Abstract
To identify the molecular signature of localized (N0M0) clear cell renal cell carcinoma (RCC) and assess its ability to predict outcome. Clinical characteristics and pathologic records of 170 patients with localized clear cell RCC who underwent nephrectomy were reviewed. Immunohistochemical analysis was done on a tissue microarray of all primary tumors using a kidney cancer-related panel of protein markers, which included CAIX, CAXII, CXCR3, gelsolin, Ki-67, vimentin, EpCAM, p21, p27, p53, pS6, PTEN, HIF-1alpha, pAkt, VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, and VEGFR-3. Associations with disease-free survival (DFS) were evaluated with Cox models, and a concordance index assessed prognostic accuracy. Median follow-up was 7.1 years. The final multivariate Cox model determined T classification, Eastern Cooperative Oncology Group performance status, and five molecular markers (Ki-67, p53, endothelial VEGFR-1, epithelial VEGFR-1, and epithelial VEGF-D) to be independent prognostic indicators of DFS. The molecular signature based on these markers predicted DFS with an accuracy of 0.838, an improvement over T classification of 0.746, and the University of California-Los Angeles Integrated Staging System of 0.780. A constructed nomogram combined the molecular, clinical, and pathologic factors and approached a concordance index of 0.904. A molecular signature consisting of five molecular markers (Ki-67, p53, endothelial VEGFR-1, epithelial VEGFR-1, and epithelial VEGF-D) can predict DFS for localized clear cell RCC. The prognostic ability of the signature and nomogram may be superior to clinical and pathologic factors alone and may identify a subset of localized patients with aggressive clinical behavior. Independent, external validation of the nomogram is required.
Highlights
Between 20% and 30% of patients with clinically localized (N0M0) renal cell carcinoma (RCC) develop metastases after undergoing a potentially curative nephrectomy [1]
The constructed nomogram containing T classification, Eastern Cooperative Oncology Group performance status (ECOG PS), and the five molecular markers approached a predictive accuracy of 0.904
The UCLA Integrated Staging System (UISS) and the SSIGN are integrated staging systems to predict survival for localized and metastatic RCC [1, 8]. Both have been externally validated with large multicenter cohorts and showed good predictive accuracy with C-indices of 0.809 (UISS, localized RCC; ref. 12) and 0.90
Summary
Between 20% and 30% of patients with clinically localized (N0M0) renal cell carcinoma (RCC) develop metastases after undergoing a potentially curative nephrectomy [1]. Adjuvant therapy is not approved for localized RCC and careful observation remains the postoperative standard of care. Patients undergoing resection of an isolated recurrence show long-term survival and those with limited disease burden respond better to systemic therapy [6, 7]. Identifying this high-risk group of patients remains a clinical challenge. Conventional pathologic and clinical factors such as tumor-node-metastasis stage, Eastern Cooperative Oncology Group performance status (ECOG PS), and nuclear grade provide robust prognostic information; alone, they cannot accurately predict disease progression. Several prognostic models combine independent prognostic factors to improve risk group assessment, but the reported accuracy indices vary [1, 8,9,10,11,12]
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