Expression patterns of HDAC6 in correlation to ARID1A status in different subtypes of endometriosis: A retrospective tissue microarray analysis.

Endometriosis is a disease affecting approximately 10% of reproductive age women. Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) occurs in some endometriosis cases. Histone deacetylase 6 (HDAC-6) is an enzyme with implication in several diseases including different cancer types and immunological disorders, where it is involved in protein trafficking and degradation, cell shape, and migration. In ARID1A-deficient ovarian cancer increased HDAC-6 expression lead to apoptosis-inhibiting post-translational modification of p53. It is not known if HDAC-6 expression is also altered in ARID1A-deficient endometriosis. The aim of this study was to assess HDAC-6 expression in endometriotic lesions in correlation to ARID1A-status. Two tissue-microarrays with 168 endometriotic lesions, including ovarian (64/168, 38 %), peritoneal (66/168, 39 %) and deep-infiltrating (38/168, 23 %) subtypes, and 73 endometrium of women without endometriosis were assessed. Mean ARID1A immunoreactivity score (IRS) in endometriosis group was 10.83 (±2.36) and 10.78 (±1.94) in the epithelium and stroma, respectively, while the respective mean HDAC6 IRS were 9.16 (±2.76) and 5.94 (±2.88). The comparison of the HDAC6 expression between endometriosis subtypes showed higher expression in deep-infiltrating endometriosis, in both, epithelium (p = 0.032) and stroma (p = 0.007). In ARID1A negative cases, epithelial expression of HDAC6 was higher in endometriosis compared to women without endometriosis (p = 0.031), and this was also specifically observed in the subset of ovarian endometriosis (p = 0.037). There were no significant differences in the stromal expression of HDAC6. In conclusion, our results demonstrate a complex expression pattern of HDAC6 depending on ARID1A status in different endometriosis subtypes. Further studies on HDAC6 and ARID1A are important to elucidate mechanisms involved in malignant transformation of endometriosis.

The Visual Effect of a Down-Regulation With Dienogest and GnRH Analogues in Endometriosis: Lessons Learned From Two-Step Surgical Approach.

OBJECTIVE: To evaluate the intraoperative visual effect of treatment with GnRH-analogues and Dienogest in endometriosis. DESIGN: Retrospective observational study. SETTING: Every laparoscopy from all the different disciplines in our hospital is documented on video and stored in a database. The study was approved by the local ethics committee. A total of 193 patients with histological proven endometriosis from 2007 to 2021 were included, who underwent 2-step surgical procedure. Indications were endometrioma before CO2-Laser therapy, missing consent because of emergencies or other surgeries from other disciplines, or high active and extended disease. When endometriosis was suspected in a surgery conducted by other disciplines, a gynecological surgeon was called during the surgery. Data and intraoperative videos were reviewed by 2 independent reviewers at one referral center. Only cases with available video of first and second look laparoscopy were included. We excluded patient who had prior hormonal treatment in the last 6 months. Lesions were classified according to the description of Khan et al. Statistical analysis was performed using SPSS (Version 27.0, IBM). Mann-Whitney U test (nonparametric analysis) and χ2 tests were applied. Percentages were calculated for categorical variables and mean and standard deviation were calculated for continuous variables. Significance level was set to p <.05. INTERVENTIONS: Seventy-seven received GnRH-analogues and 116 Dienogest for preoperative hormone down-regulation. The median duration of down-regulation with GnRH-analogues or Dienogest was 3 months. The mean age was 32.3 (SD 6.3) years for GnRH-analogues and 32.6 (SD 6.3) years for Dienogest, p = .619 respectively. The visible intraoperative effect will be demonstrated in the video. CONCLUSION: The effect of a hormonal treatment can be observed macroscopically in endometriosis. This can help to understand the in vivo response to the administrated treatment. This video is showing our past experience, as performing second-look laparoscopy is not state of the art anymore.

