RESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with 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. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.
Asunto(s)
Fumarato Hidratasa , Inmunoterapia , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Humanos , Femenino , Leiomiomatosis/genética , Leiomiomatosis/patología , Leiomiomatosis/terapia , Fumarato Hidratasa/genética , Adulto , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Mutación de Línea Germinal , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapiaRESUMEN
PURPOSE OF REVIEW: To provide an overview of diagnosis, genetic abnormalities, clinical signs and treatment options for the major heritable renal cell carcinoma (RCC) syndromes. RECENT FINDINGS: RCC in major hereditary syndromes are disorders which are typically autosomal dominant. They predispose patients to early onset of RCC and may exhibit other extrarenal manifestations. Early recognition of these diseases allows correct screening at appropriate ages as well as early detection of RCC. Moreover, expedient identification may optimize the management of extra renal manifestations as well as allow for genetic testing and screening of at-risk relatives. SUMMARY: The risk of RCC in these major heritable syndromes is higher than sporadic disease. They occur at earlier age groups and can be multifocal or bilateral. Tumours are observed until at least 3âcm before any intervention, while nephron sparing surgery is widely considered as the treatment of choice except for hereditary leiomyomatosis with renal cell cancer, of which radical nephrectomy is treatment of choice. Intervention should be timeous as there is a highly reported incidence of early metastasis. Molecular therapies have been used in the setting of patients with metastasis, some of which show favourable outcomes.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/terapia , Leiomiomatosis/genética , Leiomiomatosis/patología , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Nefrectomía , SíndromeRESUMEN
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.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/terapia , Nivolumab/uso terapéutico , Neoplasias Cutáneas/terapia , Neoplasias Uterinas/terapia , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/genética , Mutación de Línea Germinal , Humanos , Leiomiomatosis/diagnóstico por imagen , Leiomiomatosis/genética , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/diagnóstico por imagen , Síndromes Neoplásicos Hereditarios/genética , Linaje , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/genética , Tomografía Computarizada por Rayos X , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/genéticaAsunto(s)
Adenomiosis/terapia , Leiomiomatosis/terapia , Embolización de la Arteria Uterina , Neoplasias Uterinas/terapia , Adenomiosis/diagnóstico por imagen , Adulto , Femenino , Humanos , Leiomiomatosis/diagnóstico por imagen , Resultado del Tratamiento , Neoplasias Uterinas/diagnóstico por imagenRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare familial cancer syndrome with a germline mutation in the fumarate hydratase gene. Affected individuals are predisposed to development of cutaneous leiomyomas, uterine leiomyomas, and papillary renal cell carcinoma. We present a case of a mother and son pair affected with HLRCC, discuss clinical management, and examine potential syndromic manifestations in extended family members. Annual imaging surveillance for kidney cancer is recommended since 20-30% of individuals develop aggressive papillary type II renal cell carcinoma that can be difficult to treat once it has metastasized.
Asunto(s)
Predisposición Genética a la Enfermedad , Leiomiomatosis/diagnóstico , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Carcinoma de Células Renales/etiología , Femenino , Humanos , Leiomiomatosis/complicaciones , Leiomiomatosis/genética , Leiomiomatosis/terapia , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Linaje , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Síndrome , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Adulto JovenRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.
Asunto(s)
Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Crioterapia , Femenino , Fumarato Hidratasa , Humanos , Leiomiomatosis/genética , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapiaRESUMEN
Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.
Asunto(s)
Fumarato Hidratasa/genética , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/genética , Leiomiomatosis/genética , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Antineoplásicos/farmacología , Línea Celular Tumoral , Fumarato Hidratasa/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Humanos , Leiomiomatosis/tratamiento farmacológico , Leiomiomatosis/metabolismo , Metaloporfirinas/farmacología , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Síndromes Neoplásicos Hereditarios/metabolismo , ARN Interferente Pequeño/farmacología , Tratamiento con ARN de Interferencia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/metabolismoRESUMEN
BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome characterised by predisposition to cutaneous and uterine leiomyomata and renal cell carcinoma (RCC). OBJECTIVE: To define the clinical findings, molecular genetics, and prognosis in a cohort of 69 families with a fumarate hydratase (FH) pathogenic variant and/or clinical features of HLRCC. DESIGN, SETTING, AND PARTICIPANTS: Clinical and molecular findings were obtained for 185 individuals from 69 families from four UK regional genetics clinics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Ages at confirmed diagnoses, last dates of follow-up, and molecular results were attained for probands and relatives. To study the effect of potential ascertainment bias, phenotypes of probands and their affected relatives were compared. RESULTS AND LIMITATIONS: A germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/69 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9â¯yr) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0â¯yr). Of 185 individuals, 23 (12.4%) had a confirmed renal tumour, and histopathology where known (nâ¯=â¯18) was variable: seven clear cell RCCs, nine papillary RCCs (six of type 2), one collecting duct tumour, and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0â¯yr and median survival was 21.0 mo. Eighty-one individuals underwent 187 renal imaging surveillance scans; three stage 1 RCCs were detected. Mean survival of individuals diagnosed with stage 1/2 RCC was significantly longer than those diagnosed with stage 3/4 RCC (p = 0.0004). CONCLUSIONS: Management of HLRCC is challenging as RCC occurs in a minority of cases but is highly aggressive. This large multicentre series has identified novel features and evidence that renal screening in HLRCC detects early-stage RCCs. PATIENT SUMMARY: We show that hereditary leiomyomatosis and renal cell cancer is associated with a 21% lifetime risk of renal cell carcinoma (RCC; 95% confidence interval 8.2-37.1), and renal imaging screening detects early-stage RCC.
