Should RCC Patients With Nodal Disease be Reclassified?

Patients with renal cell carcinoma (RCC) classified at stage III node-positive (pT₁₂₃N₁M₀) disease had significantly worse survival than those with stage III node-negative disease (pT₁₂₃N₀M₀) and similar outcomes to those with stage IV (pT₁₂₃N_0/xM₁) disease, according to the results of a study published in Cancer.

“Pathologic staging for RCC is essential for guiding post-operative surveillance and selecting patients for potential adjuvant systemic therapy,” wrote researcher Kai-Jie Yu, MD, of The University of Texas MD Anderson Cancer Center, and colleagues.

“The current AJCC staging manual (the eighth edition) incorporates locally advanced (pT3a-c), lymph node-negative tumors and lymph node-positive disease into the same stage III grouping,” they wrote. “The results reported herein suggest that it may be prudent to revise the current staging system by classifying pN1 patients as having stage IV disease.”

Looking at data from 1993–2012, researchers at MD Anderson identified 115 patients with stage III, node-positive disease, 274 patients with stage III, node-negative disease, and 523 patients with stage IV disease. They compared overall survival (OS) and cancer-specific survival between the groups.

Patients with stage III, node-positive disease were significantly more likely to have grade IV tumors (55.7% vs 27%; P < .0001) and non-clear cell histology (40% vs 12.8%; P < .0001) compared with those with stage III, node-negative disease.

Outcomes were significantly better for patients with stage III node-negative disease for OS (10.2 vs 2.4 years) compared with patients with stage III, node-positive disease. However, no differences in OS were found between stage III node-positive and stage IV disease. Node-positive disease was significantly associated with worse OS among patients with stage III RCC (Hazard Ratio [HR], 2.44; P < .0001).

Patients with stage III node-negative disease also had better cancer-specific survival compared with node-positive disease (median not yet reached vs 2.8 years). Similar to OS, there was no significant difference in cancer-specific survival for patients with stage III node-positive disease and those with stage IV disease (2.8 years vs 2.4 years). Again, node-positive disease was significantly associated with increased risk of death from cancer (HR, 2.85; P < .0001).

“The outcomes of patients with stage III RCC due to pathologic nodal involvement are significantly

worse than the outcomes of patients with stage III RCC without nodal involvement and similar to the outcomes of patients with stage IV RCC,” Yu and colleagues wrote. “If these findings are validated in other studies, consideration should be given to reclassifying patients with stage III, pN1 disease as having stage IV disease.”

Commenting on the results of the study, Benjamin T. Ristau, MD, MPH, assistant professor of surgery at UConn Health, said that it makes sense that patients with tumors that have spread outside of the kidney and established lymphatic invasion would have worse survival outcomes than patients with locally advanced tumors without lymphatic invasion.

"One important detail is that the group of patients with lymph node-positive disease were all selected to undergo lymph node dissection. Presumably, there was a reason (i.e., clinically enlarged lymph nodes) that resulted in the decision to perform a lymph node dissection. Similarly, patients with clinically metastatic disease are a heterogeneous group. Those selected for cytoreductive nephrectomy probably had a lower total volume of disease compared to those who did not undergo surgery," Ristau told Cancer Network.

"Taken together, this could have selected for patients with larger volume lymph node metastasis in the Stage III lymph node positive group and lower volume metastasis in the Stage IV metastatic group, which may have biased the results towards confirming similar survival between patients with positive lymph node and those with metastatic disease."

"Nonetheless, the authors clearly demonstrate that patients with pathologically confirmed positive lymph nodes do worse than those with pathologically negative lymph nodes," said Ristau. "Therefore, reclassification of these patients into a subset of Stage IV disease (i.e. Stage IVa) deserves consideration."