 (86.8) 14 (13.2)
– 0.015
177 (91.7) 16 (8.3)
80 (75.5) 26 (24.5)
– <0.001
– 0.004 <0.001
SD = standard deviation.
poor CSS rate: the 5- and 10-yr survival rates were 85.5% and 69.5% for patients with capsular invasion and 95.7% and 90.6% for those without capsular invasion, respectively ( p = 0.004, Fig. 2b). Among other variables, pT stage, tumor size, and BMI were associated with the CSS rate in the univariate analysis. Multivariate analysis showed that capsular invasion, tumor size, and BMI were independent factors for CSS (Table 4). Capsular invasion remained significantly associated with RFS (HR = 2.71; 95% CI, 1.30– 5.66; p = 0.008) and CSS (HR = 4.39; 95% CI, 1.78–10.81; p = 0.001) after adjusting for the SSIGN score. Taken together, capsular invasion was associated with a risk of disease recurrence and death in patients with localized clear-cell RCC.
Because the majority of the patients in this study were pT1 (84.3%), Kaplan-Meier curves for the RFS and CSS were analyzed separately for this subgroup. The 5-yr RFS rate for the presence or absence of capsular invasion was estimated at 82% and 92% ( p = 0.006), while the 5-yr CSS rate was 89% and 96% ( p = 0.005), respectively. 4.
Discussion
It has been recently reported that the incidence of RCC, especially early-stage, small, incidentally discovered tumors is on the rise, suggesting diagnosis at an earlier stage as a result of earlier detection [1–3]. This might be explained, in part, by the increased number of early stage
Fig. 2 – (a) Recurrence-free and (b) cancer-specific survival curves for capsular invasion.
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Table 3 – Cox regression analysis for recurrence-free survival
Table 4 – Cox regression analysis for cancer-specific survival
Variable
Variable
Univariate model Presentation (symptoms/incidental) MVI Stage (pT2/pT1) Tumor size (cm)a BMI (kg/m2) (23–25/23) (25/23) Capsular invasion Grade (3 and 4 or 1 and 2) Collecting system invasion Multivariate model Capsular invasion BMI (kg/m2) (23–25/23) (25/23) Stage (pT2/pT1)
HR
95% CI
p value
2.024 3.444 2.522 1.222
1.017–4.148 1.411–8.409 1.200–5.304 1.120–1.334
0.044 0.006 0.014 0.001
0.491 0.314 3.069 1.982 2.239
0.215–1.125 0.117–0.843 1.514–6.222 0.934–4.204 0.995–5.034
0.092 0.021 0.001 0.074 0.051
3.366
1.573–7.201
0.001
0.336 0.197 2.458
0.134–0.846 0.058–0.668 1.117–5.409
0.062 0.009 0.025
Univariate model Presentation (symptoms/incidental) MVI Stage (pT2/pT1) Tumor size (cm)a BMI (kg/m2) (23–25/23) (25/23) Capsular invasion Grade (3 and 4 or 1 and 2) Collecting system invasion Multivariate model Capsular invasion BMI (kg/m2) (23–25/23) (25/23) Tumor size (cm)a
HR
95% CI
p value
1.261 1.091 2.502 1.155
0.538–2.953 0.254–4.673 1.019–6.142 1.035–1.288
0.593 0.906 0.045 0.009
0.502 0.173 4.391 1.193 1.547
0.192–1.305 0.039–0.764 1.783–10.821 0.438–3.251 0.569–4.198
0.159 0.021 0.001 0.729 0.391
4.039
1.634–9.983
0.002
0.510 0.200 1.135
0.195–1.329 0.045–0.884 1.008–1.278
0.168 0.033 0.036
HR = hazard ratio; CI = confidence interval; MVI = microvascular invasion; BMI = body mass index. a Continuous variable.
HR = hazard ratio; CI = confidence interval; MVI = microvascular invasion; BMI = body mass index. a Continuous variable.
