Immunohistochemical Markers in Endometrial Cancer: Latest Updates.

Ten years ago, The Cancer Genome Atlas (TGCA) Research Network classified endometrial cancer into four molecular categories with prognostic significance, suggesting sensitivity to postsurgical treatments [...].

Effective Surgical Management of a Large Serous Ovarian Cyst in a Morbidly Obese Middle-Aged Woman: A Case Study and Literature Review.

BACKGROUND In contemporary gynecological practice, encountering giant ovarian tumors is a rarity. While most are benign and of the mucinous subtype, the borderline variant only accounts for approximately 10% of these cases. This paper addresses the paucity of information about this specific subtype, emphasizing critical elements of managing borderline tumors that can pose life-threatening complications. Additionally, a review of other documented cases of the borderline variant in the literature is also included to foster a deeper understanding of this uncommon condition. CASE REPORT We present the multidisciplinary management of a 52-year-old symptomatic woman with a giant serous borderline ovarian tumor. Preoperative assessment showed a multiloculated pelvic-abdominal cyst responsible for compression of the bowel and retroperitoneal organs, and dyspnea. All tumor markers were negative. Together with anesthesiologists and interventional cardiologists, we decided to perform a controlled drainage of the cyst of the tumor, to prevent hemodynamic instability. Subsequent total extrafascial hysterectomy, contralateral salpingo-oophorectomy, and abdominal wall reconstruction, followed by admission to the intensive care unit, were also conducted by the multidisciplinary team. During the postoperative period, the patient experienced a cardiopulmonary arrest and acute renal failure, which were managed by dialysis. After discharge, the patient underwent oncologic followup, and after 2 years, she was found to be completely recovered and disease free. CONCLUSIONS Intraoperative controlled drainage of Giant ovarian tumor fluid, planned by a multidisciplinary management team, constitutes a valid and safe alternative to the popular choice of "en bloc" tumor resection. This approach avoids rapid changes in body circulation, which are responsible for intraoperative and postoperative severe complications.

HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review.

Low-grade stage I endometrioid endometrial carcinomas should have an excellent prognosis, but a small subset of these cancers can relapse. The search for putative immunohistochemical prognostic markers for relapse in low-risk/low-grade endometrioid endometrial cancers remains open. Among the candidate molecules that may implicate the roles of immunohistochemical risk markers, we focused our attention on human epididymis protein 4 (HE4) after a review of the literature. Few authors have devoted themselves to this topic, and none have found a correlation between the tissue expression of HE4 and the molecular classification of endometrial cancer. Five different variants of HE4 mRNA and multiple protein isoforms of HE4 were identified many years ago, but current HE4 assays only measure the total HE4 expression and do not distinguish the different proteins encoded by different mRNA variants. It is important to have an approach to distinguish specific variants in the future.

New Analytical Approach for the Alignment of Different HE4 Automated Immunometric Systems: An Italian Multicentric Study.

Human epididymal secretory protein 4 (HE4) elevation has been studied as a crucial biomarker for malignant gynecological cancer, such us ovarian cancer (OC). However, there are conflicting reports regarding the optimal HE4 cut-off. Thus, the goal of this study was to develop an analytical approach to harmonize HE4 values obtained with different laboratory resources. To this regard, six highly qualified Italian laboratories, using different analytical platforms (Abbott Alinity I, Fujirebio Lumipulse G1200 and G600, Roche Cobas 601 and Abbott Architett), have joined this project. In the first step of our study, a common reference calibration curve (designed through progressive HE4 dilutions) was tested by all members attending the workshop. This first evaluation underlined the presence of analytical bias in different devices. Next, following bias correction, we started to analyze biomarkers values collected in a common database (1509 patients). A two-sided p-value < 0.05 was considered statistically significant. In post-menopausal women stratified between those with malignant gynecological diseases vs. non-malignant gynecological diseases and healthy women, dichotomous HE4 showed a significantly better accuracy than dichotomous Ca125 (AUC 0.81 vs. 0.74, p = 0.001 for age ≤ 60; AUC 0.78 vs. 0.72, p = 0.024 for age > 60). Still, in post-menopausal status, similar results were confirmed in patients with malignant gynecological diseases vs. patients with benign gynecological diseases, both under and over 60 years (AUC 0.79 vs. 0.73, p = 0.006; AUC 0.76 vs. 0.71, p = 0.036, respectively). Interestingly, in pre-menopausal status women over 40 years, HE4 showed a higher accuracy than Ca125 (AUC 0.73 vs. 0.66, p = 0.027), thus opening new perspective for the clinical management of fertile patients with malignant neoplasms, such as ovarian cancer. In summary, this model hinted at a new approach for identifying the optimal cut-off to align data detected with different HE4 diagnostic tools.

