Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterisation study.

BACKGROUND: Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis. METHODS: We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients. RESULTS: Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69+ T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69+ cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69+ and CD69- populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis. CONCLUSIONS: This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.

Diaphragmatic peritonectomy vs. full thickness resection with pleurectomy during Visceral-Peritoneal Debulking (VPD) in 100 consecutive patients with stage IIIC-IV ovarian cancer: A surgical-histological analysis.

OBJECTIVE: To compare the surgical and histological outcomes of diaphragmatic peritonectomy vs. full thickness resection with pleurectomy during Visceral-Peritoneal Debulking. METHODS: Service evaluation protocol (Trust number 3265). All patients with stage IIIC-IV ovarian cancer who had diaphragmatic surgery between April 2009 and November 2013 were included. Clinical notes and histology reports were reviewed. Additional histology sections were undertaken. Patients were divided in Groups 1 (peritonectomy) and 2 (pleurectomy). The outcomes of interest were: surgical (intra- and post-operative morbidity, pulmonary morbidity, mortality, rate of complete resection) and histological (rate of diaphragmatic peritoneum, muscle and pleural involvement, rate of microscopic diaphragmatic free margins). RESULTS: Sixty four patients had diaphragmatic peritonectomy (Group 1), 36 patients full thickness diaphragmatic resection with pleurectomy (Group 2). There was no significant difference in the rate of mortality (3% in both groups), overall intra- and post-operative morbidity (32.8% vs. 38.8%), pulmonary morbidity (9.3% vs. 19%, P=0.14). Histology showed tumor invasion in the diaphragmatic peritoneum (96%), muscle (28%) and pleura (19.4%). Microscopic free margins were seen in 86% vs. 92% in Groups 1 and 2. CONCLUSIONS: Our study demonstrated that, in patients with ovarian cancer, diaphragmatic involvement extends to the muscle in almost 30% and to the pleura in 20% of the patients. Overall and specific morbidity was not significantly different when comparing peritonectomy vs. pleurectomy.

Prognostic characteristics, recurrence patterns, and survival outcomes of vulval squamous cell carcinoma - A twelve-year retrospective analysis of a tertiary centre.

INTRODUCTION: Vulval cancer is a rare gynaecological malignancy. In this study, we present a tertiary centre case analysis to examine the recurrence patterns and survival outcomes of vulval squamous cell carcinoma (SCC). METHODS: This is a retrospective cohort study of women who received treatment at Oxford University Hospitals between February 2010 and July 2022 for primary vulval SCC. RESULTS: We included 98 cases. The median age at diagnosis was 68 years. Human Papillomavirus (HPV) infection and lichen sclerosis were observed in 21 and 50 cases, respectively. Surgical excision was the primary treatment. Recurrence within 2 years was more common with advanced stage (p = 0.047, RR = 2.26) and extracapsular lymph node spread (p = 0.013, RR = 2.88). Local recurrence was not associated with a specific cut-off value for tumour-free margin. Poor survival outcomes were observed with higher grade (p = 0.01), advanced FIGO stage (p < 0.001), HPV-independent cancer (p = 0.048), lymph node involvement (p < 0.001, HR = 7.14), extracapsular spread (p < 0.001, HR = 7.93), lymphovascular space invasion (p = 0.002, HR = 3.17), tumour diameter wider than 23 mm (p = 0.029, HR = 2.53) and depth of invasion more than 6 mm (p = 0.006, HR = 3.62). Perineural invasion is associated with shorter disease-free survival. Five-year cancer-specific survival rates for stages I, III, and IV were 90.2%, 40.8%, and 14.3%, respectively.

The surgical, histopathological characteristics, and survival outcome of ovarian clear cell carcinoma: a retrospective case series sharing the experience of a tertiary cancer centre.

Background: Ovarian clear cell carcinoma (OCCC) is a rare and distinct subtype of epithelial ovarian cancer (EOC). It is unique in several biological aspects. This study analyzes the clinicopathological features and survival outcome of patients with OCCC, aiming to identify factors affecting recurrence, progression-free survival (PFS) and overall survival (OS). Methods: A retrospective study included 49 women with OCCC between January 2009 and December 2021 at Oxford Cancer Center. All demographic and pathological characteristics, pre-operative biomarkers, surgical procedure, complications, hospital stay, chemotherapy regimen, and disease status on follow-up, were collected from electronic medical records. Results: No residual disease (R0) was achieved in 39 out of 49 women who underwent cytoreductive surgery. The follow-up time had a mean of 8.75 years. The 3-year OS was 73.4%, and the 3-year PFS was 81.3% [95% confidence interval (CI): 84.63-118.93]. Women with stage 1 disease had the best outcome. There was a marked difference (P<0.001) in OS in the presence of residual disease. No residual disease conferred a 3-year OS of 88.6% (95% CI: 108.6-141.8), compared to only 12.5% in the presence of residual disease (95% CI: 4.48-32.11). In multivariant analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage was the only independent prognostic indicator of OS with (P<0.05), including carbohydrate antigen (CA) 125, hemoglobin, albumin, associated endometriosis, ascites, residual disease and FIGO staging. Conclusions: Surgery to achieve no residual disease is necessary to improve the prognosis in advanced OCCC. The true challenge is to predict which patients with early-stage disease at higher risk of recurrence and would most benefit from adjuvant treatments.

