SEARCH

SEARCH BY CITATION

Keywords:

  • kidney;
  • renal carcinoma;
  • prognosis;
  • oncology

Abstract

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

Study Type – Therapy (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

The presence of invasion of renal vein and perinephric fat are predictors of poor outcome in patients with RCC. The latest version of the TNM system included tumours exhibiting such parameters in the T3a stage, thus grouping tumours with distinct pathologic features.

Our study showed that patients with RCC presenting concomitant invasion of the renal vein invasion and perinephric fat invasion have significantly worse survival rates than those showing any of the parameters separately. Therefore, we conclude that these tumours should not be grouped within T3a stage since they have significantly different outcomes.

OBJECTIVE

• To evaluate the prognostic impact of tumor fat invasion (FI) and renal vein invasion (RVI) in patients with T3a renal cell carcinoma.

PATIENTS AND METHODS

• In total, 220 consecutive patients treated for renal cell carcinoma between 1992 and 2009 were analyzed. T3a stage cases were selected.

• A single pathologist reviewed all cases.

RESULTS

• The present study cohort included 46 patients with mean follow-up of 28.6 months, of whom 17 (36.9%) died from disease. Patients were initially divided into three groups including 24 (52.1%) of FI only, 11 (23.9%) of RVI only and 11 (23.9%) of both FI and RVI.

• In univariate analysis, no significant differences in disease-specific survival (DSS) were noted between FI only and RVI only groups (P= 0.91). DSS was significantly worse in the FI + RVI group compared to the other groups (P= 0.02).

• When grouped into FI or RVI vs FI + RVI, DSS remained significantly lower in the group containing the parameters concurrently (P= 0.009). Progression-free survival also was significantly lower in FI + RVI group (P= 0.01).

• Metastasis, positive lymph nodes and the presence of FI + RVI remained as isolated predictors of survival.

• Patients with FI + RVI presented a 2.6-fold increase in risk of death from cancer and a 2.5-fold increase in risk of disease progression (P= 0.04) compared to those with either of them alone.

CONCLUSION

• The isolated or concomitant presence of FI and RVI may be used as one of the criteria for staging in the next edition of the Tumour-Node-Metastasis classification because they have significantly different outcomes.


Abbreviations
DSS

disease-specific survival

FI

fat invasion

PFI

perinephric fat invasion

PFS

progression-free survival

RVI

renal vein invasion

SFI

sinus fat invasion

INTRODUCTION

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

The incidence of renal cell carcinoma (RCC) has increased recently [1]. It is the third most common malignancy of the genitourinary tract and presents as diverse tumours that have distinct and unpredictable evolutions. Improvements in its diagnosis and advances in systemic therapy have had a positive impact on survival rate [2,3].

TNM staging is the most widely accepted method of describing the anatomical extent of tumours, as it is for RCC. Its early version, published in 2002, was validated in several studies [4–6]. Nevertheless, it has been criticized with respect to the ideal threshold size of localized tumours [7–9]. Furthermore, mixed results have been reported in the T3 tumour group [10]. Recently, the Union Internationale Contre le Cancer and American Joint Committee on Cancer developed the seventh edition of the TNM for RCC, valid from 1 January 2010, in which several modifications were made. A recent multicentre study validated this update [11].

In this update, T2 tumours are divided by diameter into T2a and T2b tumours, adopting a threshold of 10 cm. Tumours that show renal vein invasion (RVI) or fat invasion (FI) have been reclassified as T3a, and those with extensions into the vena cava above and below the diaphragm have remained pT3c and pT3b, respectively. Tumours with the ipsilateral adrenal gland invasion, initially classified as T3 in the previous edition of the TNM (2002), have been added to the T4 stage because they are associated with less favourable outcomes [12–14]. All other stages have remained unchanged [15].

