SEARCH

SEARCH BY CITATION

Keywords:

  • renal cell carcinoma;
  • pT3b-stage;
  • local tumour extension;
  • fat invasion;
  • prognostic factors;
  • oncological outcome

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer-specific-survival (CSS) and progression-free-survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour-Nodes-Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow-up data were obtained from 110 patients at a median (range) of 3.2  (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05- and 2.72-times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two-fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three-fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10-year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.


Abbreviations
(WI)RV

(wall invasion) renal vein

(WI)IVC

(wall invasion) inferior vena cava

MVI

microvascular invasion

PCI

pelvicalyceal invasion

TFI

overall tumour fat invasion

RSFI

renal sinus fat invasion

PFI

perirenal fat invasion

RN

radical nephrectomy

CSS

cancer-specific-survival

PFS

progression-free survival.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The pathological stage is the most important prognostic factor in RCC; hence the TNM staging system is most widely used to judge the prognosis of patients with RCC. Renal cancers with a renal vein (RV) thrombus or inferior vena cava (IVC) thrombus (pT3b/c) comprise 10–18% of all cases [1]. It has been suggested that the current TNM classification requires revision to provide more prognostic relevance for patients with stage pT3 RCC [2–4]. Recently, Fujita et al.[5] reported that patients with pT3a features (perirenal fat invasion [PFI] and suprarenal gland involvement) in the presence of stage pT3b RCC have a 45-month shorter disease-specific survival than pT3b tumours with no pT3a features. New proposals of reclassifying patients with pT3–4 RCC have stratified pT3b/c tumours with involvement of the renal sinus fat or the perirenal fat into subgroups of pT3–4 tumours [4,6]. It is not known in pT3b/c RCC, whether registration of coexistent invasion of the perirenal fat and/or the renal sinus fat and additional involvement of negative prognostic factors such as microvascular invasion (MVI) [7,8], pelvicalyceal invasion (PCI) [9], tumour necrosis [10], sarcomatoid [11] or eosinophilic tumour differentiation [12] alone or in combination with tumour fat invasion (TFI) add useful information to predict the oncological outcome more accurately.

The aim of the present study was to evaluate the impact of additional histopathological features of tumour characteristics and invasion of patients with pT3b/c RCC on the oncological outcome to improve the prognostic relevance of pathological staging. Better stratification of risk groups for tumour progression would help to allow inclusion of patients with poorer prognosis in prospective trials of adjuvant therapy [13].

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

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 [14] and tumour grade based on the WHO classification [15]. 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).

image

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.

Download figure to PowerPoint

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)
VariableValue
  • *

    Cardiopulmonary bypass surgery not involved; RNthoab, RN and thrombectomy through a thoracoabdominal approach; RNlap, laparoscopic RN; NSS, nephron-sparing surgery.

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 
  pT3b115 (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.[16]. 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 [17], 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.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Pathological and surgical variables

In all, 118 patients with pT3b/c N0M0 RCC after complete removal of the tumour (R0) and the thrombus met the inclusion criteria for analyzing the prognostic impact of different pathohistological features. Of these, 115 patients had a T3b tumour thrombus and three patients had a pT3c thrombus, which was extracted through an inferior cavotomy without cardiopulmonary bypass.

Besides having pT3b/c N0M0 RCC, 19 patients had MVI, 23 had PCI, four had capsular invasion, with infiltrating, but not completely passing the fibrous capsule, 38 patients had TFI, 10 had PFI, and nine had RSFI and 18 had PFI + RSFI. Four patients had sarcomatoid tumour differentiation. None of the 45 patients with ipsilateral adrenalectomy had continuous or metastatic tumour spread to the adrenal gland, so that pT3a features in the present series are limited to PFI and RSFI. The numbers of cases with different coexistent invasion sites are given in Table 2.