PAX8 Positivity, Abnormal p53 Expression, and p16 Negativity in a Primary Endometrial Squamous Cell Carcinoma: A Case Report and Review of the Literature.

Primary endometrial squamous cell carcinoma (PESCC) is a rare entity. As the clinicopathologic features and the immunophenotype have not been completely defined yet, here we report our experience and review of the literature on this topic. A 73-yr-old nulliparous woman presented with pelvic pain and vaginal bleeding. Endometrial biopsy showed a carcinoma with squamous differentiation infiltrating the myometrium. Total hysterectomy with bilateral salpingo-oophorectomy and selective pelvic lymphadenectomy was performed. Definitive diagnosis was squamous carcinoma of the endometrium, with one lymph node metastasis (stage IIIC1). Immunohistochemistry evidenced immunoreactivity of the tumor cells for cytokeratin 5, p63, cytokeratin 7, PAX8, PTEN, and cyclin D1, aberrant p53 overexpression, and Ki-67 reactivity in ~70% of the tumor cells. Estrogen and progesterone receptor, PAX2, WT1, and p16 were negative. Our case was the first PAX8-positive PESCC in the literature, underlining the Mullerian system origin of this neoplasm. Abnormal p53 expression of this case confirmed its role in the pathogenesis of PESCC. Further studies on a large number of cases are needed to better understand the pathologic features and the immunophenotype of PESCC.

Immunohistochemical Markers in Endometrial Cancer.

In 2018, 382,069 new cases of uterine cancer were registered worldwide and 89,929 deaths from this cancer were reported [...].

What women want: Fertility sparing surgery in Borderline ovarian tumours patients and pregnancy outcome.

OBJECTIVE: Borderline ovarian tumours (BOTs) are characterized by the presence of cellular proliferation and nuclear atypia without stromal invasion. Compared to malignant ovarian tumours, BOTs have better prognoses. The most important treatment of BOT is surgery. Considering the good prognosis of BOT, fertility-sparing surgery (FSS) can be considered for young women who desire to preserve fertility. Our study evaluated the pregnancy rate in patients with childbearing desire, the efficacy and risk of recurrence of women affected by BOTs who have undergone FSS. MATERIALS AND METHODS: Patients characteristics have been restrospectively retrieved for diagnosis made from June 2000 to December 2017 from San Raffaele Hospital and Policlinico Cagliari. Patients underwent FSS for BOT were interviewed about child wishing and pregnancy outcomes. RESULTS: 85 patients were recruited for the study. Median age at diagnosis was 33 years. Unilateral salpingo-oophorectomy was performed in 33 patients (38%), unilateral cystectomy in 40 (47%) and 12 underwent both procedures (14%). 40 women (50%) tried to conceive after surgery. The pregnancy rate was 73% and live birth rate was 67%. Childbearing desire and age at diagnosis were significantly associated with the pregnancy rate. CONCLUSIONS: Conservative surgical treatment seems to be a reasonable therapeutic option for women with BOTs who wish to preserve fertility. Our results suggest that the obstetric outcomes after FSS are promising. Maternal desire and the age of diagnosis are the most important factors affecting PR after surgery. Fertility counselling should be an integral part of the clinical management of women with BOT.

Feasibility of hand-assisted laparoscopic sentinel node biopsy in open endometrial cancer surgery.

