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Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1

Abstract

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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Fig. 1: Main microscopical features of LOT.
Fig. 2: Main features of stroma of LOT.
Fig. 3: Immunohistochemical profile of LOT with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

References

  1. 1.

    Trpkov, K. et al. Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity? Histopathology 75, 174–184 (2019).

    PubMed  Article  Google Scholar 

  2. 2.

    Trpkov, K. et al. Novel, emerging and provisional renal entities: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod. Pathol. 34, 1167–1184 (2021).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Akgul, M., Al-Obaidy, K. I., Cheng, L., & Idrees, M. T. Low-grade oncocytic tumour expands the spectrum of renal oncocytic tumours and deserves separate classification: a review of 23 cases from a single tertiary institute. J. Clin. Pathol. https://doi.org/10.1136/jclinpath-2021-207478 (2021).

  4. 4.

    Kravtsov, O. et al. Low-grade oncocytic tumor of kidney (CK7-positive, CD117-negative): incidence in a single institutional experience with clinicopathological and molecular characteristics. Hum. Pathol. 114, 9–18 (2021).

    PubMed  Article  Google Scholar 

  5. 5.

    Lerma, L. A., Schade, G. R., & Tretiakova, M. S. Co-existence of ESC-RCC, EVT, and LOT as synchronous and metachronous tumors in six patients with multifocal neoplasia, but without clinical features of tuberous sclerosis complex. Hum. Pathol. 116, 1–11 (2021).

  6. 6.

    Guo, Q. et al. Characterization of a distinct low-grade oncocytic renal tumor (CD117-negative and cytokeratin 7-positive) based on a tertiary oncology center experience: the new evidence from China. Virchows Arch 478, 449–458 (2021).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Kryvenko, O. N., Jorda, M., Argani, P. & Epstein, J. I. Diagnostic approach to eosinophilic renal neoplasms. Arch Pathol. Lab. Med. 138, 1531–1541 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Williamson, S. R. et al. Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists. Hum. Pathol. 63, 149–156 (2017).

    PubMed  Article  Google Scholar 

  9. 9.

    Wobker, S. E. & Williamson, S. R. Modern pathologic diagnosis of renal oncocytoma. J. Kidney Cancer VHL 4, 1–12 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Zhou, J., Yang, X., Zhou, L., Zhang, P. & Wang, C. Combined immunohistochemistry for the « Three 7 » Markers (CK7, CD117, and Claudin-7) is useful in the diagnosis of chromophobe renal cell carcinoma and for the exclusion of mimics: diagnostic experience from a single institution. Dis. Markers 2019, 4708154 (2019).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Zhao, W. et al. DOG1, cyclin D1, CK7, CD117 and vimentin are useful immunohistochemical markers in distinguishing chromophobe renal cell carcinoma from clear cell renal cell carcinoma and renal oncocytoma. Pathol. Res. Pract. 211, 303–307 (2015).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Ng, K. L. et al. A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma. J. Clin. Pathol. 69, 661–671 (2016).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Huo, L. et al. C-kit expression in renal oncocytomas and chromophobe renal cell carcinomas. Hum. Pathol. 36, 262–268 (2005).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Din, N. U., Fatima, S. & Ahmad, Z. Chromophobe renal cell carcinoma: a morphologic and immunohistochemical study of 45 cases. Ann. Diagn. Pathol. 17, 508–513 (2013).

    PubMed  Article  Google Scholar 

  15. 15.

    Yamazaki, K. et al. Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 22, 847–852 (2003).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Zimpfer, A. et al. C-kit overexpression is not associated with KIT gene mutations in chromophobe renal cell carcinoma or renal oncocytoma. Pathol. Res. Pract. 210, 521–525 (2014).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Lindgren, D. et al. Cell-type-specific gene programs of the normal human nephron define kidney cancer subtypes. Cell Rep. 20, 1476–1489 (2017).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Skala, S. L. et al. Next-generation RNA sequencing–based biomarker characterization of chromophobe renal cell carcinoma and related oncocytic neoplasms. Eur. Urol. 78, 63–74 (2020).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Tong, K. & Hu, Z. FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: a study of The Cancer Genome Atlas transcriptome–based outlier mining and immunohistochemistry. Virchows Arch 478, 647–658 (2020).

