Transcriptomic Profiling Identifies a Subset of Renal Tumors with Overlapping Features of Clear Cell Papillary Renal Cell Tumor and Renal Cell Carcinoma with Fibromyomatous Stroma

Background: Renal cell carcinomas (RCCs) represent neoplasms with variable biological behaviour, some of which remain difficult to classify within the current diagnostic framework. Clear cell papillary renal cell tumor (CCPRCT) is now recognised as an indolent entity, whereas RCC with fibromyomatous stroma (RCCFMS) remains a provisional subtype with partially overlapping morphological features. Methods: We analysed a multifocal RCC with clear cell morphology and prominent fibromyomatous stroma via whole-genome and RNA sequencing. The obtained molecular profile was compared with The Cancer Genome Atlas (TCGA) pan-cancer dataset, which includes 885 RCC cases, and histological re-evaluation of 10 identified similar cases was performed. Transcriptional data were mined for potential markers, which were validated in an independent cohort. Results: The 10 TCGA cases with similar transcriptomic features were characterised by diploid genomes, absence of recurrent chromosomal alterations, and lack of VHL mutations. Reduced VHL mRNA expression was observed, with increased methylation at selected CpG sites consistent with possible epigenetic down-regulation. Diagnostic variability was identified during histological re-evaluation of the 10 similar cases by three urological pathologists. Differential expression analysis highlighted cytokeratin 17 (CK17) and collagen 17A1 (COL17A1) as candidate markers. Immunohistochemical evaluation in a small (n = 6) independent CCPRCT cohort demonstrated expression of both markers, whereas tissue microarrays from 257 clear cell and 68 papillary RCC cases were found to be negative. Conclusions: These findings suggest that a subset of renal tumors with overlapping morphological features of CCPRCT and RCCFMS may share common molecular characteristics. CK17 and COL17A1 emerged as candidate markers for recognising these tumors, although their diagnostic sensitivity and specificity require validation across a broader spectrum of renal neoplasms. These observations are exploratory and hypothesis-generating, and further studies in large, well-characterised cohorts are required to clarify the biological and diagnostic significance of this subgroup.