Co-Existence of Endometriosis with Ovarian Dermoid Cysts: A Retrospective Cohort Study.

Both endometriosis and ovarian dermoid cysts are benign conditions characterized by the presence of well-differentiated tissues in ectopic locations. The presence and surgical excision of these entities can potentially impact ovarian reserves, contributing to reduced chances of future pregnancy. The objective of our study is to investigate the bidirectional association between endometriosis and ovarian dermoid cysts, as well as to analyze the clinical characteristics of patients diagnosed with both conditions. A retrospective cohort study was conducted, including women who underwent laparoscopy and received histological diagnoses of endometriosis and/or dermoid cysts between 2011 and 2019 at the Cantonal Hospital of Schaffhausen. We identified 985 women with endometriosis and 83 women with ovarian dermoid cysts. Among these groups, 22 women presented with both endometriosis and ovarian dermoid cysts. The majority of the above patients had endometriosis stage rASRM I-II (72.7%), with peritoneal endometriosis being the most common phenotype of endometriosis (77.2%). Out of the 14 patients with a desire for future pregnancy, the majority (11/14, 78.5%) had an EFI score of 7-8. The prevalence of bilateral ovarian dermoid cysts was higher in women with both ovarian dermoid cysts and endometriosis in comparison to women with ovarian dermoid cysts without endometriosis (18% vs. 6.5%). Our study revealed that 26.5% of women with ovarian dermoid cysts also had endometriosis, a notably higher prevalence than observed in the general population. Clinicians should be aware of this co-existence, and preoperative counseling should be an integral part of the care plan for affected individuals, where the potential risks and the available options for fertility preservation should be discussed in detail.

Treatment after endometrioma recurrence: a narrative review.

INTRODUCTION: Ovarian endometrioma is a common subtype of endometriosis with a prevalence between 17 and 44%. The reported average recurrence of endometrioma after surgical management is 21.5% after 2 years and 40-50% after 5 years. The aim of this narrative review was to summarize the existing literature focusing on treatment options after endometrioma recurrence in order to provide an evidence-based approach for the clinical practice. EVIDENCE ACQUISITION: Three electronic databases (MEDLINE, EMBASE and Cochrane) were searched until September 2022 for eligible studies. EVIDENCE SYNTHESIS: The available studies showed that repeated surgery has a negative impact on ovarian function, without improving the fertility outcomes. Transvaginal aspiration as an alternative option for surgery has a high rate of recurrence, which varies from 8.20 to 43.5% depending on the technique used and on the study population. Pregnancy related outcomes were similar between transvaginal aspiration groups and no intervention groups in patients with endometrioma recurrence. Regarding medical treatments, only four studies were found, showing that progestins reduce the pain and the diameter of the ovarian cyst. CONCLUSIONS: Recurrent endometrioma is a challenging condition which could be encountered during the care of women with endometriosis. The decision about the treatment-strategy has to be individualized considering family planning status, age, ovarian reserve and transvaginal ultrasound findings. Well-designed randomized clinical trials are needed to export safer conclusions about the most appropriate treatment in each specific condition after endometrioma recurrence.

The immunohistochemical expression of GPER and classical sex hormone receptors differs in adenomyosis and eutopic endometrium.

