Microvascular Tumor Invasion, Tumor Size and Fuhrman Grade: A Pathological Triad for Prognostic Evaluation of Renal Cell Carcinoma
Article Outline
Purpose
The biological behavior and clinical outcome of renal cell carcinoma are difficult to predict. We investigated the prognostic impact of clinicopathological variables to establish a risk stratification model to predict recurrence and survival rates.
Materials and Methods
We studied 230 patients with renal cell carcinoma (stages T1–4 Nx M0) who underwent radical nephrectomy and/or nephron sparing surgery, and were followed for a median of 48 months (range 3 to 140). Univariate and multivariate analyses were performed, and the influence of clinical presentation, histological tumor size, tumor grade, lymph node involvement and microvascular tumor invasion on disease-free and cancer specific survival curves was determined. A composition model based on independent prognostic variables was then created to stratify tumors into low, intermediate and high risk of progression.
Results
The tumor recurrence rate was 17% (39 of 230) and the cancer specific mortality rate was 13% (31 of 230). Multivariate analyses determined that microvascular tumor invasion, tumor grade and tumor size were the only independent prognostic factors. Disease-free survival rates for low, intermediate and high risk tumors were 94.7%, 56.8% and 13.1%, respectively. Cancer specific survival rates were 94.7%, 61.7% and 32.0%, respectively.
Conclusions
Tumor size, Fuhrman grade and microvascular tumor invasion are strong and independent predictors of survival of patients with renal cell carcinoma. Risk assessment and stratification based on this triad of pathological features may allow better individualization of followup schedules and trials of adjuvant treatment for patients with renal cell carcinoma.
Key Words: carcinoma, renal cell, prognosis, survival, neovascularization, pathologic, microcirculation
Abbreviations and Acronyms: MVI, microvascular invasion, RCC, renal cell carcinoma
The incidence of RCC is increasing, in part due to the more frequent use of abdominal imaging.1 Although 61% of renal tumors are now incidentally detected as small masses in asymptomatic patients,2 a significant number of patients undergoing curative surgical treatment can be expected to experience relapse at distant sites.3
Several anatomical, histological, clinical and immunohistochemical features have been described as prognostic factors for disease progression and survival. In addition to well established prognostic factors such as TNM stage, tumor size and Fuhrman grade,4 the presence of microvascular tumor invasion in RCC is considered an important predictor of disease progression and recurrence.5, 6, 7, 8, 9 Nevertheless, pathological reports of MVI in renal cancer are still rare in the literature.
Because RCC is a singular disease with a highly variable natural history, the identification of a reliable set of prognostic factors may improve the treatment of patients with this disease. For instance, patients with RCC with indolent biological behavior could benefit from a more flexible followup schedule. On the other hand, high risk tumors may demand aggressive postoperative surveillance and perhaps some new available adjuvant systemic therapy.
In the present study we analyzed the role of pathological prognostic data obtained from the surgical specimen examination, identified independent variables by multivariate analysis, and established groups of patients at higher risk for disease recurrence and disease related death.
Patients and Methods
The records of 230 consecutive patients surgically treated for RCC at our institution between 1988 and 2003 were retrospectively reviewed. The present study included patients who underwent open radical nephrectomy and/or renal conservative surgery (partial nephrectomy or tumor enucleation). The exclusion criteria consisted of the presence of metastatic disease at the time of diagnosis or incomplete pathological data. The demographic data are described in table 1.
