Intravenous leiomyomatosis is inclined to a solid entity different from uterine leiomyoma based on RNA-seq analysis with RT-qPCR validation.

INTRODUCTION: Intravenous leiomyomatosis (IVL) is currently regarded as a special variant of the common uterine leiomyoma (LM). Though IVL shows a similar histological morphology to LM, IVL is characterized by unique intravenous growth patterns and low-grade malignant potential, which are quite different from LM. There are currently few studies underlying the molecular alterations of IVL, though this information is important for understanding the pathogenesis of the disease, and for identifying potential biomarkers. METHOD: We carried out a high-throughput whole transcriptome sequencing of tumor and normal tissue samples from five IVL patients and five LM patients and compared the differentially expressed genes (DEGs) between IVL and leiomyoma. We performed multiple different enrichment and target analyses, and the expression of selected DEGs was validated using RT-qPCR in formalin-fixed samples. RESULTS: Our study identified substantial different genes and pathways between IVL and LM, and functional enrichment analyses found several important pathways, such as angiogenesis and antiapoptosis pathways, as well as important related genes, including SH2D2A, VASH2, ADAM8, GATA2, TNF, and the lncRNA GATA6-AS1, as being significantly different between IVL and LM (P = .0024, P = .0195, P = .0212, P = .0435, P = .0401, and P = .0246, respectively). CXCL8, LIF, CDKN2A, BCL2A1, COL2A1, IGF1, and HMGA2 were also differently expressed between IVL and LM groups, but showed no statistical difference (P = .2409, P = .1773, P = .0596, P = .2737, P = .1553, P = .1045, and P = .1847, respectively) due to the large differences among individuals. Furthermore, RT-qPCR results for five selected DEGs in IVL tissues and adjacent nontumor tissues were mainly consistent with our sequencing results. CONCLUSION: Our results indicated that IVL may be a solid entity that is unique and different from LM, proving consistent with previous studies. Furthermore, we identified DEGs, particularly within angiogenesis and antiapoptosis pathway-related genes that may play crucial roles in the development and pathogenesis of IVL and may be potential specific biomarkers.

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids.

Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.

Uterine artery embolization: a vascular surgery procedure? One vascular surgery group's experience.

Uterine artery embolization (UAE) has been performed by interventional radiology since the 1990s for symptomatic uterine fibroids with considerable success. Endovascular-trained vascular surgeons possess the necessary skills to successfully perform this procedure after an adequate but brief training period. Fourteen successful UAE procedures were performed by two vascular surgeons over a one-year period. Indications for the procedures were bleeding (12/14 patients, 86%), pain/bloating/pressure (13/14 patients, 93%) and dyspareunia (2/14 patients, 14%). All patients were initially evaluated by a gynecologist and referred for this procedure. Complications were minor and limited. Clinical follow-up demonstrated near-complete to complete symptom resolution in all but one patient for a 93% short-term success rate. Follow-up ultrasound studies demonstrated a reduction in the uterine fibroid size in all patients three months or more postprocedure. The mean fibroid size reduction was 4.07-3.26 cm (20%), P < 0.005. UAE is a procedure of proven benefit, well-matched to many vascular surgeons' skills and practice. Up to this point, few vascular surgeons have incorporated this endovascular procedure into their practices. This initial and somewhat limited study demonstrates one vascular surgery group's early success with this procedure.

Menopause and menopausal symptoms after ovarian artery embolization: a comparison with uterine artery embolization controls.

