Low nuclear expression of HIF-hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence-free survival in clear cell renal cell carcinoma.

BACKGROUND: Hypoxia inducible factors, HIF-1α and HIF-2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments. PATIENTS AND METHODS: In this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence-free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue-microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow-up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated. RESULTS: Nuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT-stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts. CONCLUSIONS: The absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies.

Active surveillance versus initial surgery in the long-term management of Bosniak IIF-IV cystic renal masses.

There may be surgical overtreatment of complex cystic renal masses (CRM). Growing evidence supports active surveillance (AS) for the management for Bosniak IIF-III CRMs. We aimed to evaluate and compare oncological and pathological outcomes of Bosniak IIF-IV CRMs treated by initial surgery (IS) or AS. We identified retrospectively 532 patients with CRM counseled during 2006-2017. IS and AS were delivered to, respectively, 1 and 286 patients in Bosniak IIF, to 54 and 85 patients in III and to 85 and 21 patients in Bosniak IV. Median follow-up was 66 months (IQR 50-96). Metastatic progression occurred for 1 (0.3%) AS patient in Bosniak IIF, 1 IS (1.8%) and 1 AS (1.2%) patient in Bosniak III and 5 IS (3.5%) patients in Bosniak IV, respectively. Overall 5-year metastasis-free survival was 98.9% and cancer-specific survival was 99.6% without statistically significant difference between IS and AS in Bosniak IIF-IV categories. AS did not increase the risk of metastatic spread or cancer-specific mortality in patients with Bosniak IIF-IV. Our data indicate AS in Bosniak IIF and III is safe. Surgery is the primary treatment for Bosniak IV due to its high malignancy rate.