RCC now being detected as a result of widespread use of imaging modalities for evaluating a wide variety of abdominal and pelvic symptoms. Predicting the risk of recurrence after nephrectomy for low-stage RCC is crucial because a higher risk status requires closer postoperative surveillance, and earlier detection of disease recurrence may provide the most favorable outcomes. The prognosis for patients with RCC is primarily dependent on disease stage. Localized disease (pathologic stage pT1-2) confers the best prognosis, with 5-yr CSS rates after nephrectomy ranging from 71% to 97% [14,15]. Currently, tumor size (in particular, greatest tumor dimension) is the only prognostic indicator used by the TNM classification system for localized tumors. Tumor size as a single prognostic factor may be considered insufficient for describing the biological heterogeneity of renal tumors, even when localized. It then seems reasonable to introduce new variables within the T1 and T2 stages that would help define prognostic factors within this increasingly important cohort of patients. Capsular invasion has been evaluated as a prognostic indicator in localized RCC. To the best of our knowledge, there are only three retrospective studies dealing with the prognostic value of capsular invasion in RCC [6–8]. Early studies suggested that patients with this histological finding had a poor prognosis with a greater chance of disease progression [6,7]. In contrast, one study indicated no association between capsular invasion and prognosis [8]. The observed rate of capsular invasion in our study was 35.5%, equivalent to that reported by Jeong et al [7] and Su¨er et al [8]. At a mean follow-up of 60.5 mo, we clearly demonstrated the discriminating role of capsular invasion as a prognostic factor for RCC. The 5-yr RFS and CSS rates were 92.3% and 95.7% for negative capsular invasion, respectively, in contrast to 77.7% and 85.5% for positive capsular invasion. This result is in accordance with other studies. Klatte et al [6] evaluated 519 patients with localized RCC and observed RFS
in 75.6% and 86.9% of patients with or without capsular invasion, respectively, at a median follow-up of 49 mo. In their multivariate analysis, capsular invasion, collecting system involvement, Eastern Cooperative Oncology Group (ECOG) performance status, tumor grade, and tumor size affected RFS. Interestingly, they reported that patients with capsular involvement had the same RFS as patients with stage pT3aN0M0 RCC. As in the present study, tumor grade and size were associated with an incidence of capsular invasion. In addition, Jeong et al [7] analyzed 288 patients with clear-cell RCC who underwent a radical nephrectomy. They demonstrated the independent prognostic role of capsular invasion, with a marked difference in the CSS rate for stage pT2. They showed that capsular invasion was associated with a more advanced pT stage. A recent study conducted by Su¨er et al [8] did not identify capsular invasion as an independent factor. The 5-yr CSS rates in patients with or without capsular invasion were 92.68% and 90.4%, respectively. Unfortunately that study had some important limitations. The authors were unable to show that Fuhrman grade and tumor size—the most widely recognized prognostic factors for RCC—were independent prognostic factors for these patients. The mean follow-up was also relatively short (40.7 mo). These investigators suggested that capsular invasion is not an indicator of aggressive biological behavior but merely reflects that a tumor had a peripheral origin. They did not evaluate the association between capsular invasion and tumor location, but they did report a relation between capsular invasion for higher Fuhrman grade and pathologic tumor stage. From our study, patients with capsular invasion had a substantially higher risk of progression of RCC. Moreover, the risk of recurrence and death increased by 3.36 and 4.03 times, respectively. We herein report that patients with RCC tumors invading the renal capsule remain at significant risk of recurrence and death, even after adjusting for the SSIGN score. It is difficult to provide a scientifically sound
EUROPEAN UROLOGY 56 (2009) 1006–1012
explanation for this finding. Significantly greater proportions of patients with capsular invasion were symptomatic at diagnosis, had a higher tumor stage, had microvascular invasion, and had collecting system invasion. Mean tumor size was greater in capsular invading tumors. There was also a tendency for an association between capsular involvement and high-grade tumor. We believe that the association of capsular invasion with other poor prognostic pathologic findings reflects the overall aggressive biology of these tumors. Generally, worse tumor grades have been shown to be associated with an increased incidence of recurrence and poor survival [16,17]. However, an association with grade was not established in our series. Most of the literature to date has reported survival differences between low-grade (including both grades 1 and 2) and high-grade (including both grades 3 and 4) tumors, and we used such groupings as well. However, a key anomaly in our Fuhrman grade distribution must be noted: only 0.7% (4) grade IV tumors were included, and low-grade tumors made up 84.6% of the study population. As a result of such bias, the Fuhrman grade was inappropriately found not to be a prognostic factor. A comparison among the various studies of capsular invasion is difficult because of variations in inclusion criteria, nonstandardized therapeutic procedures, duration of follow-up, and definition of end points (RFS, CSS, and overall survival). Moreover, all of the studies, including the current study, were limited by the retrospective design. In the current study, we restricted our analysis to patients with localized, clear-cell RCC. We believe that we minimized the potential for confounding bias that might emanate from combining localized and advanced RCC patients into one group or combining all RCC histologic subtypes into one pathologic entity. Our findings suggest that including capsular invasion in future RCC staging systems is warranted because of the relative frequency in low-stage tumors and the independent effect of this factor on recurrence and death. By adding capsular invasion in estimating prognosis in patients with pT1-2 tumors, the predictive value of the TNM staging system can be improved considerably with regard to survival. It is important to confirm these findings prospectively by using multicentric studies to obtain more significant statistics.
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Study concept and design: Cho. Acquisition of data: Kim. Analysis and interpretation of data: Ha, Kim. Drafting of the manuscript: Cho. Critical revision of the manuscript for important intellectual content: Kim, Hwang. Statistical analysis: Hong. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Choi, Hwang. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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5.
