PATIENTS AND METHODS
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- PATIENTS AND METHODS
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Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) presented with pT3b/c RCC. All patients included in our retrospective study had been preoperatively staged by CT or MRI of the abdomen and CT of the chest or chest X-ray. Bone scans and CT/MRI of the brain were only obtained when indicated.
The following clinical and pathological variables were evaluated: age, gender, symptoms at presentation, type of surgery, presence of metastases, tumour size as the maximum tumour diameter of the surgical specimen, tumour stage as revised according to the 2002 TNM classification system  and tumour grade based on the WHO classification . In addition, we evaluated in the presence of pT3b/c RCC: coexistence of MVI defined as microscopic invasion of the venous network; pelvicalyceal (PCI), wall invasion of the RV or the IVC (WIRV or WIIVC), capsular invasion, defined as infiltration of the renal fibrous capsule. Overall tumour fat invasion (TFI) comprised of tumour cells invading the renal sinus fat (RSFI) and/or the perirenal fat invasion (PFI) in direct contact with the stroma or fat cells in the renal sinus or perirenal region. Furthermore, we assessed the pathohistological features of eosinophilic tumour differentiation referred to as the presence of areas composed by cells with eosinophilic cytoplasm, sarcomatoid tumour differentiation and tumour necrosis (Fig. 1).
Figure 1. Schematic representation of studied histopathological characteristics and invasion sites in pT3b/c RCC of the kidney. Capsular invasion (CI) as defined as infiltraton of the renal fibrous capsule; PFI, RSFI, PCI as defined as invasion of renal calyces, pelvis or ureter and WIRV.
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For evaluating the relationship between tumour size and coexistent histopathological features in the presence of pT3b/s N0M0 RCC, we used 7 cm as a threshold.
To obtain a homogenous group of patients for evaluating the oncological outcome, we excluded 57 patients (32.6%) with lymph node or distant metastases as well as patients with residual disease (R2) after surgery. Of these 57 patients, 25 (43.8%) had lymph node metastases, 41 (71.9%) had distant metastases and four (7.0%) had residual tumour after surgery. Hence, clinical and histopathological data and oncological outcome analysis are based on 118 patients. The histopathological features of these tumours were reviewed and reclassified by a single pathologist (S.B.) in 88% of the cases. In the remaining 12% of the cases, the histopathological features were present in the original pathological report.
In all, 11% of the patients had received adjuvant therapy. There was a median (range) follow-up of 3.2 (0.3–16.1) years in 110 (93.2%) of the patients, eight (6.8%) patients were lost to follow-up. The follow-up protocol consisted of a chest X-ray and CT of the abdomen every 6 months for 3 years after surgery, followed by annual controls. Table 1 summarizes the demographics of patients.
Table 1. Patient demographics, tumour size and type of surgery (n = 118)
|Median (range) follow-up, years|| 3.2 (0.3–16.1)|
|Mean (range) age at surgery, years|| 64.5 (37.8–84.9)|
|Men : woman (% men)|| 1.8:1 (64.4)|
|Median (range) tumour size, cm|| 8.0 (2.5–20)|
|N (%):|| |
| Symptomatic patients|| 78 (66.1)|
| Type of surgery*|| |
| RN|| 93 (78.8)|
| RNthoab|| 11 (9.3)|
| RNlap|| 12 (10.2)|
| NSS|| 2 (1.7)|
| Tumour thrombus level|| |
| 0|| 91 (77.1)|
| I|| 14 (11.9)|
| II|| 8 (6.8)|
| III|| 2 (1.7)|
| IV|| 3 (2.5)|
| Tumour stage|| |
| pT3b||115 (97.5)|
| pT3c|| 3 (2.5)|
| pNx|| 62 (52.5)|
| pN0 (removed lymph nodes)|| 56 (47.5)|
| (1–5)|| 37|
| (6–10)|| 10|
| (>10)|| 9|
| Tumour grade|| |
| G1–G2|| 63 (53.3)|
| G3–G4|| 55 (46.7)|
The level of the tumour thrombus was classified according to the classification by Montie et al.. Level 0, thrombus being limited to the RV; level I, thrombus extension into the IVC of <2 cm above the RV; level II, thrombus extending into the IVC of >2 cm above the RV, but below the hepatic veins; level III, thrombus reaching the intrahepatic veins, but below the diaphragm; and level IV, thrombus extension above the diaphragm.