T3a tumours exhibit distinct pathological characteristics and effect varied clinical outcomes. The presence of FI, via renal sinus fat invasion (SFI) or perinephric fat invasion (PFI), influences survival rates in patients with RCC [11]. However, there are contradictory results with regard to their prognostic importance. The same is also observed for tumours with RVI. Although some studies have suggested a significant impact of RVI on clinical outcome, others have reported no prognostic impact of the presence of tumour thrombus [16].

As noted above, there are mixed results regarding the real impact of the presence of FI and RVI in RCC patients. However, the TNM staging system used such parameters to group tumours into T3a stage, aggregating a heterogeneous group of tumours with different pathological characteristics. The present study aimed to determine the prognostic impact of FI and RVI on survival rates in patients with pT3a RCC.

MATERIALS AND METHODS

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

PATIENTS

In total, 220 consecutive cases of radical nephrectomy or partial nephrectomy for RCC performed between 1992 and 2009 were selected from the medical records of AC Camargo Hospital in Sao Paulo, Brazil. Ultimately, 46 patients in the pT3a stage were enrolled. The clinical data were obtained from medical charts. There were 29 men (63%) and 17 (37%) women. The mean (range) age was 58.3 (25–85) years. There was metastatic disease at the initial clinical presentation in nine (19.5%) patients and lymph node involvement in eight (17.4%) patients with a mean tumour size of 9.1 cm. A single pathologist (I.W.C.), who had no knowledge of the patients' outcomes, reviewed all cases with regard to uniform reclassification and selected the most representative tumour areas. Our internal review board approved the present study.

The variables included in the databank were: age, sex, Eastern Cooperative Oncology Group status, smoking, presence of symptoms, time after diagnosis, type of surgery, staging (TNM American Joint Committee on Cancer/Union Internationale Contre le Cancer 2009), Furhman grade, histological subtype, microvascular invasion, lymph node involvement, presence of tumour necrosis, follow-up period, presence of metastases, and clinical situation at the end of the study.

STATISTICAL ANALYSIS

Analyses were performed using SPSS for Windows, version 17.0 (SPSS Inc., Chicago, IL, USA). Fisher's exact test and the Pearson chi-squared test were performed to compare clinical and pathological features between groups. Differences in variables with a continuous distribution across dichotomous categories were assessed by the Mann–Whitney U-test. P < 0.05 was considered statistically significant.

Disease-specific survival (DSS) was defined as the interval between the primary surgery and the last follow-up visit or disease-related death. Progression-free survival (PFS) was defined as the interval between the primary surgery and the last follow-up visit and the absence of disease recurrence or progression. To study DSS and PFS, Kaplan–Meier curves were generated. To compare the estimated curves for each category for a given variable, the log-rank test was used. A Cox proportional hazards model was used to determine the variables that influenced DSS. Because of the large number of covariates, backward–forward stepwise regression was used to select variables that influenced survival periods. The CI was 5%.

RESULTS

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

The present study cohort included 46 patients with a mean (range) postoperative follow-up of 28.6 (3–60) months, of whom 17 (36.9%) died from disease. Patients were initially divided into three groups: 24 (52.1%) with FI only, 11 (23.9%) with RVI only and 11 (23.9%) with both FI and RVI.

There were significant differences among groups (Table 1). Patients in whom both pathologies were observed had higher Fuhrman grades (P= 0.05) and larger tumours (P= 0.03) compared to other groups. No patients in this group had incidentally discovered tumours. Furthermore, when compared to the FI-only group, the presence of microvascular invasion, metastatic disease and lymph node involvement was significantly higher in the FI + RVI group (Table 1).

Table 1.  Pathological groups demographic and pathological characteristics
CharacteristicRVIFIFI + RVIP
FI vs RVIFI + RVI vs FIFI + RVI vs RVI
  1. ECOG PS, Eastern Cooperative Oncology Group performance status; FI, fat invasion; RVI, renal vein invasion.

Mean age58.954.760.50.260.540.10
Men (%)6 (54.5)16 (66.7)7 (63.6)0.500.570.34
White, n (%)9 (81.8)22 (91.7)10 (90.9)0.660.690.52
Incidental, n (%)2 (18.1)7 (29.2)0 (0)0.460.050.21
ECOG PS (1 + 2), n (%)4 (36.4)12 (50)7 (63.6)0.250.220.19
Mean tumor size (cm)7.788.7512.60.190.0010.03
N+, n (%)3 (27.2)1 (4.2)4 (36.4)0.060.020.34
Metastasis, n (%)3 (27.2)2 (8.3)4 (36.4)0.100.060.34
High grade, n (%)4 (36.4)9 (39.1)9 (81.8)0.620.020.05
Necrosis, n (%)6 (54.5)14 (58.3)8 (72.7)0.290.210.43
Microvascular invasion, n (%)7 (63.6)6 (25.0)9 (81.8)0.010.020.45
Clear cell carcinoma, n (%)9 (81.8)18 (75.0)9 (81.8)0.140.310.26

It was observed that the 5-year DSS rates for patients in the FI-only, RVI-only and FI + RVI groups were 75%, 72% and 27%, respectively. There was no significant difference in DSS between the FI-only and RVI-only groups (P= 0.91). DSS was significantly worse in the FI + RVI group compared to the other groups (P= 0.02). DSS was lower in the FI + RVI group vs the combined FI-only and RVI-only group (P= 0.009) (Fig. 1). The 5-year PFS was also significantly lower in the FI + RVI group compared to the other groups (Fig. 2).

image

Figure 1. Disease-specific survival (DSS) probability within pT3a subcategories. A, The 5-year DSS in patients with renal vein invasion (RVI) only, fat invasion (FI) only and concomitant RVI and FI (P = 0.02). B, The 5-year DSS in patients with RVI or FI and concomitant RVI and FI (P = 0.009).

Download figure to PowerPoint

image

Figure 2. Progression-free survival (PFS) probability within pT3a subcategories. A, The 5-year PFS in patients with renal vein invasion (RVI) only, fat invasion (FI) only, and concomitant RVI and FI (P = 0.01). B, The 5-year PFS in patients with RVI or FI and concomitant RVI and FI (P = 0.01).

Download figure to PowerPoint

By multivariable analysis of clinical and pathological variables for DSS and PFS (Table 2), metastasis at diagnosis, lymph nodes involvement and concomitant FI and RVI remained as isolated predictors of survival. Patients with concomitant FI and RVI had a higher probability of death from cancer (hazard ratio, 2.6; P= 0.04) and disease progression (hazard ratio, 2.5; P= 0.04) than those with either condition alone.

Table 2.  Multivariate analysis of disease specific survival (DSS) and progression free survival (PFS)
Variable5-year DSS5-year PFS
HR (95% CI)PHR (95% CI)P
  1. DSS, disease-specific survival; ECOG PS, Eastern Cooperative Oncology Group performance status; FI, fat invasion; HR, hazard ratio; PFS, progression-free survival; RVI, renal vein invasion.

ECOG PS    
 0Reference Reference 
 1 + 21.219 (0.403–3.686)0.720.587 (0.234–1.476)0.25
Metastasis    
 NoReference Reference 
 Yes3.310 (1.059–8.248)0.041.909 (1.279–2.961)0.04
Tumour size (cm)    
 <7.0Reference Reference 
 >7.01.332 (0.275–6.457)0.721.588 (0.432–5.831)0.48
pT3a status    
 FI or RVIReference Reference 
 FI plus RVI2.677 (1.066–6.852)0.042.538 (1.014–6.352)0.04
N status    
 N0Reference Reference 
 N1 or N24.860 (1.741–13.583)0.0033.251 (1.199–8.819)0.02
Necrosis    
 NoReference Reference 
 Yes2.809 (0.421–4.622)0.582.021 (0.769–5.310)0.15
Fuhrman grade    
 1 or 2Reference Reference 
 3 or 41.073 (0.272–4.224)0.920.924 (0.418–2.045)0.92
Microvascular invasion    
 NoReference Reference 
 Yes1.091 (0.234–3.536)0.890.711 (0.247–2.049)0.52

DISCUSSION

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

Despite the development and use of nomograms and algorithms to predict overall survival and DSS, clinical stage remains the most important factor of outcome in patients with RCC [4,5]. In addition, it is able to provide a common language to describe tumour characteristics and a better stratification of the risk of cancer-related survival or recurrence [17]. Based on the description of high volume multicentre studies, detailed prognostic information related to anatomy has been discovered and updated regularly [4,8,11].

