RESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.
Assuntos
Fumarato Hidratase , Leiomiomatose , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias , Neoplasias Cutâneas , Neoplasias Uterinas , Humanos , Fumarato Hidratase/genética , Leiomiomatose/genética , Leiomiomatose/patologia , Feminino , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Linhagem , Mutação em Linhagem Germinativa , Masculino , Adulto , Predisposição Genética para Doença , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Fumarato Hidratase/genética , Leiomioma/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Análise Mutacional de DNA , Feminino , Fumarato Hidratase/metabolismo , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Leiomioma/enzimologia , Leiomioma/patologia , Leiomiomatose/enzimologia , Leiomiomatose/patologia , Mutação , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/patologia , Prevalência , Estudos Retrospectivos , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Análise Serial de Tecidos , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/patologia , Adulto JovemRESUMO
BACKGROUND: Fumarate hydratase (FH) deficiency is a rare autosomal recessive disorder which results in a major defect in cellular metabolism. It presents in infancy with progressive encephalopathy, hypotonia, seizures and failure to thrive and is often fatal in childhood. It is caused by mutations in the FH gene (1q42.1) that result in deficiency of the citric acid cycle enzyme fumarate hydratase, resulting in accumulation of fumaric acid. Heterozygous germline mutations in the FH gene predispose to an aggressive autosomal dominant inherited early-onset kidney cancer syndrome: hereditary leiomyomatosis and renal cell cancer (HLRCC). CASE PRESENTATION: Cascade FH mutation screening enabled the early diagnosis of a renal tumour in an asymptomatic parent of a child with fumarate hydratase deficiency, resulting in timely and possibly life-saving treatment. CONCLUSION: While the theoretical risk of kidney cancer in parents of children with recessive fumarate hydratase deficiency is well recognized, to our knowledge this is the first report of a kidney tumour being detected in a parent by screening performed for this indication. This underscores the importance of offering lifelong kidney surveillance to such parents and other heterozygous relatives of children born with fumarate hydratase deficiency.
Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase/deficiência , Fumarato Hidratase/genética , Neoplasias Renais/genética , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Transtornos Psicomotores/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Lactente , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Hipotonia Muscular/complicações , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/patologia , Transtornos Psicomotores/complicações , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/patologiaRESUMO
BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant tumor susceptibility syndrome, and the disease-related gene has been identified as fumarate hydratase (fumarase, FH). HLRCC-associated kidney cancer is an aggressive tumor characterized by early metastasis to regional lymph nodes and distant organs. Since early diagnosis and provision of definitive therapy is thought to be the best way to reduce the tumor burden, it is widely accepted that germline testing and active surveillance for an at-risk individual from a family with HLRCC is very important. However, it still remains controversial how we should treat HLRCC-associated kidney cancer. We successfully treated the patient with locally advanced HLRCC-associated kidney cancer, who has received active surveillance because of at-risk individual, by radical nephrectomy and extended retroperitoneal lymph node dissection, and examined surgically resected samples from a molecular point of view. CASE PRESENTATION: We recommended that 13 at-risk individuals from a family with HLRCC should receive active surveillance for early detection of renal cancer. A 48-year-old woman with a left renal tumor and involvement of multiple regional lymph nodes with high accumulation of fluorine-18-deoxyglucose on positron emission tomography was treated with axitinib as a neoadjuvant therapy. Preoperative axitinib induced the shrinkage of the tumor with decreased fluorine-18-deoxyglucose accumulation. Resected samples showed two thirds tumor tissue necrosis as well as high expression of serine/threonine kinase Akt and low expression of nuclear factor E2-related factor 2 (Nrf2) which activates anti-oxidant response and protects against oxidative stress in viable cancer cells. Targeted next-generation sequencing revealed that FH mutation and loss of the second allele were completely identical between blood and tumor samples, suggesting that FH mutation plays a direct role in FH-deficient RCC. She has remained well after radical operation for over 33 months. CONCLUSIONS: FH mutation plays a role in tumorigenic feature, a metabolic shift to aerobic glycolysis, and increased an anti-oxidant response phenotype in HLRCC-associated kidney cancer.
Assuntos
Carcinoma de Células Renais/cirurgia , Leiomiomatose/cirurgia , Linfonodos/cirurgia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Cutâneas/cirurgia , Neoplasias Uterinas/cirurgia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Feminino , Fumarato Hidratase/genética , Predisposição Genética para Doença , Humanos , Leiomiomatose/genética , Leiomiomatose/patologia , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Síndromes Neoplásicas Hereditárias , Nefrectomia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologiaRESUMO
The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes' studies may shed light on to the roles of NRF2 activation in sporadic tumours.