PURPOSE: To determine the impact on menstrual status and menopausal symptoms of ovarian artery embolization (OAE) to supplement uterine embolization (UAE) for uterine leiomyomas. MATERIALS AND METHODS: A single-center case-control study was conducted in women who underwent UAE for leiomyomas. Between May 2004 and July 2009, 77 patients underwent unilateral or bilateral OAE during UAE procedures. Contemporaneous control subjects undergoing UAE alone were identified based on age and race. Questionnaires queried menstrual cycle regularity, onset of menopause, hormone use, and subsequent leiomyoma interventions, as well as the Menopause Rating Scale (MRS), a validated menopausal symptom questionnaire. Records were reviewed for baseline clinical and procedure data. Case and control subjects were compared for baseline characteristics and outcomes with the use of appropriate statistics, with the primary outcome the summary score on the MRS. RESULTS: Of 154 patients, 51 case subjects and 49 control subjects responded to the MRS (65%). Case subjects had greater tumor volumes (median, 129.3 cm(3) vs 69.3 cm(3) in control subjects; P = .0252) and longer fluoroscopy times (mean, 20.5 min vs 14 min in control subjects; P < .0001), with no other differences. There was a lower mean MRS score in the OAE group (total mean MRS score, 7.4 in case subjects and 8.9 in control subjects; P = .023), indicating fewer menopausal symptoms and no difference in menstrual regularity or frequency of onset of menopause. Of six patients who underwent bilateral OAE and responded, all reported continued menstrual cycles. CONCLUSIONS: Compared with standard UAE, the addition of OAE does not appear to precipitate the onset of menopause nor increase menopausal symptom severity.

Uterine artery embolization versus occlusion for uterine leiomyomas: a pilot randomized clinical trial.

STUDY OBJECTIVE: To compare perioperative pain and institutional use for women undergoing transcatheter uterine artery embolization (UAE) and transcatheter uterine artery occlusion (UAO) for the treatment of heavy uterine bleeding associated with uterine leiomyomas. DESIGN: A pilot double-blind, randomized clinical trial (Canadian Task Force classification I). SETTING: Large, university-affiliated community hospital with multiple residency programs including obstetrics and gynecolgoy and radiology. PATIENTS: Premenopausal women with heavy uterine bleeding related to uterine leiomyomas were enrolled. INTERVENTIONS: Either a standard UAE with microspheres or UAO using vascular coils was used. The main outcome measures were analgesic use, institutional stay, and postprocedural numeric pain scales. MEASUREMENTS AND MAIN RESULTS: Sixteen women were enrolled and 14 underwent study procedures (UAE n = 8, UAO n = 6). Baseline Aberdeen Menorrhagia Severity Scale scores, also known as the Ruta scores, were similar in each group (UAE = 54, UAO = 53). Median preprocedural uterine volume was similar for each group (UAE = 557 mL, UAO = 612 mL). The median postprocedural pain scale was less for UAO than UAE (UAO 1, UAE 5; p <.05). Six patients with UAE and no patients with UAO required parenteral narcotic analgesia in the recovery room (p <.05) (median UAO 0 and UAE 1). Patients with UAE used 6 hospital nights and patients with UAO used 1 hospital night (p =.09) (median UAO 0 and UAE 1). Three-month Aberdeen Menorrhagia Severity Scale scores were reduced to a similar degree in each group (UAE = 58%, UAO = 63%). CONCLUSION: Transcatheter UAO is a promising alternative transcatheter technique for the treatment of symptoms related to uterine leiomyomas, with less postprocedural pain, reduced requirements for analgesics, and shorter hospital stays than transcatheter UAE. Although the results of the study are promising, larger-scale trials with longer follow-up are needed to both confirm these results and evaluate the long-term efficacy of transcatheter UAO.

Laparoscopic uterine artery occlusion combined with myomectomy for uterine myomas.

We sought to evaluate the clinical feasibility and mid- to long-term effects of laparoscopic uterine artery occlusion before myomectomy in the treatment of uterine myomas. A total of 566 patients with uterine myoma were treated by laparoscopic uterine artery occlusion before myomectomy from October 2001 through July 2007. Mean blood loss was 88.2 +/- 52.7 mL (95% CI 82.7-93.8). The highest postoperative temperature was 37.8 +/- 0.3 degrees C, and the postoperative morbidity was 5.7% (32/566). Number of days to the return of bowel movement was 1.9 +/- 0.5d and in hospital stay after surgery was 7.7 +/- 2.5d. Complications included 2 instances of subcutaneous emphysema, 1 of vaginal bleeding, and 3 of mild intestinal obstruction. At a median of 26.3 months (range 6-69 months) of follow-up, the rate of myoma recurrence was 3.0% (15/517), uterus volume reduction was 48.9%, and correction of menstruation abnormality was 97.1% (502/517). Laparoscopic uterine artery occlusion before myomectomy can expand myomectomy indications with better results.