G protein-coupled estrogen receptor (GPER) has been found to be an important key regulator in the homeostasis of sex hormone-dependent human cells. The aim of this study was to compare the expression of GPER, estrogen receptor alpha (ER-α), estrogen receptor beta (ER-ß) and progesterone receptor (PR) in adenomyosis, eutopic endometrium from the same patients, and eutopic endometrium from patients without adenomyosis. Immunohistochemical analysis of GPER, ER-α, ER-ß and PR was performed to assess the expression levels on samples of hysterectomies using tissue microarrays. 73 adenomyotic tissue probes and corresponding eutopic endometrial specimens, as well as 48 samples of eutopic endometrial control specimens from patients without adenomyosis were included in this study. Mean age of the women with adenomyosis was 51.7 (SD ± 11.1) and 65.8% were premenopausal. We found a higher nuclear stromal expression of GPER in eutopic endometrium of patients with adenomyosis in comparison to control endometrium (p < 0.001). Comparing adenomyosis to eutopic endometrium of patients with adenomyosis and to control, there was a lower expression of nuclear GPER in epithelial cells (p < 0.001 and p = 0.048, respectively). Lower epithelial nuclear ER-α in adenomyosis and higher epithelial nuclear ER-ß in eutopic endometrium of patients with adenomyosis was found in comparison to control endometrium (p = 0.008 and p = 0.017, respectively). This study showed a significant difference in the immunohistochemical expression of GPER in adenomyosis compared to eutopic endometrium of the same patients and to endometrium of control group. GPER in adenomyosis may be a potential therapeutic target for selective agonists and antagonists.

Intraoperative Appearance of Endosalpingiosis: A Single-Center Experience of Laparoscopic Findings and Systematic Review of Literature.

Background: Endosalpingiosis is assumed to be the second most common benign peritoneal pathology after endometriosis in women. Although recent studies indicate a significant association with gynecologic malignancies, many underlying principles remain unclear. This work aimed to systematically describe the intraoperative appearance of endosalpingiosis. Methods: Data and intraoperative videos of patients with histologically verified endosalpingiosis were retrospectively reviewed. The main outcome measures were macroscopic phenotype and anatomical distribution. Additionally, a systematic review searching PubMed (Medline) and Embase was conducted. Results: In the study population (n = 77, mean age 40.2 years (SD 16.4)), the mean size of lesions was 3.6 mm and the main visual pattern was vesicular (62%). The most frequent localization was the sacrouterine ligaments (24.7%). In the systematic review population (n = 1174 (210 included studies overall), mean age 45.7 years (SD 14.4)), there were 99 patients in 90 different studies with adequate data to assess the appearance of the lesions. The mean size of the lesions was 48.5 mm, mainly with a cystic visual pattern (49.5%). The majority of the lesions affected the ovaries (23.2%), fallopian tubes (20.4%), or lymph nodes (18.5%). Comparing this study to the literature population, the main differences concerned the size (p < 0.001) and main visual patterns (p < 0.001) of lesions. Conclusions: The usual intraoperative findings of endosalpingiosis appeared less impressive than described in the literature. In our study population, lesions of a few millimeters in size with a vesicular appearance were mostly seen, most frequently in the sacrouterine ligament area. Intraoperative recognition by the gynecologic surgeon and histologic diagnosis should play an important role in further understanding this entity, scientifically and clinically.

Prospective Multicenter Trial Assessing the Impact of Positive Peritoneal Cytology Conversion on Oncological Outcome in Patients with Endometrial Cancer Undergoing Minimally Invasive Surgery with the use of an Intrauterine Manipulator : Positive Peritoneal Cytology Conversion and Its Association with Oncological Outcome in Endometrial Cancer.

BACKGROUND: Minimally invasive surgery is the standard approach in early-stage endometrial cancer according to evidence showing no compromise in oncological outcomes, but lower morbidity compared with open surgery. However, there are limited data available on the oncological safety of the use of intrauterine manipulators in endometrial cancer. PATIENTS AND METHODS: This prospective multicenter study included patients with endometrial cancer undergoing laparoscopic staging surgery with the use of an intrauterine manipulator. We obtained three different sets of peritoneal washings: at the beginning of the surgical procedure, after the insertion of the intrauterine manipulator, and after the closure of the vaginal vault. The rate of positive peritoneal cytology conversion and its association with oncological outcomes was assessed. RESULTS: A total of 124 patients were included. Peritoneal cytology was negative in 98 (group 1) and positive in 26 (group 2) patients. In group 2, 16 patients presented with positive cytology at the beginning of the surgery (group 2a) and 10 patients had positive cytology conversion during the procedure (group 2b). Recurrence rate was significantly different among the study groups, amounting to 9.2%, 25.0%, and 60.0% for groups 1, 2a, and 2b, respectively (p < 0.001). Group 1 showed the best recurrence-free and overall survival, followed by group 2a, while patients in group 2b had the worst oncological outcomes (p = 0.002 and p = 0.053, respectively). Peritoneal cytology was an independent predictor of recurrence and death on multivariable analysis. CONCLUSION: A total of 8.1% of patients with endometrial cancer undergoing minimally invasive surgery with intrauterine manipulation showed positive peritoneal cytology conversion associated with significantly worse oncological outcome.

