Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma: Morphological appraisal with a comprehensive review of differential diagnoses.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts.

Diffuse Esophageal Leiomyomatosis in Pediatric Patients: A Systematic Review and Quality of Evidence Assessment.

BACKGROUND: Diffuse esophageal leiomyomatosis (DEL) is a rare disorder characterized by benign hypertrophy of esophageal smooth muscle cells. No rigorous summary of available evidence on how to best manage these patients exists. OBJECTIVE: To define the clinical features and outcomes of pediatric patients with DEL. MATERIALS AND METHODS: A systematic literature search of the PubMed and Cochrane databases was performed with respect to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (end-of-search date: October 6, 2018). The algorithm: "esophageal leiomyomatosis AND (children OR pediatric*)" was implemented. RESULTS: Thirty-five studies including a total of 58 patients were analyzed. The female:male ratio was 1.45:1. Mean patient age was 8.54 ± 4.67 years. The most common disease manifestations were dysphagia and gastrointestinal symptoms (90.0%, 95% confidence interval [CI]: 78.2-96.1), followed by failure to thrive (57.9%, 95% CI: 36.2-76.9) and pulmonary symptoms (56.4%, 95% CI: 41.0-70.7). Alport syndrome (AS) was seen in 57.7% (95% CI: 44.2-70.1) of the patients. The most commonly implemented procedure was esophagectomy (85.2%; n = 46/54; 95% CI: 73.1-92.6) with gastric transposition (37.8%; n = 17/45; 95% CI: 25.1-52.4). Postoperative complications developed in 33.3% (n = 15/45; 95% CI: 21.3-48) of the patients. All-cause mortality was 7.0% (95% CI: 2.3-17.2) and disease-specific mortality was 3.5% (95% CI: 0.3-12.6). CONCLUSION: DEL is an uncommon condition that typically occurs in the setting of AS. Esophagectomy with gastric transposition is the mainstay of treatment. Although complications develop in one-third of the patients, mortality rates are low.

One-stage surgery for removal of intravascular leiomyomatosis extending to right ventricle.

RATIONALE: Intravascular leiomyomatosis (IVL) is a rare nonmalignant tumor that can be fatal if untreated. PATIENT CONCERNS: A 49-year-old nulliparous Asian woman who underwent hysterectomy and left salpingo-oophorectomy for multiple uterine leiomyomas 18 months prior presented complaining of intermittent palpitation and chest tightness for approximately 1 month. Echocardiography revealed a large mobile tumor mass extending from the inferior vena cava (IVC) to the right atrium that partially obstructed IVC flow and tricuspid inflow. Thoracicabdominopelvic computed tomography revealed a left adnexal tumor (4.8 × 2.5 cm) causing intravascular obstruction extending from the left internal iliac vein to the IVC, right atrium, and right ventricle. DIAGNOSIS: IVL with right heart involvement INTERVENTIONS:: Under cardiopulmonary bypass, a one-stage surgery combining sternotomy and laparotomy was performed. The tumor was approached and extracted via sternotomy, and tumor detachment and removal of residual tumors was accomplished via laparotomy. OUTCOMES: A firm, smooth, and regularly shape tumor 15.5 × 5.5 × 2.5 in size was completely removed and histopathologically confirmed as IVL. The patient tolerated the surgical procedure well and no postoperative complication was noted. LESSONS: We describe a one-stage surgical approach to completely remove an IVL extending to the right ventricle.

Ulipristal acetate for pre-operative management of uterine fibroids: Modeling outcomes and costs.

OBJECTIVES: The aim of this study was to evaluate the pharmacoeconomic profile in Italy of preoperative treatment with ulipristal acetate at the dose of 5 mg/day for 13 weeks in comparison with placebo prior to surgical management of symptomatic uterine fibroids. STUDY DESIGN: The pharmacoeconomic analysis was based on the calculation of incremental cost-effectiveness ratio (ICER). Effectiveness data were derived from the randomized-controlled trial PEARL-1, whilst costs data were retrieved from the published literature. A Markov model was employed to simulate the pattern of costs and two univariate sensitivity analyses tested the robustness of the results. RESULTS: In comparison with placebo, ulipristal acetate 5 mg for presurgical therapy was estimated to be associated with an incremental cost of €351 per patient. Costs per patient were €3836 for ulipristal acetate vs €3485 for placebo. The incremental effectiveness was 0.01931 QALYs per patient (around 7 quality-adjusted days per patient). Hence, the cost effectiveness ratio was calculated to be €18,177 per QALY gained. CONCLUSIONS: Preoperative use of ulipristal acetate 5 mg in patients with uterine fibroids has a favourable pharmacoeconomic profile.

