Large (>3.8 cm) clear cell renal cell carcinomas are morphologically and immunohistochemically heterogeneous.

Heterogeneity is an inherent event to tumour development that is lately receiving much attention in oncologic research. The topic is being addressed primarily at the molecular level, and results are promising. However, translation to practical medicine is still pending. Our intention in this study is to approach the problem in a series of clear cell renal cell carcinomas with the tools that pathologists use in routine practice. Three randomly selected areas of 48 clear cell renal cell carcinomas prospectively collected in two different institutions were analysed for intratumour heterogeneity. The evaluated parameters were tumour size, cell type (clear vs. eosinophilic), Fuhrman's grade and immunohistochemical expression of carbonic anhydrase IX, BRCA1-associated protein-1 (BAP-1), cyclooxygenase-2 (COX-2) and Ki67. Intratumour heterogeneity was detected in 26 cases (54 %). Cell type, grade and Ki67 index were the parameters more frequently heterogeneous amounting, respectively, 44, 42 and 38 %. Tumour size was a significantly discriminative factor to predict tumour heterogeneity, with a cut-off of 3.8 cm (p < 0.001). Aside from tumour size, the most relevant parameters related with intratumour heterogeneity were cell type (clear vs. eosinophilic), Fuhrman's grade and Ki67 and COX-2 expression patterns. Carbonic anhydrase 9 and BAP-1 did not show statistical relevance. We conclude that heterogeneity is a common event in clear cell renal cell carcinomas that may be overlooked in cases insufficiently sampled. Tumour size appears as a reliable tool in identifying this situation since clear cell renal cell carcinomas under 3.8 cm in diameter are always homogeneous. This point may help the pathologist to make decisions in tumour sampling.