Table 2.  Histopathological features and coexistent infiltration sites in patients with pT3b/c renal cell carcinoma (n = 118)
VariableN (%)
Histological features 
 Clear cell109 (92.4)
 Non-clear cell  9 (7.6)
 Papillary RCC  4
 Chromophobe RCC  2
 Neuroendocrine RCC  1
 Mixed-tumours (clear-cell, papillary and chromophobe)  2
 Tumour necrosis 10 (8.4)
 Presence of areas composed by cells with eosinophilic cytoplasm  9 (7.6)
Sites 
 No additional infiltration sites (pT3b/c only) 70 (59.3)
 PCI 23 (19.5)
 MVI 19 (16.1)
 Capsular invasion 32 (27.1)
 WIRV, WIIVC  7 (5.9)
  TFI 38 (32.2)
  PFI 10 (8.5)
  RSFI  9 (7.6)
  PFI + RSFI 19 (16.1)

We used Cox proportional hazard regression calculations only if one of these factors was present in at least five cases.

Prognostic factors

At the last follow-up, 46 of the 110 analyzed patients had died from RCC, six had died from other causes, and two patients lacked information regarding their cause of death so they were classified as died from RCC. Seven patients had tumour progression at their latest follow-up and were still alive. The median follow-up of the surviving patients was 5 years.

In univariate analysis, grades 3 and 4 as compared to 1 and 2 (P < 0.001), capsular invasion (P = 0.002) and presence of areas composed by cells with eosinophilic cytoplasm (P = 0.017) were associated with a reduced CSS. Also, TFI was associated with a reduced CSS compared with pT3b/c tumour with no TFI (P = 0.037). In the subgroups of TFI, the combination of PFI + RSFI had a reduced CSS (P = 0.007), whereas PFI alone (P = 0.096) and RSFI alone (P = 0.397) were not associated with a reduced CSS. Other pathological features such as PCI (P = 0.157), MVI (P = 0.060) and tumour thrombus level (P = 0.066) only had a trend towards lower CSS, whereas tumour necrosis (P = 0.826) did not affect CSS in pT3b/c RCC in the present series (Table 3).

Table 3.  Univariate and multivariate (n = 96) Cox regression analyses of clinical and pathological features for predicting CSS in patients with pT3b/3c renal cell carcinoma after surgery with curative intent
VariableUnivariateMultivariateConsidered
HR (95% CI)PHR (95% CI)P
  • *

    Reference is level 0;

  • †Assessed as non-clear cell vs clear cell RCC;

  • ‡Grades 3 and 4 vs grades 1 and 2;

  • §

    §reference group is neither PFI nor RFSI.

Clinical features     
Age (continuous variable)1.01 (0.99–1.05)0.312   
Gender (female vs male)0.97 (0.52–1.80)0.911   
Symptoms (yes vs no)0.90 (0.49–1.63)0.717   
Tumour size (continuous variable)1.01 (1.00–1.01)0.210   
Tumour thrombus level* 0.066Not enteredX
 I2.10 (0.96–4.58)0.062   
 ≥II2.02 (0.92–4.41)0.078   
Histological features     
 Histology0.74 (0.23–2.37)0.607   
 Tumour grade4.20 (2.20–2.02)<0.0013.63 (1.8–7.34)<0.001X
 Presence of areas composed by cells with eosinophilic cytoplasm2.68 (1.19–6.00)0.017Not enteredX
 Tumour necrosis1.10 (0.47–2.61)0.826   
Pathological features     
 WIRV or WIIVC1.89 (0.68–5.31)0.224   
 PCI1.59 (0.84–3.01)0.157   
 MVI2.04 (0.97–4.28)0.0602.22 (1.02–4.82)0.045X
 Capsular invasion2.47 (1.39–4.40)0.0022.31 (1.121–4.41)0.011X
Overall TFI§ 0.037Not enteredX
 PFI2.51 (0.85–7.39)0.096   
 RSFI1.60 (0.54–4.70)0.397   
 PFI + RSFI2.88 (1.34–6.17)0.007   

Local tumour recurrence occurred in four patients after RN after 0.5, 1.6, 2.0 and 3.2 years. Metastatic disease developed in 24 patients after a median (range) of 1.6 (0.09–7.77) years. Seven patients developed metastases in the lung, three in the liver, two in bones, one in the brain, one in lymph nodes, five at multiple sites and five at not specified sites.