Background: The aim of this preliminary retrospective study was to assess the feasibility and accuracy of Indocyanine Green (ICG) sentinel node (SLN) sampling using a laparoscopic camera during open endometrial cancer surgery.Material and methods: Retrospective study. Fourteen women with endometrial cancer, not fit for a complete laparoscopic staging, underwent SLN mapping using the IMAGE1 camera during open surgery.Results: The median age of patients was 67 (range 33-86) years. Median BMI was 31 (range 23-58). Mean operative time 157.5 minutes and hospital stay three days. The overall detection rate of SLN mapping was 93%. Bilateral detection was 86%. No post-operative short or long-term complications were observed.Conclusions: Real-time NIR technology supported by the IMAGE1 S is a reliable system and represents a promising method for SLN mapping in selected cases with EC and severe surgical risks, during 48 traditional open approaches. The use of laparoscopy ICG in open surgery seems to be a feasible and useful tool for the detection of SLN in endometrial cancer patients with intraoperative and/or postoperative high morbidity risk. It represents a valid alternative to robotic surgery, particularly in countries and centers where the robotic platform or SPY system for open surgery are not available.

New Keystone flap application in vulvo-perineal reconstructive surgery: A case series.

OBJECTIVE: This study aimed to evaluate the application of the Keystone flap technique and the long-term results of vulvovaginal reconstruction after vulvar surgery. METHODS: This is the first case series describing the application of the Keystone perforator island flaps (KPIF) technique to close a wide defect after radical vulvectomy. We prospectively collected patient demographics, operative times, complications, pathologic results, and length of stay on all patients. The benefits, cosmetic results and satisfaction of patients were analyzed in the follow up. RESULTS: Five patients were selected for the study: four underwent radical vulvectomy for squamous cell vulvar cancer, and one underwent vulvar wide excision for Paget disease followed by reconstruction with the Keystone flap technique. The defects were successfully covered by the Keystone flap technique in all patients. CONCLUSIONS: Keystone flaps seem to be easy to design and elevate, and it offers rapid fasciocutaneous closure in wide vulvo-perineal defects with excellent long-term results.

Clinical Utility Of Elagolix As An Oral Treatment For Women With Uterine Fibroids: A Short Report On The Emerging Efficacy Data.

Uterine fibroids (UFs) are the most common gynaecological benign disease. Even though often asymptomatic, UFs can worsen women's health and their quality of life, causing heavy bleeding and anaemia, pelvic discomfort and reduced fertility. Surgical treatment of UFs could be limited by its invasiveness and the desire to preserve fertility. Thus, effective medical therapies for the management of this condition are needed. Common drugs used to control bleeding, such us hormonal contraceptive or levonorgestrel-releasing intrauterine system, have no effect on fibroids volume. Among other more efficient treatments, the gonadotropin-releasing hormone (GnRH) agonist or the selective progesterone-receptor modulators have a non-neutral safety profile; thus, they are used for limited periods or for cyclic treatments. Elagolix is a potent, orally bioavailable, non-peptide GnRH antagonist that acts by a competitive block of the GnRH receptor. The biological effect is a dose-dependent inhibition of gonadal axis, without a total suppression of estradiol concentrations. For this reason, even though comparative studies between elagolix and GnRH agonists have not been performed, elagolix has been associated with a better profile of adverse events. Recently, elagolix received US FDA approval for the treatment of moderate to severe pain caused by endometriosis. Several clinical trials assessed the efficacy of elagolix for the treatment of heavy bleeding caused by UFs and the definitive results of Phase III studies are expected. Available data on elagolix and UFs showed that the drug, with or without low-dose hormone add-back therapy, is able to significantly reduce menstrual blood loss, lead to amenorrhea and improve haemoglobin concentrations in the majority of participants in comparison with placebo. The safety and tolerability profile appeared generally acceptable. The concomitant use of add-back therapy can prevent bone loss due to the hypoestrogenic effect and can improve safety during elagolix treatment.

Systemic therapy for the treatment of endometrial cancer.

Introduction: Endometrial cancer (EC) is one of the most frequent gynecological cancers worldwide. The gold standard treatment of EC is most certainly surgery and may very well be the only therapy in the early stages of disease. To improve outcomes in non-early EC, adjuvant therapy is often employed but this is not standardized. Adjuvant options can include radiotherapy, chemotherapy or a combination of both. Adjuvant chemotherapy could be indicated in high-risk stage I and II or advanced stage EC. Several clinical trials are ongoing in an attempt to define the optimal adjuvant treatment. Furthermore, chemotherapy is the front-line therapy in advanced unresectable, metastatic or recurrent endometrial cancer. Areas covered: Herein, the authors review the first-line chemotherapy for the treatment of endometrial cancer and provide their expert perspectives on these therapies. Expert opinion: Chemotherapy is fundamental in advanced/recurrent EC. Further evidence is needed to characterize the role of adjuvant chemotherapy. Future studies should consider genomic and molecular heterogeneities to identify even more efficient tailored therapies.