The clinicopathological characteristics and survival outcomes of primary expansile vs. infiltrative mucinous ovarian adenocarcinoma: a retrospective study sharing the experience of a tertiary centre.

Background: Mucinous ovarian carcinomas (MOCs) are rare ovarian tumours accounting for 3% of all epithelial ovarian carcinomas (EOCs). They are either expansile or infiltrative, based on the tumour's histological pattern of invasion. MOCs have a distinct molecular profile, natural history, chemo-sensitivity, and prognosis compared to other EOCs. The aim of this study was to describe patient and tumour characteristics, as well as survival outcomes of expansile and infiltrative primary MOCs. Methods: This was a retrospective cohort study conducted at a tertiary cancer centre. Patients had surgery for primary MOC between Jul 1, 2010 and Oct 28, 2022. All patients discussed at the Oxford multidisciplinary team (MDT) meeting with a diagnosis of MOC were included. We excluded patients with mucinous metastatic carcinoma (MMC), dual histological diagnoses, those who died before treatment was initiated, and patients with incomplete records. Results: A total of 47 patients were identified and 14 were excluded. Out of the remaining 33 MOCs, 23 (70.6%) were expansile and 10 (30.4%) were infiltrative. The median follow-up was 37 months (95% CI: 14.1-69.8). Patients with infiltrative tumours were older than those with expansile tumours (median age 62 vs. 55 years, P=0.049). Infiltrative tumours were diagnosed at a more advanced International Federation of Gynaecology and Obstetrics (FIGO) stage compared to expansile tumours: FIGO stage II/III 50% vs. 8.2% (P=0.002). We found paired-box gene 8 (PAX8) more frequently expressed in expansile tumours (75% vs. 37.5%, P=0.099). Adjuvant treatment was administered in 50% of patients with infiltrative disease, compared to only 13% of those with expansile disease (P=0.036). 80% of patients who have relapsed had received adjuvant chemotherapy, compared to 17.2% of patients without relapse (P=0.012). At 3 years, there was a statistically significant difference in progression-free survival (PFS) (94.7% vs. 65.6%, P=0.02) between the expansile and infiltrative groups, but no difference in overall survival (OS) (88.8% vs. 90%, P=0.875). Conclusions: Patients with infiltrative tumours were older, more likely to have bilateral tumours and more likely to have an advanced FIGO stage at diagnosis. Adjuvant treatment was more likely to be administered to patients with infiltrative tumours, however, this did not prevent relapse. PFS at 3 years was significantly higher in patients with expansile tumours. PAX8 was more frequently expressed by expansile tumours.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Characterization of exosomes in peritoneal fluid of endometriosis patients.

OBJECTIVE: To demonstrate the feasibility of studying exosomes directly from peritoneal fluid, we isolated exosomes from endometriosis patient samples and from controls, and characterized their cargo. DESIGN: Case-control experimental study. SETTING: Academic clinical center. PATIENT (S): Women with and without endometriosis who underwent laparoscopic surgery (n = 28 in total). INTERVENTION (S): None. MAIN OUTCOME MEASURE (S): Concentration of exosomes within peritoneal fluid and protein content of the isolated exosomes. RESULT (S): Peritoneal fluid samples were pooled according to the cycle phase and disease stage to form six experimental groups, from which the exosomes were isolated. Exosomes were successfully isolated from peritoneal fluid in all the study groups. The concentration varied with cycle phase and disease stage. Proteomic analysis showed specific proteins in the exosomes derived from endometriosis patients that were absent in the controls. Five proteins were found exclusively in the endometriosis groups: PRDX1, H2A type 2-C, ANXA2, ITIH4, and the tubulin α-chain. CONCLUSION (S): Exosomes are present in peritoneal fluid. The characterization of endometriosis-specific exosomes opens up new avenues for the diagnosis and investigation of endometriosis.

Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients' quality of life: the FENOX study.

