Surgical strategy for intravenous leiomyomatosis spreading from uterine to the right atrium presenting with recurrent syncope.

Uterine leiomyoma invading internal iliac vein and consequently disseminating into the right atrium is an extremely rare condition, and surgical strategy is controversial. Here, we reported a specific case with successful surgical resection through one-stage total hysterectomy, bilateral oophorectomy, and the intracardiovascular lesion. This procedure would be an optimal choice for uterine leiomyoma invading inferior vena cava and spreading to right atrium.

Safety and efficacy of sirolimus in recurrent intravenous leiomyomatosis, pulmonary benign metastatic leiomyomatosis, and leiomyomatosis peritonealis disseminata: a pilot study.

BACKGROUND: Intravenous leiomyomatosis (IVL), pulmonary benign metastatic leiomyomatosis (PBML), and leiomyomatosis peritonealis disseminata (LPD) are leiomyomas with special growth patterns and high postoperative recurrence rates. We report the safety and efficacy of a pilot study of sirolimus in the treatment of recurrent IVL, PBML, and recurrent LPD. METHODS: This was a pilot study to evaluate the safety and efficacy of sirolimus in the treatment of leiomyomatosis (ClinicalTrials.gov identifier NCT03500367) conducted in China. Patients received oral sirolimus 2 mg once a day for a maximum of 60 months or until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision to stop. The primary end point of this study was the objective response rate. Secondary end points included safety and tolerability, disease control rate, and progression-free survival. RESULTS: A total of 15 patients with leiomyomatosis were included in the study, including five with recurrent IVL, eight with PBML and two with recurrent LPD. The median follow-up time was 15 months (range 6-54 months), nine patients (60%) had treatment-related adverse events (including all levels), and two patients had treatment-related grade 3 or 4 adverse events. The objective response rate was 20.0% (95% CI, 7.1-45.2%), and the disease control rate was 86.7% (95% CI, 62.1-96.3%). Partial response was achieved in three patients. The median response time in the three partial response patients was 33 months (range 29-36 months), and the sustained remission time of these three patients reached 0, 18, and 25 months, respectively. CONCLUSIONS: Sirolimus was safe and effective in the treatment of recurrent IVL, PBML, and recurrent LPD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03500367. Registered on 18 April 2018.

Clinical phenotype and genetic function analysis of a rare family with hereditary leiomyomatosis and renal cell carcinoma complicated with Birt-Hogg-Dubé syndrome.

To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt-Hogg-Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.

Diffuse Uerine Leiomyomatosis Complicated with Cerebral Thrombosis After Oral Contraceptive Treatment: A Case Report of a Athletic Patients

We would like to emphasize the differentiations of diagnosis and treatment between general uterine leiomyomas and diffuse uterine leiomyomatosis (DUL), which is a kind of extremely rare disease. Levonorgestrel-releasing intrauterine system (LNG-IUS) is an attainable option provided to treat DUL with cerebral thrombosis, as a feasible novel method. Case report: A 21-year-old female patient with DUL was due to cerebral venous thrombosis caused by oral contraceptives. The patient was persistently vaginal bleeding after decreasing intracranial pressure and anticoagulant therapy for 3 days. Subsequently, a hysteroscopic submucosal myomectomy was performed to restore the normal shape of the uterine cavity, and the placement of Mirena was given after surgery, which aimly played a good role in hemostasis, prevention of severe menorrhagia and reconstruction of endometrial function. Conclusion: This case report shows that, levonorgestrel-releasing intrauterine system (LNG-IUS) is efficient and secure to treat DUL after hysteroscopic surgery, and simultaneously does not increase the risk of venous thromboembolism (VTE). (AU)

Leiomyomatosis in an Infant With a SUFU Splice Site Variant: Case Report.

Heterozygous loss-of-function variants in the suppressor of fused protein gene (SUFU) can result in Gorlin syndrome, which is characterized by an increased frequency of basal cell carcinoma, medulloblastoma, odontogenic keratocysts, as well as other tumors. We describe a case of a 5-month-old female who presented with multiple intra-abdominal leiomyomata and was found to have a likely pathogenic splice site variant in the SUFU gene. This is the first reported case of leiomyomatosis secondary to a pathogenic SUFU variant in an infant and may represent an early, atypical presentation of Gorlin syndrome.

Intravenous Leiomyomatosis: An Uncommon Cause of Pulmonary Embolism.