Outcome of patients with uterine fibroids after 3-month ulipristal acetate therapy.

OBJECTIVES: To determine the proportion and the characteristics of patients who did or did not respond after 3 months of ulipristal acetate (UPA) therapy. STUDY DESIGN: In this retrospective cohort study conducted in the University Hospital of Bordeaux (France) and University Medical Center Ljubljana (Slovenia), symptomatic non-menopausal patients with fibroids that qualified for surgery were pretreated by 3 months of oral UPA 5 mg/day. Clinical success was defined by normalization of the bleeding score, and/or regression of pelvic pain, and/or abdominal distension. Imaging success was defined by reduction in fibroid volume ≥ 25%. RESULTS: The clinical and imaging success rates were 54/66 (82%) and 39/66 (59%) respectively. The absence of previous pregnancy (p = 0.004) and the size of the dominant fibroid ≥ 80 mm (p = 0.004) were independent factors associated with clinical failure. Age <35 years (p = 0.02) was the only independent factor associated with imaging failure. CONCLUSION: Young women developing fibroids and/or women with large fibroids may be resistant to ulipristal acetate therapy.

A Novel Diagnostic Strategy Using 16α-[18F]-Fluoro-17-ß-Estradiol (18F-FES) PET/MRI to Achieve Complete Resection of Intravenous Leiomyomatosis in Reproductive-Age Women.

Intravenous leiomyomatosis is a life-threatening leiomyoma that grows into the extrauterine venous system. A high recurrence rate has been reported in reproductive-age women who undergo only tumor excision to preserve fertility. Precise diagnosis of tumor extension is essential to achieve complete resection. A 24-year-old woman presented with hypermenorrhea. Contrast-enhanced MRI showed an intramural myoma with worm-like extension into the right parametrium. F-FES PET/MRI accurately depicted the extension with strong FES activity into the right uterine vein, whereas F-FDG PET/MRI excluded the possibility of malignancy. These modalities can be a novel strategy to manage such cases of intractable intravenous leiomyomatosis.

Intracardiac Leiomyomatosis - an Unusual Cause of Syncope in a Middle-Aged Woman.

Intracardiac leiomyomatosis is a rare complication that occurs when a uterine leiomyoma (fibroid) undergoes vascular invasion and propagates within the inferior vena cava to reach the right atrium. This article describes a case of intracardiac leiomyomatosis in a middle-aged woman, exploring the presentation, diagnosis and surgical management of this condition. In this case the presenting complaints were syncope and atrial fibrillation, illustrating the importance of performing a transthoracic echocardiogram in patients presenting with their first episode of atrial fibrillation. Clinicians should consider intracardiac leiomyomatosis when evaluating women with right heart masses, especially those with a history of uterine leiomyomas.

Real world data of 1473 patients treated with ulipristal acetate for uterine fibroids: Premya study results.

OBJECTIVES: To characterize and describe treatment with Ulipristal acetate (UPA) in a pre-operative setting and to evaluate the safety, effectiveness, and Health Related Quality of Life (HRQoL) outcomes in a population treated according to standard clinical practice in the EU. STUDY DESIGN: Multi-centre, prospective, non-interventional study (PREMYA) of patients diagnosed with moderate to severe symptoms of uterine fibroids and undergoing a pre-operative treatment with UPA (Esmya®) at 73 clinical practice sites within the EU. Patients were followed during UPA treatment and for 12 months after treatment discontinuation for a total of 15 months follow-up. Data was collected every 3 months in accordance with standard care visits. RESULTS: A total of 1568 women were enrolled, of whom 1473 were found to be eligible for data analysis. Only 38.8% of patients underwent surgery, of which the majority were of a conservative/minimally invasive nature. Physicians' assessments of patients' overall symptomatic change, as measured on the Clinical Global Impression-Improvement (CGI-I) scale, indicated that 60% of patients were much improved or very much improved at 3 months. Pain and quality of life after treatment cessation remain lower than baseline during the entire period of follow-up CONCLUSIONS: The majority of patients do not undergo surgery immediately after treatment cessation. Quality of life and pain are highly improved by Esmya® treatment.

