Spatial Distribution of Tumor Cells in Clear Cell Renal Cell Carcinoma Is Associated with Metastasis and a Matrisome Gene Expression Signature.

Simple Summary: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, but predicting its behavior remains challenging using standard histopathologic examination. This study introduces a novel approach to predict ccRCC aggressiveness by analyzing the spatial distribution of tumor cells in H&E-stained images. The researchers found that spatial analysis outperformed traditional tumor grading in predicting metastasis, particularly for intermediate-grade tumors. They identified two distinct patient groups based on spatial characteristics, with one group showing greater spatial randomness and a higher association with metastasis. Furthermore, the study revealed a gene expression signature related to the extracellular matrix (matrisome) that correlated with the spatial patterns and aggressive tumor behavior. These findings suggest that analyzing the spatial distribution of ccRCC tumor cells could provide valuable insights into tumor behavior and metastatic potential, potentially improving prognostication and personalized treatment strategies for patients with ccRCC. Background/Objectives: Predicting the behavior of clear cell renal cell carcinoma (ccRCC) is challenging using standard-of-care histopathologic examination. Indeed, pathologic RCC tumor grading, based on nuclear morphology, performs poorly in predicting outcomes of patients with International Society of Urological Pathology/World Health Organization grade 2 and 3 tumors, which account for most ccRCCs. Methods: We applied spatial point process modeling of H&E-stained images of patients with grade 2 and grade 3 ccRCCs (n = 72) to find optimum separation into two groups. Results: One group was associated with greater spatial randomness and clinical metastasis (p < 0.01). Notably, spatial analysis outperformed standard pathologic grading in predicting clinical metastasis. Moreover, cell-to-cell interaction distances in the metastasis-associated group were significantly greater than those in the other patient group and were also greater than expected by the random distribution of cells. Differential gene expression between the two spatially defined groups of patients revealed a matrisome signature, consistent with the extracellular matrix's crucial role in tumor invasion. The top differentially expressed genes (with a fold change > 3) stratified a larger, multi-institutional cohort of 352 ccRCC patients from The Cancer Genome Atlas into groups with significant differences in survival and TNM disease stage. Conclusions: Our results suggest that the spatial distribution of ccRCC tumor cells can be extracted from H&E-stained images and that it is associated with metastasis and with extracellular matrix genes that are presumably driving these tumors' aggressive behavior. [ABSTRACT FROM AUTHOR]