Clinical, Molecular, and Genetic Correlates of Lymphatic Spread in Clear Cell Renal Cell Carcinoma

BackgroundWhile it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood.ObjectiveDefine the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas.Design, setting, and participantsA retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively.MeasurementsFisher exact test or the χ2 test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread.Results and limitationsIn clinical analyses, a predictive model consisting of smoking history (p = 0.040), T stage (p < 0.0001), Fuhrman grade (p < 0.0001), Eastern Cooperative Oncology Group performance status (p < 0.0001), and microvascular invasion (p < 0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p = 0.043) and high epithelial vascular endothelial growth factor receptor 2 (p = 0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p < 0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience.ConclusionsThe low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation.