Hereditary leiomyomatosis and renal cell carcinoma

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal-dominant hereditary syndrome, which is caused by germline mutations in the FH gene that encodes the tricarboxylic acid cycle enzyme fumarate hydratase (FH). HLRCC patients are predisposed to develop cutaneous leiomyomas, multiple, symptomatic uterine fibroids in young women resulting in early hysterectomies, and early onset renal tumors with a type 2 papillary morphology that can progress and metastasize, even when small. Since HLRCC-associated renal tumors can be more aggressive than renal tumors in other hereditary renal cancer syndromes, caution is warranted, and surgical intervention is recommended rather than active surveillance. At-risk members of an HLRCC family who test positive for the familial germline FH mutation should undergo surveillance by annual magnetic resonance imaging from the age of 8 years. Biochemical studies have shown that FH-deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis. It is hoped that through ongoing clinical trials evaluating targeted molecular therapies, an effective form of treatment for HLRCC-associated kidney cancer will be developed that will offer an improved prognosis for individuals affected with HLRCC-associated kidney cancer.

Keywords: FH mutation; HLRCC; hereditary leiomyomatosis and renal cell carcinoma; type 2 papillary RCC.

Figure 1

(A–E) Clinical manifestations of hereditary leiomyomatosis and renal cell carcinoma (HLRCC): leiomyomas. Notes: (A) Multiple cutaneous leiomyomas on the torso of an HLRCC patient. (B) Histomicrograph of cutaneous leiomyoma, showing interlaced bundles of smooth-muscle fibers with a centrally located long, blunt-edged nucleus. (hematoxylin and eosin, [H&E] 10×). (C) Computed tomography image showing multiple large uterine leiomyomas (white arrows) that occur in most women with HLRCC, and that can be symptomatic. (D and E) High-power image of a uterine leiomyoma showing large prominent nuclei with an orangiophilic nucleolus (white arrows) surrounded by perinuclear halo; H&E, 300× and 400×. Images from Grubb et al (A and C), Rothman et al (B), and Sanz-Ortega et al (D and E).

Figure 2

(A–E) Clinical manifestations of hereditary leiomyomatosis and renal cell carcinoma (HLRCC): renal tumors. Notes: Computed tomography images showing (A) para-aortic nodal disease (white arrow) and (B) left renal tumor (white arrow) in HLRCC patients. RCC in HLRCC patients may present with (C) papillary morphology suggestive of type 2 papillary RCC (10×), but (D) tubular and cystic patterns may also be seen (10×). (E) Under high power, the characteristic orangiophilic or eosinophilic nucleoli with perinuclear halo are seen (40×). Images from Grubb et al. Abbreviation: RCC, renal cell carcinoma.

Figure 3

Potential biochemical pathways deregulated as a consequence of FH inactivation. Notes: FH-deficient kidney cancer has impaired oxidative phosphorylation, and undergoes a metabolic shift to aerobic glycolysis to generate adenosine triphosphate for cellular energy demands. Fumarate, which accumulates in FH-deficient cells, can competitively inhibit prolyl hydroxylase (PHD), resulting in HIF-1α stabilization and increased expression of the HIF-1α target genes VEGF and GLUT1. Elevated fumarate also succinates KEAP1, altering its conformation and inhibiting its ability to degrade nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 transcriptional activity is upregulated, leading to activation of the antioxidant-response pathway and protection against oxidative stress. Adapted from Linehan and Rouault. Abbreviations: LDHA, lactate dehydrogenase A; CoA, coenzyme A; αKG, α-ketoglutarate; FH, fumarate hydratase; GLUT1, glucose transporter 1; KEAP1, kelch-like ECH-associated protein 1; CUL3, cullin 3; HIF-1α, hypoxia-inducible factor 1 alpha; VEGF, vascular endothelial growth factor; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1.