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The impact of the new WHO classification of renal cell carcinoma on the diagnosis of hereditary leiomyomatosis and renal cell carcinoma

Degenhardt J, Tolkach Y, Amin MB, Mosiello G, Ertoy Baydar D, Cornec-Le Gall E, Dicola J, Elhag D, Frezza C, Halbritter J, Blanco I, Jewett MA, Lattouf JB, Lovitt G, Lundgren PO, Maher ER, Mulders P, Shuch B, Hartmann A, Muller RU (2025)

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Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 40

Pages Range: 1428-1432

Journal Issue: 7

DOI: 10.1093/ndt/gfaf032

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications, the vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and the potential for early metastatic spread. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland and Leydig cell tumours. The aggressive behaviour of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining predisposition for de novo primary renal tumours in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. Vascular endothelial growth factor/epidermal growth factor receptor-directed treatment regimes, such as erlotinib/bevacizumab, demonstrate efficacy against HLRCC-associated RCC. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 World Health Organization classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to discuss this impact and raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.

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How to cite

APA:

Degenhardt, J., Tolkach, Y., Amin, M.B., Mosiello, G., Ertoy Baydar, D., Cornec-Le Gall, E.,... Muller, R.U. (2025). The impact of the new WHO classification of renal cell carcinoma on the diagnosis of hereditary leiomyomatosis and renal cell carcinoma. Nephrology Dialysis Transplantation, 40(7), 1428-1432. https://doi.org/10.1093/ndt/gfaf032

MLA:

Degenhardt, Jan, et al. "The impact of the new WHO classification of renal cell carcinoma on the diagnosis of hereditary leiomyomatosis and renal cell carcinoma." Nephrology Dialysis Transplantation 40.7 (2025): 1428-1432.

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