Impact of Microscopic Wall Invasion of the Renal Vein or Inferior Vena Cava on Cancer-specific Survival in Patients with Renal Cell Carcinoma and Tumor Thrombus: A Multi-institutional Analysis from the International Renal Cell Carcinoma-Venous Thrombus Consortium

Abstract

Background

Microscopic vein invasion (MVI), with local destruction and invasion of the endothelium by tumor, is of controversial predictive value in renal cell carcinoma (RCC).

Objective

To assess the impact of venous extension and wall invasion in RCC on survival.

Design, setting, and participants

Data for 1023 RCC patients with vena cava thrombus treated with radical nephrectomy and complete tumor thrombectomy were collected within a prospectively maintained international consortium (1995–2012).

Outcome measurements and statistical analysis

The Kaplan-Meier method and univariable and multivariable Cox regression analyses were used to assess the impact of MVI on cancer-specific survival (CSS). The main two variables of interest were microscopic renal vein wall invasion (MRVI) and microscopic vena cava wall invasion (MVCI).

Results

MRVI was found in 725 cases (70.9%) and MVCI in 230 (22.5%). Patients with MRVI had larger tumors (p = 0.005), longer hospital stay (p < 0.001), higher clinical stage 0.039), higher Fuhrman grade (p = 0.028), and more frequent fat invasion. Presence of MVCI was associated with larger tumors (p < 0.001), longer hospital stay (p < 0.001), higher clinical stage (p < 0.001), lymph node involvement (p = 0.045), higher Fuhrman grade (p < 0.001), and higher thrombus level (p < 0.001). With median follow-up of 52 mo, overall 5-yr CSS was 57.4%. Multivariable analysis showed that presence of MRVI was an independent factor related to CSS (hazard ratio 2.24, 95% confidence interval 1.24–3.59, p = 0.006). The main limitation was the inability to report MVI percentages.

Conclusions

Patients with MRVI experience significantly worse survival outcomes after radical nephrectomy and tumor thrombectomy. Consideration of MRVI at final pathology is appropriate to improve decision-making for risk-adapted follow-up.

Patient summary

The behavior of locally advanced renal cell carcinoma (RCC) depends on clinical and pathologic factors. Analysis revealed that RCC patients with microscopic renal vein wall invasion experience significantly worse cancer-specific survival.

Introduction

Renal cell carcinoma (RCC) represents 2–3% of all cancers. During the last two decades there has been an annual increase of 2% in RCC, with 84 400 new cases and 34 700 cancer-related deaths in the European Union in 2012 [1]. Up to 10% of patients with RCC develop tumor thrombus involving the renal vein or vena cava [2]. Even with extensive surgery, the survival of patients with RCC and inferior vena cava thrombus is poor at 40–65% at 5 yr, dropping to 0–17% in patients with metastases [3].

Vascular tumor thrombus may take the form of a free-floating thrombus or present with adhesion to the wall with continuous invasion. Such invasion increases the risk of microscopic positive vascular margins. Moreover, it has been reported that vasculogenic mimicry plays an important function in tumor blood supply [4].

Several clinical trials are currently ongoing to evaluate the potential benefit of adjuvant targeted therapies in patients with intermediate-risk and high-risk disease, stratified according to the stage, size, grade, and necrosis (SSIGN) score using the Mayo Clinic classification [5], [6]. Preliminary results for the ASSURE trial indicate that tyrosine kinase inhibitors (TKIs) do not offer benefits beyond those of placebo [7]. Moreover, it has been suggested that overtreatment of patients eligible for enrolment according to current pathologic criteria would be reduced by the use of stricter pathologic inclusion criteria referring to more specific predictive factors [8], [9]. In the subgroup of patients with RCC and tumor thrombus, multivariable analyses have demonstrated that tumor size, perinephric fat tissue invasion, lymph node invasion, distant metastasis, and inferior vena cava invasion are prognostic factors for overall survival (OS) [10], [11], [12].

Previous studies have evaluated the predictive value of microscopically positive vascular wall margins on cancer-specific survival (CSS). These studies found that positive vascular margins were an independent factor for local recurrence but not for CSS [13]. Owing to the lack of information available in the literature on the prognostic significance of microscopic invasion of the renal vein or inferior vena cava wall in patients with RCC and tumor thrombus, the objective of this study was to analyze the impact of microscopic renal vein wall invasion (MRVI) and microscopic vena cava wall invasion (MVCI) on CSS in a large multi-institutional cohort of RCC patients with tumor thrombus.