Clinicopathological and Molecular Comparative Analysis of Hereditary vs. Sporadic Fumarate Hydratase-deficient Leiomyomatosis and Renal Carcinoma

Introduction: FLRCC is a rare renal carcinoma subtype caused by FH mutations, categorized into hereditary (germline mutations) and sporadic (somatic mutations) forms. These forms are clinically and pathologically similar, complicating differentiation without genetic testing. The aim of this study is to investigate the clinicopathological and molecular genetic differences between hereditary and sporadic fumarate hydratase (FH)-deficient leiomyomatosis and renal cell carcinoma (FLRCC) to improve diagnostic accuracy and clinical management. Method: A retrospective analysis of 14 FLRCC patients was conducted(May 2020-August 2023). Immunohistochemistry (FH, 2SC, p16), HE staining, and next-generation sequencing (NGS) of tumor tissues and blood leukocytes were performed. Results: The 14 patients with FH-deficient leiomyoma were 25-54 years old, with a mean age of 36.21 ± 8.16. 78.5% (11/14) had clinical symptoms and multiple, large-sized fibroids (median maximum volume was 75 mm). Patients with leiomyoma and FH deficiency were divided into hereditary and sporadic FLRCC based on FH gene sequencing. Patients with HLRCC had an earlier onset, and the serum tumor marker CA125 was more significant. Moreover, tumor tissues from patients with hereditary and sporadic FH-deficient LRCC differed in immunohistochemical and HE staining characteristics, including more positive p16 and greater susceptibility to invasion and metastasis in patients with HLRCC, as well as malignant proliferation in patients with sporadic FH-deficient LRCC. Discussion: Although limited by sample size, our preliminary findings indicated subtle differences in the age of onset, as well as immunohistochemical and histopathological features of hereditary and sporadic FH-deficient LRCC, facilitating the understanding and clinical diagnosis of FLRCC. Conclusion: In clinical diagnosis, all information should be fully integrated, and a comprehensive judgment should be made to make a correct pathological diagnosis and provide targeted treatment for patients with an FH gene mutation.