Repeated two cycles of ulipristal acetate treatment improve the quality of life in premenopausal women with heavy menstrual bleeding dependent on uterine myomas, without impairment of bone health.

This observational study was conducted in premenopausal women who presented themselves at the Obstetrics and Gynecology Department of the University Hospital of Cagliari (Italy), for heavy menstrual bleeding (HMB) dependent on uterine myomas. After a screening visit, 19 women without contraindications to ulipristal acetate (UPA) treatment, were included in the study that envisaged 12 months of observation in which each subject was asked to assume UPA (tablet of 5 mg, ESMYA®, one tablet a day for 3 months: first cycle) two menstrual cycles of interruption and a second ESMYA® cycle, followed by 3 months of observation (third follow-up month, visit 4). The significant decrease of myoma volume, diagnosed after the first ESMYA® cycle, persisted until the visit 4. The HMB significantly decreased during the ESMYA® treatment and persisted until visit 4. The quality of life (QoL), evaluated with the questionnaire SF-36, significantly improved during the study. The values of estradiol (E2), biochemical parameters of bone metabolism, as well as those of lumbar and hip bone mineral density, did not change during the study in comparison with basal levels. The efficacy of two repeated ESMYA® cycles to treat uterine myomas and their related symptoms improves the QoL without interfering with bone health.

Conservative treatment for well-differentiated endometrial cancer: when and why it should be considered in young women.

The aim of this review was to update current knowledge on the conservative treatment of endometrial cancer (EC) based on a literature review. A web-based search in the MEDLINE database was carried out on EC management and treatment. All relevant information has been collected and analysed. Case series were mainly found in the literature search. Conservative treatments were offered to young patients with stage I low-grade endometrioid carcinomas of the endometrium. Different options included high/low dose progestin treatments, hysteroscopic resection of the disease, a levonorgestrel intrauterine device or a combination of various strategies. The overall complete response rate was near 76.5% with a recurrence rate of up to 33.8%. Pregnancy outcomes reached rates of 64.8% for live births. The current clinical outcomes show that conservative treatment aimed at preserving fertility is feasible for stage I endometrial well-differentiated adenocarcinomas in motivated patients under close monitoring.

Investigational drugs for the treatment of endometriosis, an update on recent developments.

INTRODUCTION: Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis. AREAS COVERED: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents. EXPERT OPINION: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human.

Vilaprisan for treating uterine fibroids.

INTRODUCTION: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs's action is tissue-specific and it depends on the particular affinity and strength of each SPRM. Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids. Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding.

Deep Infiltrating Endometriosis: Comparison Between 2-Dimensional Ultrasonography (US), 3-Dimensional US, and Magnetic Resonance Imaging.

OBJECTIVES: To evaluate the diagnostic accuracy of 2-dimensional (2D) and 3-dimensional (3D) transvaginal ultrasonography (US) in comparison with magnetic resonance imaging (MRI) for identification of deep infiltrating endometriosis. METHODS: In this prospective observational study, 159 premenopausal women who underwent surgery for a clinical suspicion of deep infiltrating endometriosis were prospectively enrolled. All women underwent 2DUS, 3DUS, and MRI. The following 3 locations of deep endometriosis were considered: (1) intestinal; (2) other posterior lesions (retrocervical septum, rectovaginal septum, uterosacral ligaments, and vaginal fornix); and (3) anterior. The sensitivity, specificity, positive predictive value, and negative predictive value of 2D and 3D transvaginal US in comparison with MRI were determined. RESULTS: Intestinal deep infiltrating endometriosis was identified by 2DUS in 56 of 66 patients, by 3DUS in 59 of 66, and by MRI in 61 of 66. A receiver operating characteristic curve analysis showed optimal results for 2DUS, 3DUS, and MRI (areas under the curve, 0.86, 0.915, and 0.935, respectively) with a statistically significant difference between 2DUS and MRI (P = .0103), even when the 95% confidence interval showed an overlap. Other posterior deep infiltrating endometriosis was identified by 2DUS in 55 of 75 patients, by 3DUS in 65 of 75, and by MRI in 66 of 75. A receiver operating characteristic curve analysis showed very good results for 2DUS, 3DUS, and MRI (areas under the curve, 0.801, 0.838, and 0.857) with no statistically significant differences. In the 12 women with deep infiltrating endometriosis in the anterior location, the nodules were correctly identified by 2DUS in 3 of 12 patients, by 3DUS in 5 of 12, and by MRI in 6 of 12. CONCLUSIONS: Our results seem to suggest that there is a statistically significant difference between 2DUS and MRI for the intestinal location of deep infiltrating endometriosis, whereas no differences were found among the techniques for the other locations.