How and where to expect endosalpingiosis intraoperatively.

OBJECTIVE: To describe the anatomical distribution and intraoperative morphology of endosalpingiosis. DESIGN: Retrospective observational video study. SETTING: Data and intraoperative videos were reviewed by two independent reviewers at one referral center. The study was approved by the local ethics committee. PATIENT(S): A total of 77 patients with histologically proven endosalpingiosis from 2007-2020. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary endpoints were anatomical distribution and macroscopic phenotype. The secondary endpoints were demographic and clinical characteristics as well as associated diseases. RESULT(S): Of the 77 patients with endosalpingiosis, the mean age was 40.2 years (standard deviation, 16.4 years), mean body mass index 24.1 kg/m2 (standard deviation, 5.7 kg/m2), 59.7% (n = 46) were nulligravide, 70.1% (n = 54) nulliparous, 22.1% (n = 17) suffered of infertility, and 53.2% (n = 41) had at least one previous abdominal or vaginal surgery. Endometriosis was associated in 53.2 % (n = 41) and malignancies in 28.6% (n = 22, 7 endometrial cancers, 1 uterine carcinosarcoma, 8 borderline ovarian tumors, 5 epithelial ovarian cancers, and 1 yolk sac tumor of the ovary). Anatomic distribution and varying intraoperative phenotypes were demonstrated in the video presentation. CONCLUSION(S): In the majority of this population, endosalpingiosis was located in the pelvis. The higher prevalence of specific gynecologic tumors is consistent with previous results. In phenotype, most lesions appear to be less spectacular than prominent in the literature. For further studies on the relevance as a risk factor for malignancy and consequently clinical recommendations, sound knowledge about endosalpingiosis of laparoscopists as initial diagnosticians is crucial.

[Endosalpingiosis - an Irrelevant Incidental Finding During Laparoscopy?] / Endosalpingiose ­ ein irrelevanter laparoskopischer Zufallsbefund?

Endosalpingiosis - an Irrelevant Incidental Finding During Laparoscopy? Abstract. Endosalpingiosis refers to the ectopic presence of tubal epithelium. However, this incidental finding received little attention, although it is the second most common benign peritoneal pathology in women following endometriosis. In contrast to endometriosis, endosalpingiosis shows an increase in prevalence with age beyond the menopause. Furthermore, it does not appear to be chronically inflammatory and, according to research to this date, does not cause chronic pain or infertility. Recent epidemiological and molecular pathological studies show a significantly higher incidence of ovarian and endometrial tumors in women with endosalpingiosis. These correlations have not been conclusively clarified. Generally accepted clinical recommendations for the detection of endosalpingiosis do not yet exist. In order to better understand the disease value of endosalpingiosis and its oncological correlations, this entity should be brought to the attention of surgical gynecology and involved pathology.

The expression of histone deacetylase 1, but not other class I histone deacetylases, is significantly increased in endometriosis.