Single or repeated gonadotropin-releasing hormone agonist treatment avoids hysterectomy in premenopausal women with large symptomatic fibroids with no effects on sexual function.

AIM: The aim of our study was to explore the effects on symptoms and female sexual function of the medical management with gonadotropin-releasing hormone agonist (GnRHa) in women of more than 45 years old compared to surgical management. METHODS: Women with symptomatic uterine fibroids were enrolled to participate to the present open-label study. We offered two different treatment options: medical with GnRHa for 6 months (group A) or hysterectomy (group B). The patients were reviewed in follow-up for 24 months. The impact of medical or surgical therapy on sexual life was evaluated. RESULTS: No significant differences were found in population characteristics between the two groups. GnRHa treatment was efficient in reducing symptoms in 88% of patients but 22% of patients needed adjunctive cycles of medical therapy. After 24 months, 16% of the patients did not complete the study. The failure percentage of the medical treatment was 12%. No severe side-effects were recorded, and eight patients had reached menopause. No significant differences were observed in the Female Sexual Function Index score in each domain between the medical and surgical groups, with total scores of 18.94 ± 10.16 and 22.00 ± 8.86, respectively (mean ± standard deviation), and the prevalence of dysfunction was 12% and 22%, respectively, similar to the general population of the same age. CONCLUSION: We found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids in women of more than 45 years old.

The opioid neuropeptides in uterine fibroid pseudocapsules: a putative association with cervical integrity in human reproduction.

The myoma pseudocapsule (MP) is a fibro-vascular network rich of neurotransmitters, as a neurovascular bundle, surrounding fibroid and separating myoma from myometrium. We investigated the distribution of the opioid neuropeptides, as enkephalin (ENK) and oxytocin (OXT), in the nerve fibers within MP and their possible influence in human reproduction in 57 women. An histological and immunofluorescent staining of OXT and ENK was performed on nerve fibers of MP samples from the fundus, corpus and isthmian-cervical regions, with a successive morphometric quantification of OXT and ENK. None of the nerve fibers in the uterine fundus and corpus MPs contained ENK and the nerve fibers in the isthmian-cervical region demonstrated an ENK value of up to 94 ± 0.7 CU. A comparatively lower number of OXT-positive nerve fibers were found in the fundal MP (6.3 ± 0.8 CU). OXT-positive nerve fibers with OXT were marginally increased in corporal MP (15.0 ± 1.4 CU) and were substantially higher in the isthmian-cervical region MP (72.1 ± 5.1 CU) (p < 0.01). The distribution of OXY neurofibers showed a slight into the uterine corpus, while are highly present into the cervico-isthmic area, with influence on reproductive system and sexual disorders manifesting after surgical procedures on the cervix.

Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma.

Uterine leiomyomas are the most common benign gynecologic condition. The prevalence is three times more common among women of African ethnicity. Disparity in this disease is evidenced by earlier age of onset, greater severity of symptoms, and different response to treatment. Although the pathogenesis of disease development is not completely known, growing evidence focuses on investigating the molecular mechanisms in disease development and the influence of ethnicity. Variation in the expression levels or function of estrogen and progesterone receptors, polymorphism of genes involved in estrogen synthesis and/or metabolism (COMT, CYP17), retinoic acid nuclear receptors (retinoid acid receptor-α, retinoid X receptor-α), and aberrant expression of micro-RNAs (miRNAs) are some of the molecular mechanisms that may be involved. Nutritional factors, such as vitamin D deficiency, might also contribute to the higher incidence in dark skinned populations who are also commonly suffer from hypovitaminosis D. Culture and environmental difference might have a role in disease development. Further analysis and better understanding of these mechanisms will provide insight into the molecular basis of racial disparities in leiomyoma formation and will help to develop new innovations in leiomyoma treatment.