Percentage grade 4 tumour predicts outcome for clear cell renal cell carcinoma

Heterogeneity of tumour grading is common in clear cell renal cell carcinoma (ccRCC). WHO/ISUP grading specifies that RCC should be graded based on the highest grade present in at least one high power field. This does not take into account the proportion of high grade tumour present in a cancer, which may itself influence outcome. Cases of ccRCC accessioned by Aquesta Uropathology, Brisbane, Australia, between 2008 and 2015, were reviewed and grading assigned according to WHO/ISUP criteria. For tumours classified as grade 3 (G3) and 4 (G4), the percentage of tumour showing G3 and G4 morphology was assessed for each case. Survival analysis, with time to the development of metastases as the clinical outcome, was performed for six grading subclasses (G3 <10%, G3 10-50%, G3 >50%, G4 <10%, G4 10-50%, G4 >50%). Of the 681 cases of ccRCC in the series, there were 153 cases classified as G3 (91 cases) and G4 (62 cases) for which follow-up was available. During the follow-up period of <1-89 months, 19 (20.9%) patients with G3 and 30 (48.3%) patients with G4 cancers developed metastatic disease. The three subgroups of <10%, 10-50% and >50% G3 tumour were not significant in predicting outcome (p=0.47). Separating G3 into two groups of ≤50% vs >50% was also not significantly associated with outcome (p=0.22). For the three subgroups of G4 ccRCC (<10%, 10-50% and >50% G4) a higher percentage of G4 correlated with time to the development of metastases (p=0.01). Even though G4 tumours as a whole had a significantly worse outcome than G3 tumours (p=0.0004), the difference between G4 <10% and G3 tumours was not significant (p=0.27). On multivariate analysis, that included pT staging category and tumour size, there was a significant difference in survival between G4<10% and G4>50% tumours (p=0.018). The results of the study suggest that for ccRCC, WHO/ISUP G4 category should incorporate the percentage of G4 tumour present.