INTRODUCTION: Millions of women suffer from the consequences of endometriosis and uterine fibroids, with fibroids the cause for over 50% of hysterectomies in the USA, and direct costs for their treatment estimated at between US$4 and US$9 billion. Endometriosis commonly affects millions of women worldwide predominantly during reproductive age, with severe menstrual and non-menstrual pain and subfertility the main symptoms. Due to the 'unhappy triad' of endometriosis-lack of awareness, lack of clinically relevant biomarkers and the unspecific nature of symptoms-women wait on average for 8-12 years before the definitive endometriosis diagnosis is made. Treatment options for both conditions are not satisfactory at the moment, especially with a view to preserving fertility for the women and families affected. In the Fibroids and Endometriosis Oxford (FENOX) study, we combine the investigation of fibroids and endometriosis, and plan to collect high-quality tissue samples and medical data of participants over a time frame of 5 years after surgical intervention. METHODS AND ANALYSIS: Biological samples such as blood, saliva, urine, fat, peritoneal fluid and-if found-endometrial tissue or fibroids as well as detailed clinical and intraoperative data will be collected from women undergoing surgery and participating in the study after informed consent. We plan to recruit up to 1200 participants per disease arm (ie, endometriosis and uterine fibroids) over 5 years. Participants will fill in detailed and validated questionnaires on their medical history and quality of life, with follow-ups for 5 years. Enrolment started on 2 April 2018, and FENOX will close on 31 March 2028. We will analyse the biological samples using state-of-the-art molecular biology methods and correlate the findings with the medical records and questionnaire data. ETHICS AND DISSEMINATION: The findings will be published in high-ranking journals in the field and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13560263.

Author Correction: Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.

Expression of terminally glycosylated calcitonin receptor-like receptor in uterine leiomyoma: endothelial phenotype and association with microvascular density.

PURPOSE: The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested. Calcitonin receptor-like receptor (CL) is a G protein-coupled receptor (GPCR) that mediates effects of AM, but little information is available on its expression and functional state in human tumors. The present study attempted to determine CL potential for antiangiogenic therapy of uterine leiomyoma. EXPERIMENTAL DESIGN AND RESULTS: GPCR CL is transported to the cell surface and recognized by AM only when terminally/mature glycosylated. The presence and localization of this form of the receptor in tumor and surrounding myometrial tissues obtained from leiomyoma-bearing uteri were examined using deglycosylation, immunoblotting, and immunofluorescence analysis. The mature CL glycoprotein was expressed in both tissues and localized exclusively in normal and tumor endothelium within leiomyoma-bearing uteri. The functionality of the receptor expressed in myometrial microvascular endothelial cells (MMVEC) was examined in vitro using receptor internalization and angiogenic assays. The mature CL glycoprotein expressed by primary MMVECs was functional because AM interacted with this GPCR and induced its internalization as well as angiogenic effects (proliferation and migration) in MMVECs in vitro. Finally, the levels of tissue-expressed mature CL glycoprotein as a functional form of this GPCR were analyzed by immunoblotting. The expression of this functional form of the receptor in vivo was significantly decreased (P = 0.01) in leiomyoma tissue, and this was concurrent with the decrease in microvascular density (measured by Chalkley counting) in tumor compared with surrounding myometrium (P = 0.031). CONCLUSIONS: Our findings suggest that GPCR CL mediates angiogenic effects of AM in myometrium and that further evaluation of the properties of the CL expressed in both normal and tumor endothelium in vivo may be essential before targeting this endothelial GPCR for antiangiogenic therapies.

Heparin-binding epidermal growth factor and its receptors mediate decidualization and potentiate survival of human endometrial stromal cells.

Heparin-binding epidermal growth factor (HB-EGF) has pleiotropic biological functions in many tissues, including those of the female reproductive tract. It facilitates embryo development and mediates implantation and is thought to have a function in endometrial receptivity and maturation. The mature HB-EGF molecule manifests its activity as either a soluble factor (sol-HB-EGF) or a transmembrane precursor (tm-HB-EGF) and can bind two receptors, EGFR and ErbB4/HER4. In this study, we identify factors that modulate expression of HB-EGF, EGFR, and ErbB4 in endometrial stromal cells in vitro. We demonstrate that levels of sol- and tm-HB-EGF, EGFR, and ErbB4 are increased by cAMP, a potent inducer of decidualization of the endometrial stroma. We also show that production of sol- and tm-HB-EGF is differentially modulated by TNF alpha and TGF beta. Our data suggest that HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF alpha- and TGF beta-induced apoptosis of endometrial stromal cells.

Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst.

The mechanisms that mediate implantation of the human embryo remain poorly understood and represent a fundamental problem in reproductive biology. Candidate molecules that mediate and facilitate implantation have been identified in animal studies, and include heparin binding epidermal growth factor. Here we demonstrate a potential function for the transmembrane form of heparin-binding epidermal growth factor in mediating blastocyst attachment to the endometrium, in two different novel in vitro models for human implantation. Furthermore, we demonstrate specific localisation of the heparin-binding epidermal growth factor receptor ErbB4, on the surface of the trophectoderm in peri-implantation human blastocysts. Our data lead the way for further dissection of the molecular mechanisms of implantation of the human embryo, and have implications for infertility, in vitro fertilization and contraception.