Asunto(s)
Carcinoma de Células Renales/diagnóstico , Detección Precoz del Cáncer/métodos , Fumarato Hidratasa/genética , Neoplasias Renales/diagnóstico , Leiomiomatosis/complicaciones , Síndromes Neoplásicos Hereditarios/complicaciones , Neoplasias Cutáneas/complicaciones , Neoplasias Uterinas/complicaciones , Adolescente , Adulto , Anciano , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/terapia , Análisis Mutacional de ADN , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Pruebas Genéticas/estadística & datos numéricos , Humanos , Riñón/diagnóstico por imagen , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Neoplasias Renales/terapia , Leiomiomatosis/epidemiología , Leiomiomatosis/genética , Leiomiomatosis/terapia , Imagen por Resonancia Magnética , Masculino , Anamnesis , Persona de Mediana Edad , Epidemiología Molecular , Mutación , Estadificación de Neoplasias , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Pronóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Reino Unido/epidemiología , Neoplasias Uterinas/epidemiología , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Adulto JovenRESUMEN
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.
Asunto(s)
Leiomiomatosis/etiología , Síndromes Neoplásicos Hereditarios/etiología , Neoplasias Cutáneas/etiología , Neoplasias Uterinas/etiología , Biomarcadores de Tumor , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Fumarato Hidratasa/genética , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genómica/métodos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leiomiomatosis/diagnóstico , Leiomiomatosis/metabolismo , Leiomiomatosis/terapia , Mutación , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/metabolismo , Síndromes Neoplásicos Hereditarios/terapia , Proteoma , Transducción de Señal , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapia , Investigación Biomédica Traslacional , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/terapiaRESUMEN
CONTEXT: Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years. OBJECTIVE: To review and summarise the recent preclinical and clinical literature in hereditary renal cancer. EVIDENCE ACQUISITION: A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management. EVIDENCE SYNTHESIS: Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy. CONCLUSIONS: There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection. PATIENT SUMMARY: This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.
Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/terapia , Humanos , Leiomiomatosis/diagnóstico , Leiomiomatosis/genética , Leiomiomatosis/terapia , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Síndrome , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/terapia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/terapiaRESUMEN
Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome. We now report the results of this prospective screening strategy, with emphasis on the incidence and clinicopathologic features of FH-d morphology in uSMT, the rate of patient uptake of referral to genetic counseling, and the results of genetic testing for FH germline mutation. Among 2060 women with a uSMT, FH-d morphology was reported in 1.4% (30 women). Ten women elected to undergo FH genetic testing and 6 of 10 (60%) had a FH germline mutation: 5 were pathogenic mutations and 1 was a mutation variant of unknown significance. Therefore, the screening program led to a confirmed genetic diagnosis of HLRCC syndrome in 0.24% of all women with any type of uSMT. The women with a pathogenic mutation were ages 24 to 40 years. Although the majority of leiomyoma with bizarre nuclei exhibited FH-d morphology, the uSMT were conventional leiomyomas with FH-d morphology in 2 of 5 women found to have a pathogenic FH germline mutation. Relying on an abnormal FH immunostain result to trigger genetic counseling referral would have resulted in 2 of 5 (40%) cases with pathogenic FH germline mutation but normal FH immunoexpression going undetected, both of which were missense type mutations. There was no difference in the incidence of pathogenic FH germline mutation between FH-d morphology uSMT with an abnormal versus a normal FH immunostain result. Overall, this study demonstrates that prospective morphology-based screening, integrated with referral for genetic counseling, can result in the diagnosis of HLRCC syndrome in otherwise unselected women with uSMT. We conclude that this strategy should be incorporated in the routine pathologic examination of all uterine smooth muscle tumors.
Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Fumarato Hidratasa/genética , Asesoramiento Genético , Mutación de Línea Germinal , Leiomiomatosis/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adulto , Anciano , Biopsia , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Leiomiomatosis/terapia , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Síndromes Neoplásicos Hereditarios/terapia , Aceptación de la Atención de Salud , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Derivación y Consulta , San Francisco , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Factores de Tiempo , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Adulto JovenRESUMEN
The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
Asunto(s)
Carcinoma de Células Renales , Enfermedades Genéticas Congénitas , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neovascularización Patológica , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Hipoxia de la Célula/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Enfermedades Genéticas Congénitas/patología , Enfermedades Genéticas Congénitas/terapia , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/terapia , Leiomiomatosis/genética , Leiomiomatosis/metabolismo , Leiomiomatosis/patología , Leiomiomatosis/terapia , Modelos Biológicos , Mutación , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/metabolismo , Síndromes Neoplásicos Hereditarios/patología , Síndromes Neoplásicos Hereditarios/terapia , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neovascularización Patológica/terapia , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Disseminated peritoneal leiomyomatosis (DPL) is a rare variant of extrauterine leiomyomatosis with reported spontaneous and iatrogenic occurrences. It has been associated with hysterectomy and myomectomy. To our knowledge, reports have not yet substantiated occurrence following uterine artery embolization (UAE), which has become a routine minimally invasive alternative to surgery for the treatment of symptomatic leiomyomata. This report presents the case of a nulliparous premenopausal woman with no other contributory history who presented with DPL 3 years after UAE. The presentation of this patient suggests the potential for a causal relationship between UAE and DPL.
Asunto(s)
Leiomiomatosis/diagnóstico por imagen , Leiomiomatosis/terapia , Neoplasias Primarias Secundarias/diagnóstico por imagen , Embolización de la Arteria Uterina/métodos , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/terapia , Adulto , Biopsia , Angiografía por Tomografía Computarizada , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Imagen por Resonancia Magnética , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/patología , PremenopausiaRESUMEN
BACKGROUND: Pulmonary lymphangioleimyomatosis (PLAM) is a rare disease involving lung. PLAM primarily affects young women, a characteristic it shares with systemic lupus erythematosus (SLE). Estrogen has long been assumed to play an important role both in PLAM and SLE. We report a menopausal woman, who was found to have PLAM 1 year after she was diagnosed with SLE. Her chest radiograph was normal in the early phase of SLE. CASE PRESENTATION: A 52-year-old Chinese woman was referred to our hospital in August 2014 because of swelling in both legs. She also reported a malar rash and intermittent generalized arthralgia. Laboratory examination showed leukopenia. Her serum albumin level was 23 g/L; 24-h urinary protein excretion was 5.3 g. She tested positive for anti-Smith (Sm) antibody and anti-SS-A antibody. Renal biopsy indicated Class V + IV(G)-A lupus nephritis (LN). The condition of SLE and LN improved on a regime of tapering prednisolone and intermittent intravenous cyclophosphamide therapy until 1 year later when she developed exertional dyspnea accompanied with frequent cough. Thoracic computed tomography revealed numerous well-defined cysts and the diagnosis of PLAM was confirmed by lung biopsy. In the follow-up period, the patient continued to be on prednisolone and mycophenolate mofetil for the treatment of SLE, but only agreed to receive symptomatic treatment for PLAM. One year after the diagnosis of PLAM, during which time the SLE was stable, she died of respiratory failure and cor pulmonale. CONCLUSION: We report a patient with coexisting SLE and PLAM, who was treated with immunosuppressive therapy. SLE was stable but PLAM was not improved. Although the coexistence of SLE and PLAM might be a coincidence, the occurrence of these two diseases in a menopausal woman may warrant further mechanistic exploration.
Asunto(s)
Leiomiomatosis/complicaciones , Neoplasias Pulmonares/complicaciones , Nefritis Lúpica/complicaciones , Linfangioma/complicaciones , Menopausia , Antibacterianos/uso terapéutico , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada , Resultado Fatal , Femenino , Humanos , Inmunosupresores/uso terapéutico , Leiomiomatosis/terapia , Neoplasias Pulmonares/terapia , Nefritis Lúpica/tratamiento farmacológico , Linfangioma/terapia , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/tratamiento farmacológico , Prednisolona/uso terapéuticoRESUMEN
PURPOSE: Genetic factors have been implicated in the pathogenesis of renal cell carcinoma (RCC), with around 3% of cases having a family history. A greater knowledge of the genetics of inherited RCC has the potential to translate into novel therapeutic targets for sporadic RCC. METHODS: A literature review was performed summarising the current knowledge on hereditary RCC diagnosis, surveillance and management. RESULTS: Familial RCC is usually inherited in an autosomal dominant manner, although inherited RCC may present without a relevant family history. A number of familial RCC syndromes have been identified. Familial non-syndromic RCC is suspected when ≥ 2 relatives are affected in the absence of syndromic features, although clear diagnostic criteria are lacking. Young age at onset and bilateral/multicentric tumours are recognised characteristics which should prompt molecular genetic analysis. Surveillance in individuals at risk of inherited RCC aims to prevent morbidity and mortality via early detection of tumours. Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities. CONCLUSION: Increasing knowledge of the natural history and genetic basis has led to characterisation and tailored management of hereditary RCC syndromes. International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.