Class I histone deacetylases (HDACs-1-3) play an important role in steroid hormone-dependent gene expression and in modulating cell survival and proliferation. We analyzed their expression in a tissue microarray including 74 endometriosis samples and 30 normal endometrium controls. The mean HDAC-1 immunoreactivity score (IRS ± standard deviation) was 7.6 ± 2.5 in endometriosis and 5.3 ± 2.3 in normal endometrium (P < .001). In contrast, the IRSs of HDAC-2 and -3 were 11.7 ± 0.7 and 11.8 ± 1.1 in endometriosis and 11.6 ± 1.0 and 11.9 ± 0.4 in normal endometrium (P = .7 and P = .2), respectively. Significant correlations were found between HDAC-1 and estrogen (-alpha/-beta) and progesterone receptor expression. In conclusion, HDAC-1, but not HDAC-2/-3, was significantly increased in endometriosis and associated with steroid hormone receptor expression that may reflect interdependence. In context with the literature, specific inhibitors of HDAC-1 may have inhibitory activities similar to those of broad-spectrum HDAC inhibitors and may be clinically tolerated, which would increase their chance as an option in the treatment of endometriosis.

Expression of the G protein-coupled estrogen receptor (GPER) in endometriosis: a tissue microarray study.

BACKGROUND: The G protein-coupled estrogen receptor (GPER) is thought to be involved in non-genomic estrogen responses as well as processes such as cell proliferation and migration. In this study, we analyzed GPER expression patterns from endometriosis samples and normal endometrial tissue samples and compared these expression profiles to those of the classical sex hormone receptors. METHODS: A tissue microarray, which included 74 samples from different types of endometriosis (27 ovarian, 19 peritoneal and 28 deep-infiltrating) and 30 samples from normal endometrial tissue, was used to compare the expression levels of the GPER, estrogen receptor (ER)-alpha, ER-beta and progesterone receptor (PR). The immunoreactive score (IRS) was calculated separately for epithelium and stroma as the product of the staining intensity and the percentage of positive cells. The expression levels of the hormonal receptors were dichotomized into low (IRS < 6) and high (IRS > = 6) expression groups. RESULTS: The mean epithelial IRS (+/- standard deviation, range) of cytoplasmic GPER expression was 1.2 (+/- 1.7, 0-4) in normal endometrium and 5.1 (+/- 3.5, 0-12) in endometriosis (p < 0.001), of nuclear GPER 6.4 (+/- 2.6, 0-12) and 6.8 (+/- 2.9, 2-12; p = 0.71), of ER-alpha 10.6 (+/- 2.4, 3-12) and 9.8 (+/- 3.0, 2-12; p = 0.26), of ER-beta 2.4 (+/- 2.2; 0-8) and 5.6 (+/- 2.6; 0-10; p < 0.001), and of PR 11.5 (+/- 1.7; 3-12) and 8.1 (+/- 4.5; 0-12; p < 0.001), respectively. The mean stromal IRS of nuclear GPER expression was 7.7 (+/- 3.0; 2-12) in endometrium and 10.8 (+/- 1.7; 6-12) in endometriosis (p < 0.001), of ER-alpha 8.7 (+/- 3.1; 2-12) and 10.6 (+/- 2.4; 2-12; p = 0.001), of ER-beta 1.8 (+/- 2.0; 0-8) and 5.4 (+/- 2.5; 0-10; p < 0.001), and of PR 11.7 (+/- 0.9; 8-12) and 10.9 (+/- 2.0; 3-12; p = 0.044), respectively. Cytoplasmic GPER expression was not detectable in the stroma of endometrium and endometriosis. The observed frequency of high epithelial cytoplasmic GPER expression levels was 50% (n = 30/60) in the endometriosis and none (0/30) in the normal endometrium samples (p < 0.001). High epithelial cytoplasmic GPER expression levels were more frequent in endometriomas (14/20, 70%; p = 0.01), as compared to peritoneal (9/18, 50%) or deep-infiltrating endometriotic lesions (7/22, 31.8%). The frequency of high stromal nuclear GPER expression levels was 100% (n = 74/74) in endometriosis and 76.7% (n = 23/30) in normal endometrium (p < 0.001). The frequency of high epithelial nuclear GPER expression levels did not differ between endometriosis and normal endometrium. CONCLUSIONS: The present data indicate a unique GPER expression pattern in endometriosis, especially in endometriomas as compared to the normal endometrium. The overexpression of GPER in endometriotic lesions suggests a potential role for GPER in the hormonal regulation of endometriosis, which should be taken into consideration for future hormonal treatment strategies.

