Integrated morphological, immunohistochemical, and genomic profiling identifies uterine leiomyoma patients with hereditary leiomyomatosis and renal cell cancer syndrome: a comprehensive analysis of 252 cases

Abstract

Fumarate hydratase‐deficient uterine leiomyomas (FHd‐ULMs) represent a molecularly distinct subgroup of smooth muscle tumours associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. This study determined the detection rate of germline pathogenic FH variants in FHd‐ULMs using paired tumour‐normal sequencing and assessed the utility of integrated morphological, immunohistochemical (FH/2SC), genomic, and clinical features for selecting cases suspected of HLRCC. Histopathological assessment of the 252 FHd‐ULMs revealed consistent morphological features, whereas molecular profiling identified three biologically distinct categories. Germline FH ‐mutated (hereditary) cases constituted 35.7% (74/207) of this FHd‐ULM cohort, four of which showed concomitant somatic copy‐number alterations. This contrasted with the somatic‐mutated subgroup, which comprised 50.7% (105/207), including 18.4% (38/207) with isolated somatic copy‐number losses. The remaining 13.6% (28/207), though lacking detectable FH mutations, were classified with somatic‐mutated cases as sporadic FHd‐ULMs based on shared clinicopathological features. Molecular analysis identified shared variant distributions across exons 2–10, with exons 5 and 7 in the fumarate lyase domain emerging as the predominant mutational hotspots. Notably, truncating mutations showed significantly higher prevalence in hereditary cases versus somatic variants ( p  < 0.01). Clinically, hereditary FHd‐ULMs presented at younger ages (< 45 years) and manifested more aggressive phenotypes, including elevated rates of infertility (54.1% versus 26.4%), multifocal tumour development (86.5% versus 53.4%), increased surgical interventions (44.6% versus 11.5%), and familial leiomyoma clustering (51.4% versus 24.2%). Our results identify germline FH mutations, which confer significant HLRCC risk, in 35.7% of FHd‐ULMs, while somatic alterations account for the majority of cases. To ensure efficient resource allocation, we propose a stratified diagnostic approach: initial universal FH/2SC immunohistochemical screening for ULMs displaying ≥ 3 FH‐deficient morphological features, followed by confirmatory genetic testing in high‐risk individuals, defined by either aberrant FH/2SC immunoreactivity or, in immunohistochemically normal cases, age < 45 years together with a personal/family history of multiple symptomatic leiomyomas or HLRCC‐associated neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.