The Improvement of Laparoscopic Surgical Skills Obtained by Gynecologists after Ten Years of Clinical Training Can Reduce Peritoneal Adhesion Formation during Laparoscopic Myomectomy: A Retrospective Cohort Study.

OBJECTIVE: To evaluate if improvement of laparoscopic skills can reduce postoperative peritoneal adhesion formation in a clinical setting. STUDY DESIGN: We retrospectively evaluated 25 women who underwent laparoscopic myomectomy from January 1993 to June 1994 and 22 women who underwent laparoscopic myomectomy from March 2002 to November 2004. Women had one to four subserous/intramural myomas and received surgery without antiadhesive agents or barriers. Women underwent second-look laparoscopy for assessment of peritoneal adhesion formation 12 to 14 weeks after myomectomy. Adhesions were graded according to the Operative Laparoscopy Study Group scoring system. The main variable to be compared between the two cohorts was the proportion that showed no adhesions at second-look laparoscopy. RESULTS: Demographic and surgical characteristics were similar between the two cohorts. No complications were observed during surgery. No adverse events were recorded during postoperative course. At second-look laparoscopy, a higher proportion of adhesion-free patients was observed in women who underwent laparoscopic myomectomy from March 2002 to November 2004 (9 out of 22) compared with women who underwent the same surgery from January 1993 to June 1994 (3 out of 25). CONCLUSION: The improvement of surgeons' skills obtained after ten years of surgery can reduce postoperative adhesion formation.

Peritoneal adhesions after laparoscopic gastrointestinal surgery.

Although laparoscopy has the potential to reduce peritoneal trauma and post-operative peritoneal adhesion formation, only one randomized controlled trial and a few comparative retrospective clinical studies have addressed this issue. Laparoscopy reduces de novo adhesion formation but has no efficacy in reducing adhesion reformation after adhesiolysis. Moreover, several studies have suggested that the reduction of de novo post-operative adhesions does not seem to have a significant clinical impact. Experimental data in animal models have suggested that CO2 pneumoperitoneum can cause acute peritoneal inflammation during laparoscopy depending on the insufflation pressure and the surgery duration. Broad peritoneal cavity protection by the insufflation of a low-temperature humidified gas mixture of CO2, N2O and O2 seems to represent the best approach for reducing peritoneal inflammation due to pneumoperitoneum. However, these experimental data have not had a significant impact on the modification of laparoscopic instrumentation. In contrast, surgeons should train themselves to perform laparoscopy quickly, and they should complete their learning curves before testing chemical anti-adhesive agents and anti-adhesion barriers. Chemical anti-adhesive agents have the potential to exert broad peritoneal cavity protection against adhesion formation, but when these agents are used alone, the concentrations needed to prevent adhesions are too high and could cause major post-operative side effects. Anti-adhesion barriers have been used mainly in open surgery, but some clinical data from laparoscopic surgeries are already available. Sprays, gels, and fluid barriers are easier to apply in laparoscopic surgery than solid barriers. Results have been encouraging with solid barriers, spray barriers, and gel barriers, but they have been ambiguous with fluid barriers. Moreover, when barriers have been used alone, the maximum protection against adhesion formation has been no greater than 60%. A recent small, randomized clinical trial suggested that the combination of broad peritoneal cavity protection with local application of a barrier could be almost 100% effective in preventing post-operative adhesion formation. Future studies should confirm the efficacy of this global strategy in preventing adhesion formation after laparoscopy by focusing on clinical end points, such as reduced incidences of bowel obstruction and abdominal pain and increased fertility.