L1CAM Expression and Molecular Alterations Distinguish Low Grade Oncocytic Tumor (LOT) from Eosinophilic Chromophobe Renal Cell Carcinoma

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the “other oncocytic tumors” category in the 2022 WHO Classification. While the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data is relatively limited. The morphologic overlap between LOT and other low grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n=67) and E-chRCC (n=69) and revealed notable differences between the two entities. Clinically, LOT predominantly affected females whereas E-chRCC showed a male predilection. Histologically, while almost all LOT dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the TSC-mTOR Complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1CAM, a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.