In univariate analysis, tumour grade (P < 0.001), presence of areas composed by cells with eosinophilic cytoplasm (P = 0.011), capsular invasion (P < 0.001), MVI (P = 0.037), TFI (P = 0.001) and PFI + RSFI (P = 0.005) were associated with a shorter PFS (Table 4).

Table 4.  Univariate and multivariate (n = 96) Cox regression analyses of clinical and pathological features for predicting PFS in patients with pT3b/3c renal cell carcinoma after surgery with curative intent
VariableUnivariateMultivariate 
HR (95% CI)PHR (95% CI)PConsidered
  • *

    Reference is level 0;

  • †Assessed as non-clear cell vs clear cell RCC;

  • ‡Grades 3 and 4 vs grades 1 and 2;

  • §

    §Reference group is neither PFI nor RFSI.

Clinical features     
Age (continuous variable)1.02 (0.99–1.04)0.266   
Gender (female vs male)1.06 (0.60–1.89)0.833   
Symptoms (yes vs no)0.99 (0.57–1.73)0.982   
Tumour size (continuous variable)1.00 (1.00–1.01)0.300   
Tumour thrombus level* 0.080Not enteredX
 I1.98 (0.95–4.13)0.067   
 ≥II1.72 (0.86–3.71)0.167   
Histological features     
 Histology0.69 (0.21–2.21)0.528   
 Tumour grade3.44 (1.93–6.15)<0.0012.72 (1.45–5.20)0.002X
 Presence of areas composed by cells with eosinophilic cytoplasm2.81 (1.27–6.26)0.011Not enteredX
 Tumour necrosis1.30 (0.58–2.89)0.523   
Pathological features     
 WIRV or WIIVC2.01 (0.80–5.07)0.138   
 PCI1.75 (0.96–3.18)0.067Not enteredX
 MVI2.05 (1.04–4.02)0.037Not enteredX
 Capsular invasion2.73 (1.58–4.71)<0.001Not enteredX
Overall TFI§ 0.001 0.004X
 PFI2.13 (0.73–6.20)0.1672.69 (0.91–7.96)0.074 
 RSFI1.50 (0.51–4.36)0.4561.22 (0.42–3.55)0.721 
 PFI + RSFI4.18 (2.13–8.22)0.0053.36 (1.69–6.68)0.001 

In multivariate analysis, grading was associated with a reduced PFS (HR 2.72) and reduced CSS (HR 3.63); and capsular invasion (HR 2.31) and MVI (HR 2.22) were associated with a reduced CSS. TFI (P = 0.004) and specifically PFI + RSFI (HR 3.63) were associated with reduced PFS. Meanwhile, PFI showed a trend towards a reduced PFS, whereas RSFI did not have such an impact in multivariate analysis, where no fat infiltration (neither PFI nor RSFI) was always used as a reference (Table 3 and 4).

Kaplan–Meier analyses for the subgroups of TFI are shown in Fig. 2A for CSS and in Fig. 2B for PFS. The 5- and 10-year CSS for all patients (n = 118) were 62% and 39%, for patients with no additional infiltration sites (n = 62) 74% and 47%, for patients with PFI + RSFI (n = 17) 51% and 25%. The 5-and 10-year PFS for all patients were 53% and 36%, for patients with no additional infiltration sites 68% and 45%, and for patients with PFI + RSFI 19% and 10%.

image

Figure 2. A, CSS of patients with pT3b/c RCC and no additional infiltration site as compared with coexistent overall TFI such as PFI, RSFI and PFI + RSFI. B, PFS of patients with pT3b/c RCC and no additional infiltration site as compared with coexistent overall TFI such as PFI, RSFI and PFI + RSFI.

Download figure to PowerPoint

Combination of histopathological features

In multivariate analysis, we analyzed the impact of histopathological features of tumour characteristics and invasion on the oncological outcome of pT3b/c N0M0 RCC (Tables 3 and 4). Furthermore, we analyzed the combination of overall TFI with any other histopathological feature studied for an affect on CSS and PFS in pT3b/c N0M0 RCC. Interestingly, only the combination of TFI + MVI gave a reduced PFS as compared with patients with TFI only (Table 5).

