Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC): A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma

Skala, Stephanie L.; Dhanasekaran, Saravana M.; Mehra, Rohit

doi:10.5858/arpa.2018-0216-ra

Cited by 42 publications

(33 citation statements)

References 88 publications

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“…Several case reports describe associations of HLRCC with adrenal cortical hyperplasia, pheochromocytoma, and adrenal cortical carcinoma [46]. In the study conducted by Shuch et al, 20 of 255 patients with HLRCC had micronodular and/or macronodular adrenal hyperplasia, justifying the assumption that these may represent additional elements of HLRCC [47].…”

Section: Figure 5 -(A-d) Immunohistochemical Staining Showing Diffuse Positivity For Actin (A ×50) and Vimentin (B ×50) Positivity For CDmentioning

confidence: 99%

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Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

Popa

Lutuc

Mihai

et al. 2020

Rom J Morphol Embryol

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Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is an exceptionally rare autosomal dominant condition caused by a germline heterozygous mutation of the fumarate hydratase gene. It manifests as multiple piloleiomyomas, associated with numerous, early-onset uterine leiomyomas in female patients, as well as a highly increased risk of renal cell carcinoma (RCC), most often type 2 papillary RCC. HLRCC has been described in association with adrenal cortical hyperplasia, pheochromocytoma, adrenal cortical carcinoma, and other solid tumors, but the exact relationship between these disorders has not yet been clarified. We present a case of HLRCC associated with bilateral adrenal cortical hyperplasia and discuss the pathogenesis, clinical and paraclinical features of HLRCC, as well as the adequate management of these patients.

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Section: Figure 5 -(A-d) Immunohistochemical Staining Showing Diffuse Positivity For Actin (A ×50) and Vimentin (B ×50) Positivity For CDmentioning

confidence: 99%

“…Other solid tumors, such as breast cancer, bladder cancer, and testicular Leydig cell tumors have been described in association with HLRCC in isolated case reports [46].…”

Section: Figure 5 -(A-d) Immunohistochemical Staining Showing Diffuse Positivity For Actin (A ×50) and Vimentin (B ×50) Positivity For CDmentioning

confidence: 99%

Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

Popa

Lutuc

Mihai

et al. 2020

Rom J Morphol Embryol

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“…It is sometimes combined with renal cysts. Renal malignancies in this familial cancer syndrome are often type II papillary carcinomas [16]. Mutations of the fumarate hydratase (FH) tumor suppressor gene are responsible for HLRCC.…”

Section: Hereditary Leiomyomatosis and Rcc (Hlrcc)mentioning

confidence: 99%

Application Areas of Traditional Molecular Genetic Methods and NGS in relation to Hereditary Urological Cancer Diagnosis

Mikhaylenko

Танас

Zaletaev

et al. 2020

Journal of Oncology

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Next generation sequencing (NGS) is widely used for diagnosing hereditary cancer syndromes. Often, exome sequencing and extended gene panel approaches are the only means that can be used to detect a pathogenic germline mutation in the case of multiple primary tumors, early onset, a family history of cancer, or a lack of specific signs associated with a particular syndrome. Certain germline mutations of oncogenes and tumor suppressor genes that determine specific clinical phenotypes may occur in mutation hot spots. Diagnosis of such cases, which involve hereditary cancer, does not require NGS, but may be made using PCR and Sanger sequencing. Diagnostic criteria and professional community guidelines developed for hereditary cancers of particular organs should be followed when ordering molecular diagnostic tests for a patient. This review focuses on urological oncology associated with germline mutations. Clinical signs and genetic diagnostic laboratory tests for hereditary forms of renal cell cancer, prostate cancer, and bladder cancer are summarized. While exome sequencing, or, conversely, traditional molecular genetic methods are the procedure of choice in some cases, in most situations, sequencing of multigene panels that are specifically aimed at detecting germline mutations in early onset renal cancer, prostate cancer, and bladder cancer seems to be the basic solution for molecular genetic diagnosis of hereditary cancers.

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“…Unlike a low penetrance phenotype for RCCs, nearly all patients with FH‐deficient HLRCC syndrome present with early‐onset uterine leiomyomas that tend to be multiple, large and symptomatic, usually leading to myomectomy and even hysterectomy at less than 30 years of age . Importantly, characteristic morphological features common to FH‐deficient/mutated leiomyomas, including hypercellularity, eosinophilic hyaline globules, prominent nucleoli and perinucleolar halos, nuclear atypia, staghorn vasculature, fibrillary/neurophil‐like cytoplasm and alveolar oedema, have been reproducibly recognised . Given the high prevalence of leiomyoma specimens submitted for histopathological evaluation, evaluation for FH ‐ deficient/mutated leiomyomas by trained gynaecological pathologists and general surgical pathologists could identify patients with HLRCC at an earlier age and allow entry into surveillance prior to the development of aggressive, metastatic RCCs .…”

Section: Introductionmentioning

confidence: 99%

Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients

et al. 2020

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Aims Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH‐negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. Methods and results We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)‐based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH‐negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil‐like cytoplasm. We found that six (86%) of seven FH‐negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. Conclusion Our study showed a relatively high rate of FH germline mutation in FH‐negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.

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Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC): A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma

Cited by 42 publications

References 88 publications

Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

Application Areas of Traditional Molecular Genetic Methods and NGS in relation to Hereditary Urological Cancer Diagnosis

Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients

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