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating Human SWI/SNF complexes, which have an important role in the control of cell proliferation and tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas, and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. Here, we examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n=136) served as a control. Epithelial BAF250a expression was assessable in 90/104 (87%) and stromal BAF250a expression in 95/104 (91%) of the endometriosis, and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n=3/20, 15%) and one deep-infiltrating endometriosis sample (n=1/22, 5%), but in none of the peritoneal endometriosis (n=0/16) and eutopic endometrium samples (n=0/30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (P<0.0005), as well as peritoneal (P=0.003) and deep-infiltrating endometriosis (P=0.02). Our data demonstrates that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriomas. In addition, we report that a partial loss of BAF250a expression is occurring in the form of cell clusters indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be of importance in the determination of individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be further studied.

Expression pattern of class I histone deacetylases in vulvar intraepithelial neoplasia and vulvar cancer: a tissue microarray study.

BACKGROUND: Epigenetic regulation is an important mechanism leading to cancer initiation and promotion. Histone acetylation by histone deacetylases (HDACs) represents an important part of it. The development of HDAC inhibitors has identified the utility of HDACs as a therapeutic target. Little is known about the epigenetic regulation of vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell cancer (VSCC). In this study, the expression of class I HDACs (HDAC 1, 2 and 3) was compared in a series of VIN and VSCC tissues. METHODS: A tissue micro array (TMA) with specimens from 106 patients with high-grade VIN and 59 patients with vulvar cancer was constructed. The expression of HDACs 1, 2 and 3 were analyzed with immunohistochemistry (IHC). The nuclear expression pattern was evaluated in terms of intensity and percentage of stained nuclei and was compared between vulvar preinvasive lesions and vulvar cancer. RESULTS: HDAC 2 expression was significantly higher in VIN than in VSCC (p < 0.001, Fisher's test). Also, 88.7% (n = 94/106) of VIN samples and only 54.5% (n = 31/57) of VSCC samples were scored at the maximum level. Conversely, HDAC 3 expression was significantly higher in VSCC (93%, 53/57) compared to VIN (73.6%, 78/106, p = 0.003), whereas only a small difference in the expression of HDAC 1 was found between these two entities of vulvar neoplasia. CONCLUSIONS: These results suggest that epigenetic regulation plays a considerable role in the transformation of VIN to invasive vulvar neoplasia.

Outcome of treated anogenital intraepithelial neoplasia among human immunodeficiency virus-infected women.

OBJECTIVE: To determine characteristics and clinical course of high-grade anogenital intraepithelial neoplasia (AIN) in human immunodeficiency virus (HIV)-infected women. STUDY DESIGN: HIV-positive women with biopsy-proven high-grade (II and III) vulvar (VIN), vaginal (VAIN) or perianal intraepithelial neoplasia (PAIN) were identified in the electronic databases of 2 colposcopy clinics. RESULTS: A total of 31 patients were identified from 1992 to 2007, of which 30 had a mean follow-up of 47.7 months (SD = 46.0; range, 2.6-166.2). Of the patients, 77.4% had VIN, 12.9% VAIN and 9.7% PAIN at first diagnosis. Age at diagnosis of IN was 36.2 years (SD +/- 5.2; range, 23.5-47.0). Ninety percent of patients received antiretroviral therapy at first diagnosis of IN; 65% (13 of 20) of patients with a follow-up of > 2 years required a second treatment, and 2 developed invasive vulvar cancer (10%). CONCLUSION: AIN among HIV-positive women shows a high relapse rate despite treatment modality used and a substantial invasive potential.