Conclusions
Capsular invasion is associated with specific clinical findings, as well as poor prognostic variables, and it is an important independent predictor of survival for patients with localized clear-cell RCC. If corroborated at other large centers, the addition of capsular invasion will add additional prognostic information to the TNM system, which currently is based only on tumor size.
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Author contributions: Tae-Kon Hwang had full access to all the data in
carcinoma treated with radical nephrectomy based on tumor
the study and takes responsibility for the integrity of the data and the
stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168:
accuracy of the data analysis.
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[14] Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H.
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Editorial Comment on: Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma Alessandro Volpe Division of Urology, Maggiore della Carita` Hospital, University of Eastern Piedmont, Corso Mazzini, 18, 28100, Novara, Italy [email protected] Renal cell carcinoma (RCC) is characterized by very heterogeneous biological and clinical behavior. Despite timely and technically correct surgical treatment, some patients with localized RCC develop unexpected recurrence. Accurate prognostic factors are needed to identify low-stage tumors at higher risk of recurrence that should be followed with stricter postoperative surveillance protocols. Pathologic features such as tumor size, nuclear grade, and microvascular and collecting system invasion were already found to have prognostic implications for organ-confined RCCs. The presence of a fibrous pseudocapsule in renal tumors has been described since the late 1940s. Minervini et al recently presented a detailed histopathologic analysis of tumoral pseudocapsule in patients who underwent enucleation of RCC, confirming the presence of a continuous, nonfenestrated layer of dense connective tissue completely surrounding the tumor in all cases [1]. The potential prognostic role of RCC capsular invasion has attracted little attention until recently [2–4]. In this issue of European Urology, Cho et al investigate the impact of capsular invasion on disease recurrence and survival in a series of 299 patients who underwent radical nephrectomy or nephron-sparing surgery for pT1-T2 N0 M0 clear-cell RCC at their institution [5]. The authors observed that capsular invasion without perirenal fat infiltration is a frequent finding in localized tumors (35.5%) and significantly correlates with age, symptomatic presentation, tumor size, pathologic stage, collecting system invasion, and microvascular invasion. At multivariate analysis, capsular invasion was found to be an independent prognostic factor of recurrence and of cancer-related death. This study is limited by a relatively small sample size and by its retrospective nature, but it suggests that capsular involvement may be a marker of aggressive biology in RCC, reflecting a tumor with invasive and perhaps metastatic potential. If larger prospective multicentric studies will confirm these findings, capsular invasion may be incorporated into future staging systems
178:425–8. [17] Minervini A, Lilas L, Minervini R, Selli C. Prognostic value of nuclear grading in patients with intracapsular (pT1-pT2) renal cell carcinoma. Long-term analysis in 213 patients. Cancer 2002;94:2590–5.
for RCC. Patients with localized pT1-2 RCCs and capsular invasion may have similar outcomes compared to patients with perirenal fat invasion and may be therefore incorporated in the pT3a category in a future update of the TNM classification [4]. Capsular invasion may be also integrated with other pathologic and molecular prognostic markers in designing better prognostic nomograms for localized RCC. Further research is needed on the topic of RCC capsular invasion. Standardized and reproducible definitions for histologic assessment of capsular infiltration after radical and partial nephrectomy are required. Furthermore, several questions have to be answered: Does the depth of tumor penetration in the pseudocapsule correlate with the oncologic outcomes? Does the pattern of capsular invasion (tumor infiltration, tumor cell nests within the pseudocapsule, tumor expansion in the pseudocapsule) indicate a different ability of the tumor to progress and to infiltrate? Does invasion of the pseudocapsule on the parenchymal side and on the perirenal side have the same prognostic significance? This information is expected to further define the role of capsular invasion as a valuable prognostic factor for risk stratification of localized RCC.
References [1] Minervini A, di Cristofano C, Lapini A, et al. Histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. Eur Urol 2009; 55:1410–8. [2] Jeong IG, Jeong CW, Hong SK, Kwak C, Lee E, Lee SE. Prognostic implication of capsular invasion without perinephric fat infiltration in localized renal cell carcinoma. Urology 2006;67:709–12. [3] Suer E, Ergun G, Baltaci S, Beduk Y. Does renal capsular invasion have any prognostic value in localized renal cell carcinoma? J Urol 2008;180:68–71. [4] Klatte T, Chung JS, Leppert JT, et al. Prognostic relevance of capsular involvement and collecting system invasion in stage I and II renal cell carcinoma. BJU Int 2007;99:821–4. [5] Cho H-J, Kim SJ, Ha U-S, et al. Prognostic value of capsular invasion for localized clear-cell renal cell carcinoma. Eur Urol 2009; 56:1006–12.
DOI: 10.1016/j.eururo.2008.11.032 DOI of original article: 10.1016/j.eururo.2008.11.031