Magnetic resonance imaging (MRI) analysis of fibroid location in women achieving pregnancy after uterine artery embolization.

The purpose of this study was to evaluate the fibroid morphology in a cohort of women achieving pregnancy following treatment with uterine artery embolization (UAE) for symptomatic uterine fibroids. A retrospective review of magnetic resonance imaging (MRI) of the uterus was performed to assess pre-embolization fibroid morphology. Data were collected on fibroid size, type, and number and included analysis of follow-up imaging to assess response. There have been 67 pregnancies in 51 women, with 40 live births. Intramural fibroids were seen in 62.7% of the women (32/48). Of these the fibroids were multiple in 16. A further 12 women had submucosal fibroids, with equal numbers of types 1 and 2. Two of these women had coexistent intramural fibroids. In six women the fibroids could not be individually delineated and formed a complex mass. All subtypes of fibroid were represented in those subgroups of women achieving a live birth versus those who did not. These results demonstrate that the location of uterine fibroids did not adversely affect subsequent pregnancy in the patient population investigated. Although this is only a small qualitative study, it does suggest that all types of fibroids treated with UAE have the potential for future fertility.

Sexuality and body image after uterine artery embolization and hysterectomy in the treatment of uterine fibroids: a randomized comparison.

In this paper the effect of uterine artery embolization (UAE) on sexual functioning and body image is investigated in a randomized comparison to hysterectomy for symptomatic uterine fibroids. The EMbolization versus hysterectoMY (EMMY) trial is a randomized controlled study, conducted at 28 Dutch hospitals. Patients were allocated hysterectomy (n = 89) or UAE (n = 88). Two validated questionnaires (the Sexual Activity Questionnaire [SAQ] and the Body Image Scale [BIS]) were completed by all patients at baseline, 6 weeks, and 6, 12, 18, and 24 months after treatment. Repeated measurements on SAQ scores revealed no differences between the groups. There was a trend toward improved sexual function in both groups at 2 years, although this failed to reach statistical significance except for the dimensions discomfort and habit in the UAE arm. Overall quality of sexual life deteriorated in a minority of cases at all time points, with no significant differences between the groups (at 24 months: UAE, 29.3%, versus hysterectomy, 23.5%; p = 0.32). At 24 months the BIS score had improved in both groups compared to baseline, but the change was only significant in the UAE group (p = 0.009). In conclusion, at 24 months no differences in sexuality and body image were observed between the UAE and the hysterectomy group. On average, both after UAE and hysterectomy sexual functioning and body image scores improved, but significantly so only after UAE.

Uterine artery embolization versus hysterectomy in the treatment of symptomatic uterine fibroids: 2 years' outcome from the randomized EMMY trial.

OBJECTIVE: The purpose of this study was to compare the 2 years' efficiency of uterine artery embolization (UAE) with hysterectomy in the treatment of menorrhagia caused by uterine fibroids in a randomized controlled trial. STUDY DESIGN: Twenty-eight Dutch hospitals recruited patients with uterine fibroids and menorrhagia, who were eligible for hysterectomy. Patients were randomized to UAE or hysterectomy. The primary endpoint was if UAE could avoid a subsequent hysterectomy in at least 75% of cases. Secondary endpoints were changes in pain, bulk-related complaints, and uterine and dominant fibroid volume reduction. RESULTS: One hundred seventy-seven patients were randomized to UAE (n = 88) or hysterectomy (n = 89). Two years after treatment 23.5% of UAE patients had undergone a hysterectomy. There were no significant differences in improvement compared to baseline in pain and bulk-related complaints. Uterine and dominant fibroid volume reduction in UAE patients was 48.2% and 60.5%, respectively. CONCLUSION: UAE is a valuable alternative treatment for symptomatic uterine fibroids. Nevertheless, when patients seek for certainty on the cessation of bleeding problems, a hysterectomy remains the treatment of choice.

