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Seminars in Cancer Biology Apr 2020Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline... (Review)
Review
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.
Topics: Biomarkers, Tumor; Disease Management; Disease Susceptibility; Fumarate Hydratase; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Genetic Testing; Genomics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leiomyomatosis; Mutation; Neoplastic Syndromes, Hereditary; Proteome; Signal Transduction; Skin Neoplasms; Translational Research, Biomedical; Uterine Neoplasms
PubMed: 31689495
DOI: 10.1016/j.semcancer.2019.10.016 -
Indian Journal of Dermatology 2018Multiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reed's syndrome, is a rare genodermatosis, with an autosomal dominant pattern of inheritance. It...
Multiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reed's syndrome, is a rare genodermatosis, with an autosomal dominant pattern of inheritance. It results from a germline heterozygous mutation of fumarate hydratase gene, that is classified as a tumor suppressor gene. Hereditary leiomyomatosis and renal cell cancer is characterized by the association of MCUL with renal cell carcinoma. We report a case of a 57-year-old woman, with multiple cutaneous leiomyomas as the presenting sign of Reed's syndrome.
PubMed: 29937565
DOI: 10.4103/ijd.IJD_69_18 -
Methods in Enzymology 2019Dysregulated cellular metabolism is an emerging hallmark of cancer. Improved methods to profile aberrant metabolic activity thus have substantial applications as tools...
Dysregulated cellular metabolism is an emerging hallmark of cancer. Improved methods to profile aberrant metabolic activity thus have substantial applications as tools for diagnosis and understanding the biology of malignant tumors. Here we describe the utilization of a bioorthogonal ligation to fluorescently detect the TCA cycle oncometabolite fumarate. This method enables the facile measurement of fumarate hydratase activity in cell and tissue samples, and can be used to detect disruptions in metabolism that underlie the genetic cancer syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC). The current method has substantial utility for sensitive fumarate hydratase activity profiling, and also provides a foundation for future applications in diagnostic detection and imaging of cancer metabolism.
Topics: Citric Acid Cycle; Click Chemistry; Cycloaddition Reaction; Enzyme Assays; Female; Fluorescent Dyes; Fluorometry; Fumarate Hydratase; Fumarates; Humans; Leiomyomatosis; Neoplastic Syndromes, Hereditary; Skin Neoplasms; Uterine Neoplasms
PubMed: 31155064
DOI: 10.1016/bs.mie.2019.02.037 -
The Cochrane Database of Systematic... Jan 2020Fibroids are the most common benign tumours of the female genital tract and are associated with numerous clinical problems including a possible negative impact on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Fibroids are the most common benign tumours of the female genital tract and are associated with numerous clinical problems including a possible negative impact on fertility. In women requesting preservation of fertility, fibroids can be surgically removed (myomectomy) by laparotomy, laparoscopically or hysteroscopically depending on the size, site and type of fibroid. Myomectomy is however a procedure that is not without risk and can result in serious complications. It is therefore essential to determine whether such a procedure can result in an improvement in fertility and, if so, to then determine the ideal surgical approach.
OBJECTIVES
To examine the effect of myomectomy on fertility outcomes and to compare different surgical approaches.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Epistemonikos database, World Health Organization (WHO) International Clinical Trials Registry Platform search portal, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and reference list of relevant papers. The final search was in February 2019.
SELECTION CRITERIA
Randomised controlled trials (RCTs) examining the effect of myomectomy compared to no intervention or where different surgical approaches are compared regarding the effect on fertility outcomes in a group of infertile women suffering from uterine fibroids.
DATA COLLECTION AND ANALYSIS
Data collection and analysis were conducted in accordance with the procedure suggested in the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS
This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I = 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I = 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate.
AUTHORS' CONCLUSIONS
There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.
Topics: Abortion, Spontaneous; Cesarean Section; Female; Humans; Infertility, Female; Leiomyomatosis; Live Birth; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic; Uterine Myomectomy; Uterine Neoplasms
PubMed: 31995657
DOI: 10.1002/14651858.CD003857.pub4 -
Acta Dermato-venereologica Jan 2020Hereditary leiomyomatosis and renal cell cancer is a genodermatosis with an autosomal dominant inheritance pattern. It is a tumour predisposition syndrome characterized...