Radical nephrectomy (RN) including generally regional lymphadenectomy was performed from a flank incision using a standard technique , when the tumour thrombus was limited to a thrombus level of ≤II. A tumour thrombus level of ≥III or very large tumours were approached from a thoracoabdominal access or a bilateral Chevron incision ± sternotomy (left sided tumours). Surgery with cardiopulmonary bypass was not necessary in the 118 selected cases. Ipsilateral adrenalectomy was performed when clinically indicated. In highly selected cases with a tumour thrombus limited to the RV, laparoscopic RN was performed (12 patients) or nephron-sparing surgery for an imperative indication (two patients).
Data are given as the median (range) or as absolute and relative frequencies. The cancer-specific survival (CSS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Cox regression was used to compare survival between different groups. Multivariate Cox proportional hazard models were used to assess the prognostic impact of multiple factors. Only factors with a univariate P-value ≤0.1 were considered in forward-likelihood-ratio models. The associations between features studied and outcome variables are presented with hazard risk ratios (HRs) and 95% CIs. All tests were two-sided. As this is an exploratory study and no adjustment for multiple testing was done, P-values are descriptive only.
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- PATIENTS AND METHODS
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The diagnosis of RCC is mostly incidental with 4–10% of patients having RCC with tumour extension into the RV or the IVC [18,19]. The mean CSS for these patients is 32–64%. From the wide range of mortality it is obvious that the current TNM classification system does not provide detailed prognostic information for patients with stage pT3 RCC , e.g. for stratification of patients into protocols of adjuvant therapy.
A recent proposal for reclassifying patients with pT3–4 RCC has suggested that pT3 RCC with either only TFI or only RV/IVC thrombus should be classified as pT3a, while tumours with combined RV/IVC thrombus and TFI should be classified as pT3b . Ficarra et al. proposed for classification of pT3 RCC that either TFI or only RV/IVC thrombus below the diaphragm should be pT3a, TFI and RV/IVC thrombus below the diaphragm should be pT3b, and tumours with IVC thrombus above the diaphragm should be pT4. Thompson et al. reported different outcomes for patients with pT3b RCC according to different thrombus levels and combination with additional TFI and suggested a revised reclassification as stages pT3a–d.
The renal sinus is a compartment of fatty tissue harbouring a great variety of microvessels. The fibrous capsule of the kidney reaches the hilum but does not cover it completely leaving access for the growth of tumours into this microvascular network . In the present series, the pT3a criteria were PFI and RSFI, not a single patient had invasion or metastases to the ipsilateral adrenal gland. However, patients with pT3b/c RCC and additional PFI + RSFI had a reduced CSS and were more likely to develop tumour progression than patients with RSFI alone, PFI alone or with no additional invasion sites in Kaplan–Meier analyses (Fig. 2A,B). Terrone et al. found in 513 patients that patients with coexistent PFI + RSFI pT3a RCC had a reduced 5-year CSS of 41.6% compared with >60% for RSFI or PFI alone.
Fujita et al. reported in patients with pT3b RCC, that those patients (20) with pT3a factors had a 45-month shorter CSS as compared with patients (23) with pT3b RCC with no T3a factors. In the paper of Ficarra et al. with analyses of 1969 patients who underwent RN for pT3–4 RCC at 12 European Centers, TFI was an independent prognosticator apart from the presence and level of a tumour thrombus. A meticulous evaluation of the surgical specimen for PFI is important  and has been addressed in published guidelines . Therefore one pathologist reviewed and reclassified stages and histopathological features as well as the nuclear grade according to the TNM staging system, 6th edition  and the WHO classification , which was necessary in 88% of the present cases.
Thompson et al. reported that patients with pT3a RCC and RSFI were 63% more likely to die of RCC compared with patients with PFI. In a recent retrospective study comprising 365 patients with pT3a RCC, Margulis et al. reported no difference in 5-year CSS between 166 patients with RSFI only and 199 with PFI only (50.4% vs 58.1%, P = 0.782).
We studied further the affect of other aspects of tumour invasion such as MVI and PCI in pT3b/c RCC. Whereas PCI did not have a major impact on CSS (P = 0.157) or PFS (P = 0.067) in the present cohort, Klatte et al. reported PCI as being a significant prognosticator for survival in univariate analysis (P = 0.04) in 321 consecutive patients, who were surgically treated for pT3b/c RCC including metastatic disease. MVI had a negative affect on PFS in the present series (P = 0.037) and showed a trend towards reduced CSS in univariate analysis (P = 0.06). The negative impact of MVI on PFS and CSS has been reported previously [7,8]. Ishimura et al. described a tumour-recurrence rate of 25% in patients presenting with MVI, whereas only 6.9% of patients with no MVI developed tumour progression. Interestingly, PFI + RSFI had a stronger affect on PFS than MVI in the present series (Table 4).
