Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors

Simple Summary Our understanding of renal tumors has increased in the last years with the description of several novel entities. The expanding morphological spectrum complicates the pathologist’s diagnosis, often requiring immunohistochemical analysis. The role of cathepsin K immunoexpression is widened as a diagnostic tool in several renal tumors. This review describes the usefulness of cathepsin K in the differential diagnosis of renal neoplasms, highlighting the biological knowledge underpinning its expression. Moreover, cathepsin K seems to be a downstream marker of different genetic alterations, with a possible role as a predictive marker that may prospectively guide the development of therapeutic approaches as a molecular target. Abstract Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.