Allelic loss studies do not provide evidence for the "endometriosis-as-tumor" theory.

OBJECTIVE: To identify consistent genetic changes in endometriosis samples to determine whether endometriosis lesions are true neoplasms. DESIGN: We analyzed ovarian endometriosis lesions for loss of heterozygosity (LOH) at 12 loci of potential importance (D9S1870, D9S265, D9S270, D9S161, D11S29, D1S199, D8S261, APOA2, PTCH, TP53, D10S541, and D10S1765), including some at which genetic changes were previously reported in endometriosis. SETTING: Molecular biology laboratory in a university hospital department. PATIENT(S): Seventeen women with ovarian endometriosis. INTERVENTION(S): Laser capture microdissection to separate the endometriotic epithelium, the adjacent endometriotic stroma, and surrounding normal ovarian stromal tissue, followed by DNA extraction and polymerase chain reaction amplification of polymorphic microsatellite markers. MAIN OUTCOME MEASURE(S): Fluorescence-based quantitation for the LOH analysis. RESULT(S): We identified LOH in only one lesion at one locus (D8S261). CONCLUSION(S): Our data do not support the hypothesis that ovarian endometriosis is a true neoplasm.

Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome.

OBJECTIVE: To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome. DESIGN: A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists. SETTING: Research institute. PATIENTS: A total of 108 affected individuals, including 46 probands and 62 affected relatives. MAIN OUTCOME MEASURES: The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL. RESULTS: Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL. CONCLUSIONS: Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.

Pathology of ovarian cancers in BRCA1 and BRCA2 carriers.

PURPOSE: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer. EXPERIMENTAL DESIGN: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated. RESULTS: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21-2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P < 0.0001), had a higher percentage solid component (P = 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers. CONCLUSIONS: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively aggressive and may be expected to have poor prognosis, although this may be treatment dependent.

The mitogenic potential of heparin-binding epidermal growth factor in the human endometrium is mediated by the epidermal growth factor receptor and is modulated by tumor necrosis factor-alpha.

Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is implicated in a variety of biological processes, including reproduction. Previous studies describe increased levels of HB-EGF in the human endometrium during the midsecretory stage of the menstrual cycle, suggesting a function for HB-EGF in implantation of the human blastocyst. Here we have investigated the expression and function of the soluble and transmembrane forms of HB-EGF in the human endometrium. We show that the expression of the transmembrane form of HB-EGF in the human endometrium is modulated according to the stage of the menstrual cycle. We present data demonstrating that both the soluble and transmembrane forms of HB-EGF induce DNA synthesis in human endometrial stromal cells. Furthermore, TNFalpha has a cooperative effect on HB-EGF, EGF, TGFalpha, and betacellulin-induced DNA synthesis in stromal cells, suggesting roles for the EGF family and TNFalpha in regeneration and maturation of human endometrium. Induction of DNA synthesis by HB-EGF and its modulation by TNFalpha in endometrial stromal cells are mediated by the EGF receptor and not the HB-EGF receptor ErbB4. Our data suggest key functions for HB-EGF, TNFalpha, and the EGF receptor in endometrial maturation, via autocrine/paracrine and juxtacrine pathways, in preparation for embryo implantation.

1170 consecutive hysterectomies: indications and pathology.

OBJECTIVE: An analysis of consecutive hysterectomies during 1997-99 exploring the relationship between histological findings, operation performed and clinical indication was conducted to observe any trends. METHODS: A retrospective review of histology reports for hysterectomies performed in a large district teaching hospital. RESULTS: The rate of hysterectomy for women aged over 25 years was 23 per 10,000 women. Menstrual disturbance including endometriosis was the indication in 45%, pelvic tumours including fibroids in 21%, prolapse in 17% and malignant or pre-malignant conditions in 15%; 1% were performed in relation to childbirth. 79% were total abdominal hysterectomies, 4% subtotal and 17% vaginal. 50% included removal of both ovaries and in 8% omentectomy was also performed. The uterus was histologically normal in 20% of abdominal hysterectomies, the rate rising to 70% for vaginal hysterectomies. CONCLUSIONS: The rate of hysterectomy has not changed over the past 15 years, despite the introduction of alternative medical and surgical therapies for managing menstrual problems and fibroids. There may have been a greater proportion performed for malignant and premalignant conditions and genital tract prolapse. There were fewer specimens with no evidence of pathology than is often suggested.