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The aggregate literature suggests that chromophobe renal cell carcinoma (RCC) is biologically a tumor of low malignant potential with reported 5-year and 10-year survival rates of 78% to 100% and 80% to 90%, respectively. The conventional prognostic parameters that determine the outcome of the tumors that progress remain to be fully characterized. Clinicopathologic features of 145 cases were correlated with outcome. The mean age of the patients was 59 years (range, 27 to 82) and the male to female ratio was 1.1:1. Most tumors were well circumscribed and averaged 8.0 cm (range, 1.0 to 30.0 cm); multifocality and bilaterality were present in 8% and 3% of patients. Sixty (41%) were eosinophilic variant (greater than 80% eosinophilic cells), 18 (12%) were classic type (greater than 80% pale cells), and 67 (46%) were mixed (containing variable admixture of pale and eosinophilic cells). A subset of eosinophilic chromophobe RCC contained or had areas similar to renal oncocytomas. These tumors tended to be more commonly bilateral (11%) and multifocal (22%) and were not associated with necrosis or sarcomatoid change. Sarcomatoid change was present in 12/145 (8%) tumors. By histologic grade, 1%, 19%, 74%, 6% were Fuhrman nuclear grade 1, 2, 3, and 4. Nineteen percent, 21%, 28%, 13%, 4%, 1%, and 3% were pT (2002) stage pT1a, pT1b, pT2, pT3a, pT3b, pT3c, and pT4 tumors. Two percent tumors were pN1 at presentation and 2.8% tumors were M1 at presentation. Follow-up (1 to 182 mo, mean 48 mo, median 37 mo) was available in 123 cases. Disease progression (local recurrence 4, metastasis 15, and/or death 10) was seen in 20 patients. In univariable analysis, tumor size (P=0.025), pT stage (P<0.001), broad alveolar architecture (P=0.012), Fuhrman nuclear grade (P<0.001), microscopic tumor necrosis (P=0.001), vascular invasion (P=0.020), and sarcomatoid change (P≤0.001) were associated with progression. A multivariable Cox regression model revealed sarcomatoid change (P=0.013, estimated relative hazard 4.7), microscopic necrosis (P=0.020, relative hazard=3.5), and pT stage (P=0.025, relative hazard 3.4) as independent predictors of aggressive chromophobe RCC. Although the large majority of chromophobe RCCs have a favorable prognosis, a distinct subset of patients progress. The pT stage of tumor, tumor necrosis, and sarcomatoid change all predict aggressive phenotype of chromophobe RCC. The adverse presence of these features in a nephrectomy specimen with chromophobe RCC warrants active surveillance, and these patients may be candidates for adjuvant therapies as they become available.