TNM is the most widely used classification system of several malignancies. It receives constant updates and undergoes revisions that reflect contemporary observations in the treatment and clinical outcome [10]. In its latest issue, patients with FI and RVI were grouped into T3a stage [11]. Because they are distinct pathologies, they are expected to effect disparate survival rates. The present study confirms the observations of previous studies and contrasts with others.

The prognostic impact of venous invasion is debated. Previous series have suggested lower survival rates for this subcategory of T3 disease, calculating a median survival of 11–20 months for metastatic disease. However, for patients with non-metastatic disease and no unfavourable pathological findings, median survival varies widely in the range 38–116 months [16,18,19]. Klatte et al.[20] analyzed 321 patients who underwent surgery for RCC with thrombus extension, observing no difference in survival rates regardless of thrombus level. Wagner et al.[18] also evaluated T3 patients with thrombus extension in a multicentre study, noting worse outcomes in patients who developed vena cava thrombus compared to those with tumour thrombus limited to the renal vein.

There was no significant difference in survival between those patients with SFI and PFI. Thus, both parameters have been merged into FI. The present series confirms findings in which the location of extrarenal extension had no prognostic significance. In a cohort of 365 pT3a patients, RCC-specific survival did not differ between patients with PFI, SFI and concomitant PFI and SFI [21]. Although a previous study showed no significant impact of isolated PFI in T3 stage patients, tumour size remained the most significant prognostic factor in the survival analysis. Based on the previous edition of the staging system (TNM, 2002), T1N0M0 stage patients have outcomes comparable to T3N0M0 patients [22].

The prognostic significant of the presence of SFI has been described. Bonsib [23] implicated renal sinus fat as a possible route of metastatic spread as a result of the abundance of vascular and lymph vessels in the region. Some studies noted an impact of SFI only by univariate survival analysis [24], whereas others showed isolated predictive value by multivariate analysis [25]. Kresowik et al.[26] observed lower survival rates in those with concomitant SFI and PFI compared to SFI-only and PFI-only groups.

Patients in the FI + RVI group were associated with larger tumours and higher histological grade, suggesting more aggressive behaviour. Moreover, the association between FI and RVI had a significant impact on survival rates by univariate and multivariate analysis compared to the individual pathologies. These findings are consistent with other studies. Margulis et al.[27] analyzed 419 patients who were treated for pT3a stage RCC, observing poorer survival rates in patients with FI + RVI compared to patients with either condition alone, suggesting a modification in the TNM staging system. Compared with the 2002 TNM, the classification that they proposed was more effective in predicting survival [27].

Other groups have reported similar findings [19]. A recent European multicentre study [11] validated the latest edition of the TNM (2009), evaluating 503 cases of T3a stage RCC and noting significantly lower survival rates in patients with concomitant FI and RVI vs those with the individual pathologies.

The present study has some limitations that should be highlighted. The study comprised a single-centre retrospective analysis with a relatively small group of patients, yet the results obtained are similar to previously published series, suggesting that FI and RVI, alone or in combination, can be used as a criterion for staging in the next edition of the TNM classification because they have significantly different outcomes.

A multicentre, high-volume series must be examined rigorously with regard to pathological to confirm these findings before a change in the current TNM staging system can be proposed.

In conclusion, in pT3a RCC, the presence of FI + RVI is associated with a worse prognosis than FI or RVI alone. Therefore, they should not be classified within the same stage, as performed in the current TNM system.

REFERENCES

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