Purpose To evaluate clinicopathologic features and survival outcomes of unilocular cystic renal cell carcinoma (cRCC) compared with purely solid renal cell carcinoma (RCC), and to evaluate the oncologic aggressiveness of unilocular cRCC. Methods The relevant data of 957 patients with sporadic unilateral RCCs underwent surgical treatment in 2 institutions from Jan 2014 to Oct 2018 were obtained. We excluded multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), RCCs with multilocular cysts and necrotic RCCs. 74 unilocular cRCCs were identified by pathology reports. We performed propensity score matching (PSM) and randomly selected 148 purely solid RCCs. The clinicopathologic features and survival outcomes were compared properly. Results After PSM, age, BMI, Charlson Comorbidity Index, and postoperative Chronic Kidney Disease grade were not significantly different. Both overall survival and cancer-specific survival of unilocular cRCCs were significantly better than the purely solid RCCs by the log-rank test. Twenty-five cases of solid RCCs were in the pT3 or pT4 stage, while no pT3 or pT4 tumors were found in unilocular cRCCs. Fuhrman grade, pT stage, lymphatic metastasis and tumor diameter were found to be independent prognostic factors. Conclusion Unilocular cRCCs have a lower Fuhrman grade and pathological stage and a better prognosis compared with solid RCC. Unilocular cRCCs still probably have lymphatic metastasis at diagnosis and may have postoperative metastasis, which is different from MCRNLMP. We recommend that the diagnosis of unilocular cRCC should be reflected in pathology reports. Different subtypes of cRCC should be taken into consideration in counseling and management.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel–Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency–induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation–dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l -methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.

To evaluate clinicopathological features and survival outcomes of unilocular cystic renal cell carcinoma (ucRCC) compared with purely solid renal cell carcinoma (sRCC), and to evaluate the oncologic aggressiveness of ucRCC. The relevant data of 957 patients with sporadic unilateral renal cell carcinoma (RCC) underwent surgical treatment in 2 institutions from Jan 2014 to Oct 2018 were obtained. We excluded multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), RCC with multilocular cysts and necrotic RCC. 74 ucRCCs were identified by pathology reports. We performed propensity score matching (PSM) and eventually selected 144 sRCCs. The clinicopathological features and survival outcomes were compared properly. After PSM, age, BMI, Charlson Comorbidity Index, and postoperative Chronic Kidney Disease grade were not significantly different. Both overall survival and progression-free survival of ucRCC were significantly better than sRCC by the log-rank test. Twenty-five cases of sRCCs were in the pT3 or pT4 stage, while no pT3 or pT4 tumors were found in ucRCCs. Fuhrman grade and lymphatic metastasis were found to be significant prognostic factors for the overall survival of ucRCC. Unilocular cystic RCC has a lower Fuhrman grade and pathological stage and a better prognosis compared with solid RCC. Patients with ucRCC still probably have lymphatic metastasis at surgery and may have postoperative metastasis, which is different from MCRNLMP. We recommend that the diagnosis of ucRCC should be reflected in pathology report. Different subtype of cystic RCC should be taken into consideration in counseling and management.