Low-grade oncocytic renal tumor (LOT) is an emerging provisional entity, described as rare solid renal oncocytic/eosinophilic tumor sharing diffuse CK7 and negative CD117 immunoprofile. The links between LOT and other eosinophilic chromophobe like-renal cell carcinomas (RCC) are currently discussed. We sequenced tumoral DNA with a next generation sequencing panel for kidney cancer and carried out immunohistochemical analyses with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies in a series of ten cases of LOT (9 females, 1 male; mean age at surgery: 66 years, 42.3 to 83.4) retrospectively diagnosed from a cohort of 272 tumors initially classified as chromophobe RCC (CHRCC). All LOT were single, without known hereditary predisposition, classified stage pT1 (70%), pT2 (20%) or pT3a (10%). Morphological features were similar to previous descriptions and clinical behavior was indolent for the six cases with available follow-up. We identified genetic variations in mTOR pathway related genes in 80% of cases, MTOR (7 cases) or TSC1 (1 case). Expression of FOXI1 was absent in all cases. In 9 LOT, 4EBP1-P and S6K-P were overexpressed, suggesting mTOR pathway activation.
Our data highlights the major role of mTOR pathway in tumorigenesis of LOT mostly due to activating MTOR gene variations. Absence of FOXI1 expression is a strong argument to distinguish LOT from eosinophilic CHRCC and to bring them closer to other recently described FOXI1 negative eosinophilic-CHRCC like with MTOR/TSC mutations. Altogether, our data argue to consider LOT as a distinct entity with a favorable clinical outcome. However, in case of metastasis, an accurate diagnosis of LOT would be essential for the patient’s management and could allow targeted therapy.
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All data generated or analyzed during this study are included in this published article [and its supplementary information files].
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We wanted to thank Marine Largeau from the biological Resources Center and Tumor Bank Platform (BB-0033-00063) of Georges Pompidou European Hospital, Gisele Legall from the biological Resources Center and Tumor Bank Platform of Necker Enfants Malades Hospital, Sophie Hajosi and technicians from the Department of Pathology of Georges Pompidou European Hospital for technical assistance for TMA.
Immunohistochemistry of mTOR pathway and Tom Drossart was partly funded by Fondation ARC (PGA1 RF20190208466).
Ethics approval and consent to participate
Our study was approved by the French national ethics committee (Comité de Protection des Personnes Number 19.05.27.61541; national identification 2018-A03147-48).
The authors declare no competing interests.
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Morini, A., Drossart, T., Timsit, MO. et al. Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00906-7