Table 1. Demographic data
| No. (%) | |
|---|---|
| Gender: | |
 Male | 168 (73.0) |
| Female | 62 (27.0) |
| Clinical presentation: | |
| Incidental | 120 (52) |
| Symptomatic | 110 (48) |
| Surgery: | |
| Radical | 180 (79.3) |
| Nephron sparing | 47 (20.7) |
| Tumor size (cm): | |
| 7 or less | 169 (73.5) |
| Greater than 7 | 61 (26.5) |
| Tumor characteristics: | |
| Single | 212 (92.2) |
| Multiple | 18 (7.8) |
| Histological type: | |
| Clear | 148 (64.3) |
| Chromophobe | 23 (10.0) |
| Papillary | 45 (19.6) |
| Sarcomatoid | 13 (5.7) |
| Bellini’s cell | 1 (0.4) |
| Fuhrman grade: | |
| 1 or 2 | 145 (63.3) |
| 3 or 4 | 84 (36.7) |
| Lymph nodes: | |
| Neg | 216 (93.9) |
| Pos | 14 (6.1) |
| MVI: | |
| Neg | 171 (74.3) |
| Pos | 59 (25.7) |
Clinical staging (T1–T4 Nx M0) was preoperatively determined by imaging studies (computerized tomography, magnetic resonance imaging and chest x-rays). Bone scans and excretory urography were performed in selected cases. All pathological microscopic slides from each case were reviewed by a single pathologist (KRL), and to avoid a sampling bias during pathological analysis the entire tumor specimen was sectioned. The presence of MVI was evaluated and defined as positive when there were cancer cells inside intratumor microvessels.
Pathological features were recorded for each specimen, including clinical presentation (symptomatic or incidental), histological type (clear cell, chromophobe, papillary, Bellini duct or sarcomatoid renal carcinoma), Fuhrman grade (1 and 2—low grade, 3 and 4—high grade), tumor size (less than 7 vs more than 7 cm), lymph node tumor involvement and presence of MVI. Most patients were followed after surgery with physical examination, serum creatinine and chest-abdominal computerized tomography every 6 months. Survival time was calculated from the time of partial or radical nephrectomy to the last known followup.
The log rank test was used to determine the correlation between survival and potential prognostic factors including clinical presentation, histological type, Fuhrman nuclear grade, tumor size, lymphatic invasion and MVI. Disease-free and cancer specific survival curves were obtained using the Kaplan-Meier method. Multivariate analyses were performed using the Cox proportional hazards model to identify independent prognostic factors.
Survival curves were constructed based on tumor grade, tumor size and MVI. The tumors were considered low risk—low grade (1 or 2), diameter 7 cm or less, MVI absent; high risk—high grade (3 or 4), diameter greater than 7 cm, MVI present; and intermediate risk—1 or 2 high risk variables.
Results
A total of 230 patients were studied, and consisted of 168 men (73%) and 62 women (27%) with a mean age of 59 years (range 9 to 90). Tumor size was 7 cm or less in 73.5% of cases. However, radical nephrectomy was performed in almost 80% of patients. This can be explained by the fact that we only performed partial nephrectomies in cases with tumors 4 cm or smaller with a favorable anatomical location in the kidney. Median followup was 48 months (range 3 to 140) with a recurrence rate of 17% (39 of 230) and a cancer specific mortality rate of 13% (31 of 230). Eight patients (3.5%) with recurrent tumors were still alive by the end of followup. The 5-year cancer specific survival rate was 75% (95% CI 66.0%; 84.2%) and the overall 5-year disease-free survival rate was 73% (95% CI 64.2%; 81.2%).
After multivariate analysis 3 independent variables to predict cancer specific survival and overall disease-free survival arose, and included MVI, tumor grade and tumor size (Table 2, Table 3). Using these 3 risk factors survival probabilities could be categorized into low, intermediate and high risk as depicted in Fig. 1, Fig. 2.
Table 2. Cox regression analysis for disease-free survival
| Hazard Ratio | 95% CI | p Value | Analysis | |
|---|---|---|---|---|
| Clinical presentation | 2.21 | 0.96; 5.11 | 0.062 | Univariate |
| Histological type | 1.02 | 0.76; 1.35 | 0.908 | Univariate |
| Lymph nodes | 1.18 | 0.51; 2.73 | 0.704 | Univariate |
| Grade | 2.43 | 0.97; 6.08 | 0.058 | Univariate |
| Tumor size | 2.09 | 1.06; 4.14 | 0.034 | Univariate |
| MVI | 3.56 | 1.41; 9.01 | 0.007 | Univariate |
| Grade | 2.52 | 1.02; 6.25 | 0.045 | Multivariate |
| Tumor size | 2.35 | 1.20; 4.62 | 0.013 | Multivariate |
| MVI | 4.53 | 1.87; 10.97 | 0.001 | Multivariate |
Table 3. Cox regression analysis for cancer specific survival
| Hazard Ratio | 95% CI | p Value | Analysis | |
|---|---|---|---|---|
| Clinical presentation | 2.43 | 0.93; 6.30 | 0.068 | Univariate |
| Histological type | 1.01 | 0.73; 1.39 | 0.967 | Univariate |
| Lymph nodes | 0.94 | 0.36; 2.43 | 0.892 | Univariate |
| Grade | 2.67 | 0.96; 7.47 | 0.060 | Univariate |
| Tumor size | 1.99 | 0.94; 4.22 | 0.074 | Univariate |
| MVI | 3.14 | 1.12; 8.80 | 0.029 | Univariate |
| Grade | 2.69 | 0.98; 7.41 | 0.055 | Multivariate |
| Tumor size | 2.19 | 1.03; 4.65 | 0.042 | Multivariate |
| MVI | 3.87 | 1.45; 10.35 | 0.007 | Multivariate |
Fig. 1.