Assuntos
Leiomiomatose/genética , Fator 2 Relacionado a NF-E2/genética , Neoplasias Cutâneas/genética , Tirosinemias/genética , Neoplasias Uterinas/genética , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Mutação , Síndromes Neoplásicas HereditáriasRESUMO
OBJECTIVE: This study presents a detailed analysis of the clinical and genetic characteristics of uterine leiomyoma associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), combined with exploration of family history, pathology, and management procedures, supported by thorough evidence collection. METHODS: Blood samples were collected from the proband, and the pathogenic variant was verified using Sanger sequencing. A comprehensive review of family history, FH deficiency pathology, FH and 2SC immunohistochemistry staining was conducted. Functional evidence was derived from clinical and genetic information, supplemented by a literature collection and mutation was reclassified based on ACMG/AMP guidelines. RESULTS: The study successfully identifies a novel missense mutation (c.1240A>G; p.Lys414Glu) in exon 9 of FH, with no prior reports in existing databases. The patient's phenotype and family history, coupled with evidence collected from the literature, contribute to the preliminary determination of the variant as likely pathogenic. We also emphasize that the importance of combining FH-deficient morphology and immunohistochemical staining with 2SC for enhanced sensitivity. CONCLUSION: This research adds a novel missense mutation to the repertoire of FH gene variants, emphasizing its likely pathogenic nature based on a multidimensional analysis of phenotype, family history, and literature evidence. The findings enhance our understanding of the genetic landscape associated with FH and underscore the importance of thorough characterization for accurate variant classification.
RESUMO
Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist's ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors.
RESUMO
Background: Fumarase deficiency is an autosomal recessive condition characterized by severe neurologic abnormalities due to homozygous mutations in the fumarate hydratase (FH) gene. Heterozygous carriers of FH mutations have increased risk of developing uterine fibroids that can be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). The association between FH mutations and infertility remains uncertain. The objective of our study was to characterize the infertility diagnoses, treatments, and outcomes in women presenting to a fertility center who were found to be carriers of fumarase deficiency based on the presence of heterozygous FH mutations. Case Presentation: A retrospective case series was conducted including 10 women presenting to an academic fertility center who were found to be FH carriers based on genetic carrier screening. Of the 9 women who were engaged in further workup, 2 had imaging results consistent with uterine fibroids. One woman underwent hysteroscopic myomectomy prior to two courses of ovulation induction with timed intercourse (OI/TIC) followed by one successful cycle of IVF. Of the remaining patients, only 1 woman successfully delivered after a cycle of ovulation induction with intrauterine insemination (OI/IUI). Other patients pursuing OI/IUI, OI/TIC, or monitored natural cycles had unsuccessful experiences. Conclusion: Patients with infertility who are offered genetic testing should be screened for FH mutations, as the carriers are at risk of developing HLRCC-associated uterine fibroids, which can influence fertility and pregnancy. Additional research is needed to investigate the impacts of FH mutations on infertility.
RESUMO
FH Tumour Predisposition Syndrome, also known as Hereditary Leiomyomatosis and renal cell cancer (HLRCC), or Reed Syndrome, is an autosomal dominant condition clinically characterized by multiple cutaneous leiomyomas, multiple early-onset uterine leiomyomas and early-onset renal cell cancer. Here we report a young female with FH Tumour Predisposition Syndrome with no clinical features except early-onset uterine leiomyomas. Whilst there is a significant history of uterine leiomyomas in her family, there is no history of cutaneous leiomyomas or renal cell cancer (RCC). Uterine leiomyomatosis in young adults may represent a narrow phenotypic variant of FH Tumour Predisposition Syndrome. It is important that young women who present with multiple leiomyomata or leiomyomata with atypical features are referred for molecular genetic testing.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Leiomiomatose , Síndromes Neoplásicas Hereditárias , Neoplasias Cutâneas , Neoplasias Uterinas , Adolescente , Carcinoma de Células Renais/genética , Feminino , Fumarato Hidratase/genética , Predisposição Genética para Doença , Humanos , Neoplasias Renais/genética , Leiomiomatose/genética , Leiomiomatose/patologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto JovemRESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase gene (FH). Individuals with FH mutations are at risk of developing renal cell carcinoma (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is as yet no standardized therapy for advanced HLRCC-RCC. We report an aggressive RCC case in a 49-year-old man. Nine weeks after undergoing a total nephroureterectomy of the right kidney, he had a metastasectomy at port site. Within 14 weeks of the initial surgery, multiple recurrent tumors developed in the right retroperitoneal space. The pathological diagnosis was FH-deficient RCC. Genetic testing identified a heterozygous germline mutation of FH (c.641_642delTA), which confirmed the diagnosis of HLRCC-RCC. He received combination therapy with the immune checkpoint inhibitors (ICIs) nivolumab and ipilimumab as the first-line therapy. After 31 weeks of ICI treatment, a complete response was achieved. The disease-free condition has been prolonged for 24 months since the initial surgical treatment. This is the first case report of successful treatment of HLRCC-RCC with nivolumab plus ipilimumab. This combination immunotherapy is expected to be an effective approach to treat patients with advanced-stage HLRCC-RCC.