Several studies have discussed the correlation between prognosis and tumour thrombus level [27–29]. In the present series, tumour thrombus level (level ≤ I vs level ≥ II) did not affect CSS or PFS. In the paper of Zini et al. WIRV at the orifice of the RV in 13 of 32 patients with pT3b/c RCC was associated with a higher risk of death in multivariate analysis. We did not specifically examine WIRV at the orifice, but in the present series WIRV or WIIVC did not have an affect on CSS or PFS (P = 0.224 and P = 0.138).
We also analyzed histopathological factors such as tumour necrosis and sarcomatoid or presence of areas composed by cells with eosinophilic cytoplasm. Whereas sarcomatoid tumour differentiation could not be evaluated due to the small numbers, tumour necrosis, surprisingly, did not have an impact on CSS (P = 0.826) or PFS (P = 0.523). In contrast, presence of areas composed by cells with eosinophilic cytoplasm had a negative impact on CSS (P = 0.017) and PFS (P = 0.011) in univariate analysis. This finding in the present series can be explained with the correlation to high nuclear grade of 3 in all nine cases.
The combination of TFI and other histopathological features of pT3b/c RCC did not reveal an increased negative impact on CSS or PFS in most combinations except for patients with TFI + MVI showing a 5-year PFS of 16.5% as compared with 31.5% with TFI only (log-rank, P = 0.049; Table 5).
For the definition of T1 and T2 stages and in several prediction models, tumour size is an important prognosticator for tumour progression and survival , especially the threshold of 7 cm has been proposed to have a major impact on CSS in pT3b tumours, as Lambert et al. have reported recently. In the present series, tumour size did not have an affect on CSS (P = 0.210) or PFS (P = 0.300) in pT3b/c N0M0 RCC, although all of the tumours >7 cm had PFI and tumors >7 cm were more often grade 3 tumors and showed more often combined PFI+RSFI compared to tumors <7 cm. A weakness of the present study is the few patients associated with additional pathological sites of invasion in the presence of pT3b/c RCC. It is a retrospective single-centre analysis with all the biases associated with it. Nevertheless, there was a negative affect of coexistent PFI + RSFI in pT3b/c RCC for CSS and PFS, whereas PFI alone and RSFI alone did not reveal such an impact. Furthermore, capsular invasion and presence of areas composed by cells with eosinophilic cytoplasm were associated with a reduced CSS and a reduced PFS in univariate analysis and with MVI there was a two-fold increased risk of tumour progression in univariate analysis.
In multivariate analysis, tumour grade had a negative affect on CSS (HR 3.63, 95% CI 1.8–7.34, P < 0.001) and PFS (HR 2.72, 95% CI 1.45–5.20, P = 0.002). MVI (HR 2.22, 95% CI 1.02–4.82, P = 0.045) and capsular invasion (HR 2.31, 95% CI 1.21–4.41, P = 0.011) resulted in a reduced CSS.
Surprisingly, TFI (P = 0.004) and specifically coexistent PFI + RSFI (HR 3.36, 95% CI 1.69–6.68, P = 0.001) was correlated negatively to PFS in multivariate analysis, whereas for PFI alone there was a trend towards a reduced PFS (HR 2.69, 95% CI 0.91–7.96, P = 0.074) and RSFI alone was not associated with PFS in pT3b/c RCC in multivariate analysis (Table 4). To our knowledge, this finding has not been reported by other investigators.
Other known risk factors of RCC such as tumour necrosis, sarcomatoid tumour differentiation and PCI in pT3b/c RCC as discussed by Ficarra et al. in their new proposal for reclassification of pT3 tumours must be addressed in series with larger numbers. As local tumour extension is a fundamental feature of all available integrated prognostic systems, its correct definition seems to be important for improvement of prognostic models, especially if stratification of patients for protocols of adjuvant therapy is required.
In conclusion, the present data support the importance of revising the TNM classification system for pT3 RCC, as patients with pT3b/c tumours and additional combined PFI + RSFI have a worse prognosis than patients with pT3b/c tumours with no additional invasion of neighbouring fatty tissue. We detected a negative affect on CSS and PFS by univariate analysis for tumour grade, presence of areas composed by cells with eosinophilic cytoplasm, capsular invasion, MVI and TFI, especially for PFI + RSFI. In multivariate analysis, tumour grade, TFI, PFI + RSFI, MVI and capsular invasion were correlated with a reduced PFS and/or CSS. Other histopathological features such as tumour size, tumour necrosis, sarcomatoid tumour differentiation or PCI probably due to small numbers did not show an impact alone. Nevertheless, when the present results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.