Development and validation of a prognostic model incorporating tumor thrombus grading for nonmetastatic clear cell renal cell carcinoma with tumor thrombus: A multicohort study

Abstract

There is significant variability with respect to the prognosis of nonmetastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). By applying multiregion whole-exome sequencing on normal-tumor-thrombus-metastasis quadruples from 33 ccRCC patients, we showed that metastases were mainly seeded by VTT (81.8%) rather than primary tumors (PTs). A total of 706 nonmetastatic ccRCC patients with VTT from three independent cohorts were included in this study. C-index analysis revealed that pathological grading of VTT outperformed other indicators in risk assessment (OS: 0.663 versus 0.501-0.610, 0.667 versus 0.544-0.651, and 0.719 versus 0.511-0.700 for Training, China-Validation, and Poland-Validation cohorts, respectively). We constructed a risk predicting model, TT-GPS score, based on four independent variables: VTT height, VTT grading, perinephric fat invasion, and sarcomatoid differentiation in PT. The TT-GPS score displayed better discriminatory ability (OS, c-index: 0.706-0.840, AUC: 0.788-0.874; DFS, c-index: 0.691-0.717, AUC: 0.771-0.789) than previously reported models in risk assessment. In conclusion, we identified for the first-time pathological grading of VTT as an unheeded prognostic factor. By incorporating VTT grading, the TT-GPS score is a promising prognostic tool in predicting the survival of nonmetastatic ccRCC patients with VTT.

Keywords: clear cell renal cell carcinoma; pathological grading; prognostic model; risk stratification; venous tumor thrombus.

FIGURE 1

The genomic landscape and phylogenic tree structures. (A) The top panel shows the number of mutations identified in each tumor sample; the middle panel shows mutations of the top 29 driver genes across all samples; the bottom panel shows source of each site. (B) Phylogenic tree structure of evolution relationship among primary (P), thrombus (T) and metastatic (M) of ccRCC patients 07. Heatmap indicates the regional distribution of all mutations in patient 07. The columns next to each heatmap show three categories of mutations and their percentages: public mutations (green); shared mutations (yellow); private mutations (red).

FIGURE 2

(A) The flow diagram of patient selection. ccRCC, clear cell renal cell carcinoma; VTT, venous tumor thrombus. (B) Sankey diagram illustrating the associations between the PT and VTT grading. Left, China‐Training cohort; Middle, China‐Validation cohort; Right, Poland‐Validation cohort. Significance was assessed by chi‐square test. PT, primary tumor; VTT, venous tumor thrombus.

FIGURE 3

Kaplan–Meier estimates of OS (upper) and DFS (lower) stratified by VTT grading in (A) Training cohort, and (B) China‐Validation cohort, and (C) Poland‐Validation cohort (only OS). ROC curve analysis for comparing the prognostic accuracy of VTT Grading with other variables to predict OS (upper) and DFS (lower) in (D) Training cohort, (E) China‐Validation cohort, and (F) Poland‐Validation cohort. P values represented the significant difference between other variables and VTT Grading at 5 years. OS, overall survival; DFS, disease‐free survival; PT, primary tumor; VTT, venous tumor thrombus; AUC; area under the curve; ROC; receiver operating characteristic; CI; confidence interval.

FIGURE 4

Kaplan–Meier estimates of OS (upper) and DFS (lower) stratified by the TT‐GPS score in (A) Training cohort, (B) China‐Validation cohort, and (C) Poland‐Validation cohort (only OS). ROC curve analysis for comparing the prognostic accuracy of the TT‐GPS score with currently reported prognostic models to predict OS (upper) and DFS (lower) in (D) Training cohort, (E) China‐Validation cohort, and (F) Poland‐Validation cohort. p Values represented the significant difference between other variables and VTT grading at 5 years. OS, overall survival; DFS, disease‐free survival; TT‐GPS, VTT height, VTT grading, Perinephric fat invasion, sarcomatoid differentiation in PT. AUC, area under the curve; ROC, receiver operating characteristic; SSIGN, the Mayo Clinic Stage, Size, Grade and Necrosis; UISS, the University of California Los Angeles Integrated Staging System; GRANT, the GRade, Age, Nodes and Tumor; CI, confidence interval.

FIGURE 5

Kaplan–Meier estimates of OS (upper) and DFS (lower) stratified by the TT‐GPS risk classification in (A) Training cohort, (B) China‐Validation cohort, and (C) Poland‐Validation cohort (only OS). OS, overall survival; DFS, disease‐free survival; low, low‐risk group; inter, intermediate‐risk group; high, high‐risk group; TT‐GPS, VTT height, VTT grading, perinephric fat invasion, sarcomatoid differentiation in PT.