Hereditary leiomyomatosis and renal cell cancer is a genodermatosis with an autosomal dominant inheritance pattern. It is a tumour predisposition syndrome characterized by cutaneous and uterine leiomyomas, and increased susceptibility to develop renal cell carcinoma. There are 200-300 families with hereditary leiomyomatosis and renal cell carcinoma reported worldwide, but the syndrome is believed to be underdiagnosed. Cutaneous leiomyomas are small smooth muscle tumours that tend to grow over time. Larger lesions, in particular, can cause pain or itching. Uterine leiomyomas have a high penetrance in women with hereditary leiomyomatosis and renal cell cancer. They frequently cause symptoms, and surgical intervention is often necessary. Hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas have a high potential to metastasize. Patients are diagnosed by genetic testing if a pathogenic mutation is demonstrated in the gene encoding fumarate hydratase. Immunohistochemistry may be a useful diagnostic approach in patients without a detectable pathogenic mutation. Diagnosed patients should be monitored for renal tumours in a lifelong surveillance programme.
Topics: Adult; Female; Genetic Predisposition to Disease; Humans; Leiomyomatosis; Male; Neoplastic Syndromes, Hereditary; Skin Neoplasms; Syndrome; Uterine Neoplasms; Young Adult
PubMed: 31663596
DOI: 10.2340/00015555-3366 -
Advances in Chronic Kidney Disease Jan 2014Inherited susceptibility to kidney cancer is a fascinating and complex topic. Our knowledge about types of genetic syndromes associated with an increased risk of disease... (Review)
Review
Inherited susceptibility to kidney cancer is a fascinating and complex topic. Our knowledge about types of genetic syndromes associated with an increased risk of disease is continually expanding. Currently, there are 10 syndromes associated with an increased risk of all types of kidney cancer, which are reviewed herein. Clear cell kidney cancer is associated with von Hippel Lindau disease, chromosome 3 translocations, PTEN hamartomatous syndrome, and mutations in the BAP1 gene as well as several of the genes encoding the proteins comprising the succinate dehydrogenase complex (SDHB/C/D). Type 1 papillary kidney cancers arise in conjunction with germline mutations in MET and type 2 as part of hereditary leiomyomatosis and kidney cell cancer (fumarate hydratase [FH] mutations). Chromophone and oncocytic kidney cancers are predominantly associated with Birt-Hogg-Dubé syndrome. Patients with Tuberous Sclerosis Complex (TSC) commonly have angiomyolipomas and rarely their malignant counterpart epithelioid angiomyolipomas. The targeted therapeutic options for the kidney cancer associated with these diseases are just starting to expand and are an area of active clinical research.
Topics: Birt-Hogg-Dube Syndrome; Carcinoma, Renal Cell; Chromosomes, Human, Pair 3; Genetic Predisposition to Disease; Hamartoma Syndrome, Multiple; Humans; Kidney Neoplasms; Leiomyomatosis; Neoplastic Syndromes, Hereditary; Proto-Oncogene Proteins c-met; Skin Neoplasms; Succinate Dehydrogenase; Translocation, Genetic; Tuberous Sclerosis; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Uterine Neoplasms; von Hippel-Lindau Disease
PubMed: 24359990
DOI: 10.1053/j.ackd.2013.10.001 -
Archives of Pathology & Laboratory... Nov 2014Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of... (Review)
Review
CONTEXT
Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of the correct nature of the tumor, especially in biopsy specimens, is paramount for patient management.
OBJECTIVE
To review the diagnostic approach to eosinophilic renal neoplasms with light microscopy and ancillary techniques.
DATA SOURCES
Review of the published literature and personal experience.
CONCLUSIONS
The following tumors are in the differential diagnosis of oncocytic renal cell neoplasm: oncocytoma, chromophobe renal cell carcinoma (RCC), hybrid tumor, tubulocystic carcinoma, papillary RCC, clear cell RCC with predominant eosinophilic cell morphology, follicular thyroid-like RCC, hereditary leiomyomatosis-associated RCC, acquired cystic disease-associated RCC, rhabdoid RCC, microphthalmia transcription factor translocation RCC, epithelioid angiomyolipoma, and unclassified RCC. In low-grade nonpapillary eosinophilic neoplasms, distinction between oncocytoma and low-grade RCC mostly rests on histomorphology; however, cytokeratin 7 immunostain may be helpful. In high-grade nonpapillary lesions, there is more of a role for ancillary techniques, including immunohistochemistry for cytokeratin 7, CA9, CD10, racemase, HMB45, and Melan-A. In papillary eosinophilic neoplasms, it is important to distinguish sporadic type 2 papillary RCC from microphthalmia transcription factor translocation and hereditary leiomyomatosis-associated RCC. Histologic and cytologic features along with immunohistochemistry and fluorescence in situ hybridization tests for TFE3 (Xp11.2) and TFEB [t(6;11)] are reliable confirmatory tests. Eosinophilic epithelial neoplasms with architecture, cytology, and/or immunoprofile not qualifying for either of the established types of RCC should be classified as unclassified eosinophilic RCC and arbitrarily assigned a grade (low or high).