The feasibility of contrast-enhanced ultrasound during uterine artery embolization: a pilot study.

PURPOSE: To evaluate the feasibility of using contrast-enhanced ultrasound (CEUS) during uterine artery embolization (UAE) in order to define the correct end-point of embolization with complete devascularization of all fibroids. METHODS: In this prospective study of 10 consecutive women undergoing UAE, CEUS was performed in the angiographic suite during embolization. When the angiographic end-point, defined as the "pruned-tree" appearance of the uterine arteries was reached, CEUS was performed while the angiographic catheters to both uterine arteries were kept in place. The decision whether or not to continue the embolization was based on the findings at CEUS. The results of CEUS were compared with those of contrast-enhanced magnetic resonance imaging (MRI) 1 day as well as 3 months following UAE. RESULTS: CEUS was successfully performed in all women. In 4 cases injection of particles was continued based on the findings at CEUS despite angiographically complete embolization. CEUS imaging at completion of UAE correlated well with the findings at MRI. CONCLUSION: The use of CEUS during UAE is feasible and may increase the quality of UAE.

Spatial differences in biologic activity of large uterine leiomyomata.

OBJECTIVE: To evaluate the growth pattern of the large uterine leiomyomata (ULM), we examined the spatial gene distributions, vessel density, proliferative activity, and hyaline degeneration. DESIGN: Tissue sections from three-dimensional large ULM, matched myometrium, and small ULM were collected and microarrayed. The spatial difference of the tumor activity was mapped in large ULM. SETTING: University clinical research laboratory. PATIENT(S): Hysterectomy specimens from 7 patients with large (>10 cm) ULM and 3 patients with large (>10 cm) uterine leiomyosarcomas. INTERVENTION(S): Tissue microarray analysis by the immunohistochemistry. MAIN OUTCOME MEASURE(S): Selected gene products, vessel density, and the percentage of hyaline degeneration were all scored in tissue cores/sections of large and small ULM against matched myometrium. RESULT(S): We found that there was a spherical spatial difference of the tumor activities in large ULM. The tumor region next to the periphery, the most biologically active zone, demonstrated higher levels of gene expression, a higher density of vessels, a higher proliferative rate and a lower level of hyaline degeneration. The large ULM have higher levels of gene products (except for estrogen and progesterone receptors) than small ULM. CONCLUSION(S): In comparison of the spatial patterns of the gene activity between the large ULM and the large uterine leiomyosarcoma, the large ULM illustrate a growth pattern of nutritional dependence.

Long-term outcome of uterine artery embolization of leiomyomata.

OBJECTIVE: To determine the long-term outcome from uterine artery embolization for leiomyomata. METHODS: In a prospective study, 200 consecutive patients treated with uterine embolization were each followed for 5 years. Outcome, including symptom status compared with baseline, reinterventions, menstrual status, and satisfaction were recorded. Summary statistics were used to report baseline characteristics and outcome at each interval. Predictors of subsequent interventions, failure, and satisfaction with treatment were analyzed using logistic regression and Cox proportional hazards models. Failure was defined as subsequent hysterectomy, definitive myomectomy, repeat embolization, or failure of symptom improvement at the patient's final follow-up interval. RESULTS: Of the 200 patients initially treated, 5-year follow-up was completed in 182 (91%), with 18 patients missing. At 5 years after treatment, 73% had continued symptom control, whereas 36 (20%) had failed or recurred. There had been 25 hysterectomies (13.7%), 8 myomectomies (4.4%), and 3 repeat embolizations (1.6%). Long-term failure was more likely in those not improved at 1 year (relative risk [RR] 5.73; 95% confidence interval [CI] 2.32-14.12, P < .001) and in those with baseline leiomyoma volumes greater than the median (RR 2.18; 95% CI 1.05-4.51, P = .036). After adjustment, patients in the first tertile of leiomyoma volume reduction (< or = 30.5%) were 3 times more likely to be dissatisfied with outcome compared with women in the third tertile (> or = 56.3% volume reduction) (RR 3.23; 95% CI 1 07-9.81, P = .037). CONCLUSION: Uterine embolization provides durable symptom relief for most patients, with a 25% chance of failure of symptom control or recurrence over the course of a 5-year follow-up. LEVEL OF EVIDENCE: II-3.

Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome.

The Mendelian tumour syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis with phaeochromocytomas (HPGL) result from mutations in nuclear genes (FH and SDHB/C/D, respectively) that encode Krebs cycle enzymes. HPGL tumours are highly vascular and there is evidence that inactivation of SDH leads to activation of the hypoxia/angiogenesis pathway. In contrast, uterine leiomyomas are not generally regarded as particularly vascular lesions. In order to test the possibility that activation of the hypoxia/angiogenesis pathway contributes to tumourigenesis in HLRCC, increased vascularity and hypoxia pathway activation were searched for in HLRCC tumours. Microvessel density was markedly higher in uterine leiomyomas from HLRCC than in the surrounding myometrium; it was notable that sporadic uterine leiomyomas were actually less vascular than normal myometrium. In HLRCC tumours, there was increased expression of transcripts from the hypoxia-responsive genes vascular endothelial growth factor (VEGF) and BNIP3; sporadic uterine leiomyomas did not show these changes. All uterine leiomyomas showed decreased expression of thrombospondin 1. Although sporadic and HLRCC uterine leiomyomas appear to have identical morphology, their pathways of tumourigenesis may be fundamentally different. As is the case in HPGL, it is probable that failure of the Krebs cycle in HLRCC tumours causes inappropriate signalling that the cell is in a hypoxic state, leading to angiogenesis and perhaps directly to clonal expansion and tumour growth through some uncharacterized, cell-autonomous effect.

Gestrinone in the treatment of uterine leiomyomata: effects on uterine blood supply.

Gestrinone has been shown to reduce uterine volume and stop bleeding in women with uterine leiomyomata. In the present study, we demonstrated a reduction in the volume of uterine myomas and in the uterine artery blood perfusion over a 6-month period of gestrinone administration in premenopausal women.

Effects of gonadotropin-releasing hormone agonists on uterine volume and vasculature and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) in uterine leiomyomas.

We investigated the effect of the GnRH agonist (GnRH-a) on the uterine volume and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) and the vasculature of leiomyomas. Twenty-five women were treated with leuprorelin acetate for 3 months; 46 untreated patients were enrolled as a control group. The uterine volume was measured by ultrasonography. After myomectomy or hysterectomy, the immunoexpression of bFGF and the endothelial marker, CD34, was studied and compared in treated and untreated leiomyomas. Uterine volume decreased after therapy. The number of cells expressing bFGF and the vascularity were diminished in treated leiomyomas. Reduction in the blood supply might be responsible, in part, for uterine-volume shrinkage after GnRH-a therapy.

Uterine arterial embolization for the treatment of diffuse leiomyomatosis.

Diffuse leiomyomatosis of the uterus is an extremely rare condition and presents as a diffuse involvement of the myometrium by numerous leiomyomata. Despite patients being in only the third or fourth decades of life, all previously reported patients with this condition have undergone hysterectomy because myomectomy is impossible for this condition. Uterine arterial embolization (UAE) successfully reduced the uterine volume of diffuse leiomyomatosis without major complications in the case presented herein, and the symptoms improved remarkably. Enhanced magnetic resonance imaging after intravenous injection of gadolinium demonstrated global infarction of the vast majority of nodules.