BACKGROUND Intravenous leiomyomatosis (IVL) is a rare benign smooth muscle tumor originating in the uterus or in the uterine vessels. It is characterized by continuous intraluminal growth that may extend through iliac veins and inferior vena cava (IVC) to right chambers of the heart and pulmonary vasculature, leading to life-threatening complications. This case report describes an uncommon cause of non-thrombotic pulmonary embolism in young woman caused by extensive IVL. CASE REPORT A 39-year-old woman was admitted after multiple syncopal episodes. She was initially found to have a bilateral pulmonary embolism and large right atrial mass believed to be a thrombus. After an unsuccessful attempt to remove the thrombus with AngioVac (AngioDynamics, Latham, NY), subsequent sternotomy revealed a large pedunculated mass extending to the infra-hepatic IVC. Further abdominal imaging showed multiple uterine masses, with the largest about 17 cm, infiltrating the parauterine vessels and extending through the right iliac vein and inferior vena cava up to the right atrium. Pathology examination of the atrial mass revealed benign leiomyoma consistent with further pathology findings after hysterectomy. The pulmonary embolism was believed to be caused by tumor tissue, and anticoagulation was abandoned. Pulmonary nodule raised a suspicion of benign pulmonary metastases, but, fortunately, remained stable during follow-up and the patient had a successful recovery. CONCLUSIONS Available information about IVL is scarce. This tumor, although benign and rare, should be included in the differential diagnosis of cardiac tumors and non-thrombotic pulmonary emboli in women with predisposing risk factors, as potential complications are life-threatening.

Hematometra y hematocervix en paciente postmenopáusica: reporte de caso / Hematometry and hematocervix in postmenopausal patient: case repor

El hematometra es la retención de sangre en el útero y comúnmente se presenta en mujeres jóvenes con anomalías mullerianas pero puede aparecer también en mujeres postmenopausicas por causas secundarias como traumas, tumores, terapia de remplazo hormonal, estenosis cervical, entre otras. En esta presentación de caso interesante se describe una mujer postmenopáusica bajo terapia de remplazo hormonal. Dicha mujer inicia con hemorragia uterina anormal por lo que se le realiza ultrasonido evidenciando hematómetra y hematocervix. Como método diagnóstico y terapéutico de la hemorragia postmenopáusica se le realiza histerectomía abdominal en la cual la patología evidencia leiomiomatosis uterina con endometrio secretor

Hematometra is the retention of blood in the uterus and commonly occurs in young women with Mullerian abnormalities but can also appear in postmenopausal women due to secondary causes such as trauma, tumors, hormone replacement therapy, cervical stenosis, among others. In this presentation an interesting case is described a postmenopausal woman under hormone replacement therapy. She said woman began with abnormal uterine bleeding, so an ultrasound was performed showing hematometer and hematocervix. As a method diagnosis and treatment of postmenopausal hemorrhage, abdominal hysterectomy is performed in which the pathology shows uterine leiomyomatosis with secretory endometrium

Intravenous leiomyomatosis misdiagnosed with large thrombosis in inferior vena cava.

OBJECTIVE: The aim of this report is to highlight the importance of a comprehensive preoperative evaluation in the case of intravenous leiomyomatosis. CASE REPORT: A 49-year-old women was presented with dyspnea and abdominal distension. Imaging studies revealed a large leiomyoma with intravenous leiomyomatosis from this mass to the right parauterine veins, right ovarian vein reaching the inferior vena cava. Complete resection was performed by a two-stage operation by a multidisciplinary team. Final pathology confirmed it to be intravenous leiomyomatosis and uterine leiomyomas. CONCLUSION: Intravenous leiomyomatosis is a benign and rare disease that can be a fatal condition. Precise diagnosis and appropriate treatment are important for the best outcome. Gynecologists should consider this rare disease when a patient with a uterine tumor shows symptoms such as chest pain and dyspnea.

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

Fumarate hydratase as a therapeutic target in renal cancer.

INTRODUCTION: Renal cell carcinoma (RCC) is a heterogeneous group of cancers that can occur sporadically or as a manifestation of various inherited syndromes. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is one such inherited syndrome that predisposes patients to HLRCC-associated RCC. These tumors are notoriously aggressive and often exhibit early metastases. HLRCC results from germline mutations in the FH gene, which encodes the citric acid cycle enzyme fumarate hydratase (FH). FH loss leads to alterations in oxidative carbon metabolism, necessitating a switch to aerobic glycolysis, as well as a pseudohypoxic response and consequent upregulation of various pro-survival pathways. Mutations in FH also alter tumor cell migratory potential, response to oxidative stress, and response to DNA damage. AREAS COVERED: We review the mechanisms by which FH loss leads to HLRCC-associated RCC and how these mechanisms are being rationally targeted. EXPERT OPINION: FH loss results in the activation of numerous salvage pathways for tumor cell survival in HLRCC-associated RCC. Tumor heterogeneity requires individualized characterization via next-generation sequencing, ultimately resulting in HLRCC-specific treatment regimens. As HLRCC-associated RCC represents a classic Warburg tumor, targeting aerobic glycolysis is particularly promising as a future therapeutic avenue.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): Report of a Family Pedigree.

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.

Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance. METHODS: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence. RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10-3 (1 in 393) and 1.20 × 10-3 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%. CONCLUSIONS: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.

Surgical treatment of fibroids for subfertility.

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; I2 = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I2 = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I2 = 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; I2 = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I2 = 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.