Table 5.  Combinations of overall TFI with MVI, PCI, tumour necrosis or presence of areas composed by cells with eosinophilic cytoplasm in 118 patients with pT3b/c N0M0 RCC for prediction of CSS and PFS using the log-rank test (P < 0.05)
Histopathological featuresNo. of patients5-year survival, %Median survival, yearsP*
  • *

    Reference is TFI alone (log-rank-test). Patients may appear in more than in one group.

CSS    
 TFI + MVI1837.31.00.177
 TFI + PCI1945.42.00.681
 TFI + tumour necrosis 525.00.70.654
 TFI + presence of areas composed by cells with eosinophilic cytoplasm 751.46.40.600
PFS    
 TFI + MVI1816.50.590.049
 TFI + PCI1935.20.90.502
 TFI + tumour necrosis 5 00.50.096
 TFI + presence of areas composed by cells with eosinophilic cytoplasm 728.62.10.825

Relation of tumour size to histopathological features

To investigate a possible relationship between tumour size and histopathological features of tumour characteristics and invasion of pT3b/c N0M0 RCC, we used the 7 cm as the current staging threshold. We could not detect an association of tumour size with most of the negative prognosticators studied in Tables 3 and 4. Nonetheless, all tumours with PFI were >7 cm and 66.6% of the tumours with PFI + RSFI were >7 cm (Table 6).

Table 6.  Histopathological characterization in patients and tumour invasion in patients with pT3b/c N0M0 RCC stratified for tumour sizes ≤7 cm and >7 cm (median tumour size 8.0 cm)
Patients and histopathological featuresNTumour size, cm
≤7>7
  1. Number of patients and absolute values are given.

All patients1174473
Histopathological features, n   
 Grade 1 and 2 622834
 Grade 3 and 4 551639
 Tumour necrosis 10 6 4
 Presence of areas composed by cells with eosinophilic cytoplasm  9 1 8
Tumour invasion, n   
 MVI 19 712
 PCI 22 616
 PFI 10 010
 RSFI  9 4 5
 PFI + RSFI 18 612

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

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%[20]. 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 [2], 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 [18]. Ficarra et al.[3] 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.[6] 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 [21]. 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.[22] 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.[5] 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.[4] 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 [23] and has been addressed in published guidelines [24]. Therefore one pathologist reviewed and reclassified stages and histopathological features as well as the nuclear grade according to the TNM staging system, 6th edition [14] and the WHO classification [15], which was necessary in 88% of the present cases.