Topics: Adenoma, Oxyphilic; Angiomyolipoma; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carcinoma, Renal Cell; Chromosomes, Human, X; Eosinophilia; Female; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Leiomyomatosis; Male; Microphthalmia-Associated Transcription Factor; Neoplastic Syndromes, Hereditary; Skin Neoplasms; Translocation, Genetic; Uterine Neoplasms
PubMed: 25357116
DOI: 10.5858/arpa.2013-0653-RA -
Orphanet Journal of Rare Diseases Jan 2021Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genodermatosis characterized by cutaneous leiomyoma (CLM), uterine leiomyoma (ULM) and renal cell... (Review)
Review
BACKGROUND
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genodermatosis characterized by cutaneous leiomyoma (CLM), uterine leiomyoma (ULM) and renal cell carcinoma (RCC). Five HLRCC patients are presented with a compiled database of published HLRCC cases to increase understanding of HLRCC. Furthermore, a surveillance program is suggested. Our review is based on a PubMed search which retrieved case reports and cohort studies published before November 2019. The search yielded 97 original papers with a total of 672 HLRCC patients.
RESULTS
CLMs were present in 474 patients (71.5%), developed at the mean age of 28 years. Five patients had cutaneous leiomyosarcomas. ULMs were present in 356 women (83%), while two had uterine leiomyosarcoma. ULMs were diagnosed at a mean age of 32 years, with the youngest diagnosed at age 17 years. The most common surgical treatment for ULMs was hysterectomy, performed at a mean age of 35 years, with the youngest patient being 19 years old. RCCs were present in 189 patients (34.9%), of which half had metastatic disease. The mean age of diagnosis was 36 years with the youngest patient diagnosed with RCC at the age of 11 years.
CONCLUSION
We suggest a surveillance program for HLRCC including a dermatological examination once every 2 years, annual magnetic resonance imaging starting at the age of 10 years to monitor for early RCCs, annual gynecological examinations from the age of 15 years and counseling regarding risk of hysterectomy and family planning at the age of 18 years. CLMs are often the earliest manifestation of HLRCC, which is why recognizing these lesions, performing a biopsy, and making a prompt referral to genetic counseling is important in order to diagnose HLRCC early.
Topics: Adolescent; Adult; Carcinoma, Renal Cell; Child; Female; Fumarate Hydratase; Humans; Kidney Neoplasms; Leiomyomatosis; Neoplastic Syndromes, Hereditary; Skin Neoplasms; Young Adult
PubMed: 33461594
DOI: 10.1186/s13023-020-01653-9 -
Frontiers in Oncology 2021Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant hereditary cancer syndrome characterized by a predisposition to cutaneous... (Review)
Review
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant hereditary cancer syndrome characterized by a predisposition to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). It is known to be caused by germline mutations of the fumarate hydratase (FH) gene, which encodes an enzyme component of the citric acid cycle and catalyzes the conversion of fumarate to L-malate. Currently, there is no standardized treatment for HLRCC, which may be due in part to a lack of understanding of the underlying mechanisms. Here, the underlying molecular mechanisms by which the inactivation of FH causes HLRCC are discussed. Additionally, potential therapeutic pharmacological strategies are also summarized to provide new perspectives for the prevention and treatment of HLRCC.
PubMed: 34113573
DOI: 10.3389/fonc.2021.686556 -
Clinical Medicine (London, England) Dec 2017This article provides an overview of selected genetic skin conditions where multiple inherited cutaneous tumours are a central feature. Skin tumours that arise from skin... (Review)
Review
This article provides an overview of selected genetic skin conditions where multiple inherited cutaneous tumours are a central feature. Skin tumours that arise from skin structures such as hair, sweat glands and sebaceous glands are called skin appendage tumours. These tumours are uncommon, but can have important implications for patient care. Certain appendageal tumours, particularly when multiple lesions are seen, may indicate an underlying genetic condition. These tumours may not display clinical features that allow a secure diagnosis to be made, necessitating biopsy and dermatopathological assessment. Coupled with robust clinical assessment, biopsy findings can guide genetic testing as, increasingly, the causative genes are known for these conditions. Here we review illustrative examples of appendageal tumours and relevant advances made in genetic discovery, and suggest when referral to a geneticist may need to be considered.
Topics: Birt-Hogg-Dube Syndrome; DNA Mismatch Repair; Fibroma; Fumarate Hydratase; Hamartoma Syndrome, Multiple; Humans; Leiomyomatosis; Muir-Torre Syndrome; Neoplastic Syndromes, Hereditary; PTEN Phosphohydrolase; Proto-Oncogene Proteins; Skin Neoplasms; Tumor Suppressor Proteins; Uterine Neoplasms
PubMed: 29196359
DOI: 10.7861/clinmedicine.17-6-562