    PubMed  Article  Google Scholar 

  20. 20.

    Trpkov, K. et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod. Pathol. 34, 1392–1424 (2021).

    PubMed  Article  Google Scholar 

  21. 21.

    Ohashi, R. et al. Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype. Cancers 11, 1492–1506 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  22. 22.

    Thoenes, W. et al. Chromophobe cell renal carcinoma and its variants—a report on 32 cases. J. Pathol. 155, 277–287 (1988).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Amin, M. B. et al. Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am. J. Surg. Pathol. 32, 1822–1834 (2008).

    PubMed  Article  Google Scholar 

  24. 24.

    Davis, C. F. et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319–330 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Alaghehbandan, R. et al. Comprehensive review of numerical chromosomal aberrations in chromophobe renal cell carcinoma including its variant morphologies. Adv. Anat. Pathol. 28, 8–20 (2021).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Morini, A. et al. Immunohistochemical evaluation of the mTOR pathway of genetically characterized chromophobe renal cell carcinomas: a pilot study of 20 cases. abstracts from uscap 2020: genitourinary pathology (860-1046). Mod. Pathol. 33, 1002–1063 (2020).

    Article  Google Scholar 

  27. 27.

    Siadat, F. & Trpkov, K. ESC, ALK, HOT and LOT: three letter acronyms of emerging renal entities knocking on the door of the WHO classification. Cancers 12, 168–184 (2020).

    PubMed Central  Article  Google Scholar 

  28. 28.

    de Andrade Melo, C. G. R., Xavier, M. V. N., Pimenta, I. S. & Athanazio, D. A. Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive). Surg. Exp. Pathol. 3, 22 (2020).

    Article  Google Scholar 

  29. 29.

    Palsgrove, D. et al. Eosinophilic Solid and Cystic (ESC) renal cell carcinomas harbor TSC mutations: molecular analysis supports an expanding clinicopathologic spectrum. Am. J. Surg. Pathol. 42, 1166–1181 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Ricketts, C. J. et al. The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23, 313–326 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Roldan-Romero, J. M. et al. Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome. Mod. Pathol. 33, 2580–2590 (2020).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Chen, Y.-B. et al. Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm. Am. J. Surg. Pathol. 43, 121–131 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Mehra, R. et al. Somatic Bi-allelic loss of TSC genes in eosinophilic solid and cystic renal cell carcinoma. Eur. Urol. 74, 483–486 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Guo, J. et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am. J. Surg. Pathol. 38, 1457–1467 (2014).

    PubMed  Article  Google Scholar 

  36. 36.

    Yang, P. et al. Renal cell carcinoma in tuberous sclerosis complex. Am. J. Surg. Pathol. 38, 895–909 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Gupta, S. et al. Renal neoplasia in tuberous sclerosis: a study of 41 patients. Mayo Clin. Proc. 96, 1470–1489 (2021).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    TCGA-KICH: https://portal.gdc.cancer.gov/projects/TCGA-KICH

  39. 39.

    Tjota, M. et al. Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study. Am. J. Surg. Pathol. 44, 943–954 (2020).

    PubMed  Article  Google Scholar 

  40. 40.

    Tjota, M. Y., Wanjari, P., Segal, J. & Antic, T. TSC/MTOR mutated eosinophilic renal tumors are a distinct entity that are CK7+/CK20-/vimentin-: a validation study. Hum. Pathol. 115, 84–95 (2020).

    PubMed  Article  Google Scholar 

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Acknowledgements

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.

Funding information

Immunohistochemistry of mTOR pathway and Tom Drossart was partly funded by Fondation ARC (PGA1 RF20190208466).

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Contributions

V.V.E. performed study concept and design. A.P.G.R., A.M.E., A.M.O., and M.O.T. provided acquisition of clinical data. A.M.O., J.F., M.S., V.V.A., and V.V.E. provided acquisition of pathological and immunohistochemical data. A.P.G.R., N.B., and T.D. provided acquisition of genetic analysis. C.B. and J.F. provided technical and material support. A.M.O., N.B., and V.V.E. performed development of methodology, writing, review, and revision of the paper. A.M.O., N.B., T.D., and V.V.E. provided analysis, interpretation of data, and statistical analysis. All authors read and approved the final paper.

Corresponding author

Correspondence to Virginie Verkarre.

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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).

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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

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