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Leiomiomatose/terapia , Síndromes Neoplásicas Hereditárias/terapia , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/terapia , Neoplasias Uterinas/terapia , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/genética , Mutação em Linhagem Germinativa , Humanos , Leiomiomatose/diagnóstico por imagem , Leiomiomatose/genética , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/genética , Linhagem , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/genética , Tomografia Computadorizada por Raios X , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/genéticaRESUMO
We experienced a case of fumarate hydratase (FH) -deficient renal cell carcinoma (RCC) suspected of hereditary leiomyomatosis renal cell carcinoma (HLRCC) and herein report our findings. A 42-year-old man with an unremarkable medical history was referred to our hospital with an initial impression of renal cancer, cT3aN2M0. He underwent a right radical nephrectomy with lymph node dissection and showed a pathological diagnosis of FH-deficient RCC, pT3aN2. Clinicopathologic features indicated the possibility of HLRCC; however,-associated RCC. genetic testing showed negative for pathogenic FH mutation.HLRCC is an autosomal dominant condition caused by an FH gene mutation on chromosome 1q43. It is also a syndrome that develops in the smooth muscles of the skin and uterus, and has a renal cancer risk of 10-16%. HLRCC-associated RCC tends to metastasize early and shows poor prognosis. In FH-deficient RCC, the possibility of HLRCC-related RCC should be considered; thus, if patients fulfill the clinical diagnostic criteria, genetic counseling and screening of HLRCC are needed. Even if genetic testing does not confirm HLRCC, FH-deficient RCC still has a poor prognosis and careful follow-up is required.
RESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.
RESUMO
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare but aggressive disease. Immune checkpoint inhibitors (ICIs) have been an indispensable component for the management of advanced renal cell carcinoma, and stereotactic body radiotherapy (SBRT) has offered additional immunological effect boost for improving the treatment outcomes of the patients. However, the synergistic effect of ICIs with SBRT in HLRCC remains largely unexplored. We present the case of a 34-year-old woman with advanced HLRCC who underwent radical nephrectomy but soon relapsed at the retroperitoneal lymph nodes (RPLN). She was prescribed sunitinib but still progressed on twenty cycles with bulky RPLN and ascites. She was then treated with axitinib and pembrolizumab for twenty months, and received SBRT for the progression of RPLN upon which the first abscopal effect was observed via significant shrinkage of in-field and out-field tumor lesions. Five months later, she underwent a second course of SBRT for pelvic mass progression and the second abscopal effect was observed. Genetic and immunologic characteristics revealed a large number of tumor-infiltrating immune cells and high levels of PD-L1 expression. This case report demonstrates the synergistic effect of ICIs and SBRT in HLRCC and the potential mechanism for the repeated SBRT-induced abscopal effect, supporting the application of SBRT to oligometastatic lesion during ICIs treatment to delay disease progression. Further studies are needed to verify the strategy of combining ICIs and SBRT in advanced HLRCC.
RESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated kidney cancer is a rare and exceptionally aggressive, with early metastasis and die at a young age. Most reported patients usually present with back pain and hematuria, and died within 5 years after diagnosis. Currently, there is not a guideline or census about the management of HLRCC. On April 19, 2019, the Food and Drug Administration (FDA) of the USA approved the combination of pembrolizumab and axitinib for first-line treatment of patients with advanced renal cell carcinoma based on the results of KEYNOTE-426 trial. Thus, the combination of immunotherapy and targeted therapy should be considered for HLRCC. We present a case of 46-year-old man without family history, possessing specific mutation and sensitive to the combination of immunotherapy and targeted therapy. After he completed seven cycles of combined treatments, his discomfort improved and the lesions of pleura almost disappeared and the mass in the left kidney area was basically stable. This patient might be the first one to receive the combination therapy and the efficacy seemed acceptable.
RESUMO
Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydratase gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.