Disease-free survival in 3 risk categories
Fig. 2.
Cancer specific survival in 3 risk categories
Discussion
The outcome of patients treated for localized RCC has usually been difficult to predict. Tumor stage is traditionally considered the single most important prognostic factor of RCC.10 Other variables have been considered for prognostic assessment of patients with RCC. In this regard the presence of clinical manifestations,11 tumor size,12 Fuhrman grade,13, 14 lymph node involvement and tumor necrosis13 have a major role, and are extensively used in the clinical setting. Recent knowledge in the pathogenesis, molecular behavior and progression of RCC, as well as the evaluation of clinical and pathological predictive factors, have led to suggestions for new algorithms to define the prognosis of patients with RCC.
In the present study 3 pathological tumor features, namely MVI, tumor size and Fuhrman grade, stand out as independent survival predictive factors. This pathological triad provided a precise risk assessment for cancer specific survival and overall disease-free survival.
Because systemic progression in RCC depends on tumor access to microvasculature,7, 9 most available data indicate a significant prognostic value for microvascular invasion in such patients.14, 15, 16, 17, 18 Lang et al found that MVI is an independent prognostic factor for survival of patients with stage pT1 to pT3b disease.19 Ishimura et al found that MVI is a predictor of disease recurrence after surgery in patients with stage pT1 or pT2 disease.20
Furthermore, disease progression was observed in 39% to 55.5% of patients with positive MVI.7, 9 In addition, Mrstik et al have shown that the 5-year survival rate is reduced in individuals with positive MVI tumors (35%) compared to patients without MVI (90%).6 The present study clearly demonstrates the discriminator role of MVI as a prognostic factor for RCC. The 5-year disease-free and cancer specific survival rates were 87.1% and 91.4%, respectively, for negative MVI, in contrast to 32.6% and 39.7% seen in MVI positive tumors.
Although Sevinc et al did not find statistical significance for MVI alone in multivariate analysis, this variable acquired clinical relevance when it was considered with Fuhrman grade.8 In our study multivariate analysis showed MVI not only as a strong independent factor, but also as the most significant predictor of RCC outcome compared to other variables such as tumor size, Fuhrman grade and sarcomatoid degeneration. Furthermore, taking into account the 3 independent pathological parameters evaluated (tumor size, Fuhrman grade and MVI) we improved our capability to predict the biological behavior of RCC.
Although our study was retrospective, it was strengthened by the fact that all pathological slides were reviewed by a single pathologist. Furthermore, all classic pathological features were evaluated and compared to MVI, which stood out as the most relevant predictor of tumor aggressiveness. Finally, we clearly defined a prognostic pathological feature that can be easily determined by the pathologist and used to accurately predict the biological behavior of RCC.
Conclusions
According to the present study among various candidates for prognostic indicators only 3 pathological features, namely tumor size, Fuhrman grade and microvascular tumor invasion, remained strong and independent predictors of survival after a meticulous statistical analysis. Risk assessment and patient stratification based on this triad of pathological features may result in individualization of followup schedules and better treatment for patients with RCC.
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Nothing to disclose.
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 732 and 733.
PII: S0022-5347(07)00776-8
doi:10.1016/j.juro.2007.03.128
© 2007 American Urological Association. Published by Elsevier Inc. All rights reserved.