Tubulocystic renal cell carcinoma with aggressive behavior-insights from molecular profiling and single-cell analysis: A case report

Abstract

BACKGROUND

Tubulocystic renal cell carcinoma (TRCC) is a rare subtype of renal cell carcinoma that is generally regarded as an indolent malignancy with a favorable prognosis.

CASE SUMMARY

We report an exceptional case of aggressive TRCC characterized by rapid postoperative recurrence, distant metastasis, and resistance to multiple therapeutic modalities. Next-generation sequencing (NGS) was performed to identify genomic alterations in the patient, while single-cell RNA sequencing (scRNA-seq) was used to delineate the phenotypic heterogeneity of tumor cells and characterize the tumor microenvironment. Targeted NGS identified a germline missense fumarate hydratase mutation and somatic mutations in AFF3, MDM2, and LRP1B. scRNA-seq revealed marked activation of angiogenesis-related pathways in recurrent TRCC cells, along with a tumor microenvironment characterized by a high proportion of naïve T cells and SPP1⁺ tumor-associated macrophages. These findings suggest that enhanced angiogenic signaling in tumor cells, together with an immunosuppressive macrophage-rich microenvironment, may contribute to the aggressive behavior of the tumor and its resistance to therapy.

CONCLUSION

This study provides a comprehensive characterization of the molecular landscape and tumor microenvironment of aggressive TRCC, offering insights into its biological behavior and identifying potential therapeutic targets for future clinical intervention.

Keywords: Metastatic tubulocystic renal cell carcinoma; Tumor microenvironment; Genetic profiling; Single-cell RNA sequencing; Case report

Core Tip: Tubulocystic renal cell carcinoma (TRCC) is generally considered an indolent malignancy. However, we report an exceptional aggressive case characterized by rapid recurrence and metastasis. Using next-generation sequencing and single-cell RNA sequencing, we identified a germline missense mutation in fumarate hydratase and somatic alterations in AFF3, MDM2, and LRP1B. The recurrent tumor exhibited enhanced angiogenic activity and an immunosuppressive microenvironment enriched in naïve T cells and SPP1⁺ tumor-associated macrophages. These findings provide insights into the molecular mechanisms underlying aggressive TRCC and highlight potential therapeutic targets for future clinical management.