Renal Cancer in Hereditary Leiomyomatosis and Renal Cell Cancer: A Scoping Review of Epidemiology, Clinical Features, Management, and Outcomes

Purpose: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by germline pathogenic variants in the fumarate hydratase ( FH ) gene. Affected individuals face up to a 15% to 20% lifetime risk of developing aggressive renal cell carcinoma (RCC). Despite well-defined syndromic features—cutaneous and uterine leiomyomas (ULs)—diagnosis is often delayed, and optimal management strategies remain poorly defined. This review aims to synthesize current evidence on the epidemiology, clinical features, diagnostic pathways, treatment strategies, and outcomes of HLRCC-associated RCC and to identify knowledge gaps and inform clinical and research priorities. Materials and Methods: We conducted a scoping review in accordance with PRISMA-ScR and the Arksey and O'Malley framework. Six databases (MEDLINE, Embase, Scopus, Web of Science, CENTRAL, ClinicalTrials.gov) were searched from inception through July 30, 2024. Studies with original data on RCC in confirmed or suspected HLRCC were included. Data were extracted and synthesized from individual patient data (IPD) and observational cohorts and presented using descriptive statistics and narrative synthesis. Results: A total of 149 studies were included, comprising 382 IPD from case reports/series and 16 observational cohorts. RCC occurred at a mean age of 39.4 years and presented symptomatically in > 85% of cases. Despite frequent syndromic features (ULs: 80.9%, cutaneous leiomyomas: 47.5%), < 15% of patients underwent FH testing before cancer diagnosis. Tumors were large (mean 7.6 cm), often metastatic (stage IV in 52.3% of IPD), and showed high rates of FH loss (95.9%) and 2SC positivity (94%-100%). Nephrectomy was the most common treatment; systemic therapy was infrequently reported. Limited observation data suggest potential benefit of tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, and immune-targeted therapies. Early-stage disease was associated with improved survival (>80 months). Median survival in metastatic cases ranged from 15 to 35 months. Conclusions: HLRCC-associated RCC remains underdiagnosed and frequently presents at advanced stages. Earlier genetic testing, greater syndromic recognition, and multidisciplinary surveillance are needed to enable timely detection. Evidence for systemic therapy is limited, and prospective trials are urgently needed to define optimal management. Coordinated research efforts and biomarker-driven diagnostic strategies will be essential to improving outcomes for this aggressive hereditary kidney cancer subtype.