Thompson et al.[25] 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.[26] 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.[18] 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.[7] 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.[30] 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 [10], especially the threshold of 7 cm has been proposed to have a major impact on CSS in pT3b tumours, as Lambert et al.[31] 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.[3] 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.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
  • 1
    Kaplan S, Ekici S, Dogan R, Demircin M, Ozen H, Pasaoglu I. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 2002; 183: 2929
  • 2
    Leibovich BC, Cheville JC, Lohse CM et al. Cancer specific survival for patients with pT3 renal cell carcinoma – can the 2002 primary tumour classification be improved? J Urol 2005; 173: 7169
  • 3
    Ficarra V, Novara G, Iafrate M et al. Proposal for reclassification of TNM staging system in patients with locally advanced (pT3–4) renal cell carcinoma according to the cancer-related outcome. Eur Urol 2007; 51: 72231
  • 4
    Ficarra V, Galfano A, Guillé F et al. A new staging system for locally advanced (pT3–4) renal cell carcinoma: a multicenter European study including 2,000 patients. J Urol 2007; 178: 41824
  • 5
    Fujita T, Iwamura M, Yanagisawa N et al. Prognostic impact of perirenal fat or adrenal gland involvement in patients with pT3b renal cell carcinoma. Urology 2007; 69: 83942
  • 6
    Thompson RH, Cheville JC, Lohse CM et al. Reclassification of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy. Cancer 2005; 104: 5360
  • 7
    Ishimura T, Sakai I, Hara I, Eto H, Miyake H. Microscopic venous invasion in renal cell carcinoma as a predictor of recurrence after radical surgery. Int J Urol 2004; 11: 2648
  • 8
    Lang H, Lindner V, Letourneux H, Martin M, Saussine C, Jacqmin D. Prognostic value of microscopic venous invasion in renal cell carcinoma: long-term follow-up. Eur Urol 2004; 46: 3315
  • 9
    Terrone C, Cracco C, Guercio S et al. Prognostic value of the involvement of the urinary collecting system in renal cell carcinoma. Eur Urol 2004; 46: 4726
  • 10
    Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumour stage, size, grade and necrosis: the SSIGN score. J Urol 2002; 168: 2395400
  • 11
    Dall’Oglio MF, Arap MA, Antunes AA, Cury J, Leite KR, Srougi M. Impact of clinicopathological parameters in patients treated for renal cell carcinoma. J Urol 2007; 177: 168791
  • 12
    Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 2000; 89: 60414
  • 13
    Bleumer I, De Mulder PH, Mulders PF. The role of adjuvant therapy in non-metastatic RCC. Can J Urol 2006; 13 (Suppl. 2): 5762
  • 14
    Sobin LH, Wittekind C. International Union Against Cancer (UICC) TNM Classification of Malignant Tumours, 6th edn. New York: Wiley-Liss Publications, 2002
  • 15
    Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press, 2004
  • 16
    Montie JE, El Ammar R, Pontes JE et al. Renal carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 1991; 173: 10715
  • 17
    Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. Trans Am Assoc Genitourin Surg 1968; 60: 1229
  • 18
    Klatte T, Pantuck AJ, Riggs SB et al. Prognostic factors for renal cell carcinoma with tumour thrombus extension. J Urol 2007; 178: 118995
  • 19
    Jibiki M, Iwai T, Inoue Y et al. Surgical strategy for treating renal cell carcinoma with thrombus extending into the inferior vena cava. J Vasc Surg 2004; 39: 82935
  • 20
    Swierzewski DJ, Swierzewski MJ, Libertino JA. Radical nephrectomy in patients with renal cell carcinoma with venous, vena caval and atrial extension. Am J Surg 1994; 168: 2059
  • 21
    Bonsib SM, Gibson D, Mhoon M, Greene GF. Renal sinus involvement in renal cell carcinomas. Am J Surg Pathol 2000; 24: 518
  • 22
    Terrone C, Gontero P, Volpe A et al. Proposal of an improved prognostic classification for pT3 renal cell carcinoma. J Urol 2008; 180: 728
  • 23
    Kirkali Z, Algaba F, Scarpelli M, Trias I, Selvaggi FP, Van Poppel H. What does the urologist expect from the pathologist (and what can the pathologist give) in reporting on adult kidney tumour specimens? Eur Urol 2007; 51: 1194201
  • 24
    Algaba F, Trias I, Scarpelli M, Boccon-Gibbod L, Kirkali Z, Van Poppel H. Handling and pathology reporting of renal tumor specimen. Eur Urol 2004; 45: 43743
  • 25
    Thompson RH, Leibovich BC, Cheville JC et al. Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol 2005; 174: 121821
  • 26
    Margulis V, Tamboli P, Matin SF, Meisner M, Swanson DA, Wood CG. Location of extrarenal tumour extension does not impact survival of patients with pT3a renal cell carcinoma. J Urol 2007; 178: 187882
  • 27
    Kim HL, Zisman A, Han KR, Figlin RA, Belldegrun AS. Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different? J Urol 2004; 171: 58891
  • 28
    Moinzadeh A, Libertino JA. Prognostic significance of tumor thrombus level in patients with renal cell carcinoma and venous tumor thrombus extension. Is all T3b the same? J Urol 2004; 171: 598601
  • 29
    Wagner B, Patard JJ, Méjean A et al. Prognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma. Eur Urol 2008 [Epub ahead of print]; 10.1016/j.eururo.2008.07.053
  • 30
    Zini L, Destrieux-Garnier L, Leroy X et al. Renal vein ostium wall invasion of renal cell carcinoma with an inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. J Urol 2008; 179: 4504
  • 31
    Lambert EH, Pierorazio PM, Shabsigh A, Olsson CA, Benson MC, McKiernan JM. Prognostic risk stratification and clinical outcomes in patients undergoing surgical treatment for renal cell carcinoma with vascular tumor thrombus. Urology 2007; 69: 10548