Hereditary Leiomyomatosis and Renal Cell Cancer: A Syndrome Associated With an Aggressive Form of Inherited Renal Cancer

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Urology (Impact Factor: 4.47). 07/2007; 177(6):2074-9; discussion 2079-80. DOI: 10.1016/j.juro.2007.01.155
Source: PubMed


Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors.
A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%).
Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases.
Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary.

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    • "(E) Under high power, the characteristic orangiophilic or eosinophilic nucleoli with perinuclear halo are seen (40×). Images from Grubb et al.32 "
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    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.
    International Journal of Nephrology and Renovascular Disease 06/2014; 7:253-60. DOI:10.2147/IJNRD.S42097
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    • "Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant hereditary cancer syndrome characterized by a predisposition to develop cutaneous and uterine leiomyomas and a very aggressive form of papillary kidney cancer [1–7]. HLRCC-associated renal tumors demonstrate a distinctive architectural and morphology and have a propensity to metastasize early [8]. The predisposition of HLRCC-associated kidney cancer to readily metastasize to both regional and distant lymph nodes is distinctly different and significantly more aggressive than other types of genetically defined kidney cancer. "
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    ABSTRACT: Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP) that either generate NADPH (oxidative) or do not (non-oxidative), we utilized [U-(13)C]-glucose, [U-(13)C,(15)N]-glutamine, and [1,2- (13)C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived α-ketoglutarate through to fumarate. [1,2- (13)C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66%) that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of α-ketoglutarate and fatty acid synthesis for rapid proliferation and is essential for defense against increased oxidative stress. This increased NADPH producing PPP activity was shown to be a strong consistent feature in both fumarate hydratase deficient tumors and cell line models.
    PLoS ONE 08/2013; 8(8):e72179. DOI:10.1371/journal.pone.0072179 · 3.23 Impact Factor
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    • "Hereditary leiomyomatosis renal cell carcinoma: Type II papillary kidney cancer Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an autosomal dominant, hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and kidney cancer (Fig. 5; Zbar et al. 1995; Launonen et al. 2001). HLRCC-associated kidney cancer is a very aggressive form of kidney cancer in which very small tumors have the potential to metastasize (Grubb et al. 2007; Merino et al. 2007). "
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    ABSTRACT: Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease.
    Genome Research 10/2012; 22(11). DOI:10.1101/gr.131110.111 · 14.63 Impact Factor
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