Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51-62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51-71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

Stage one endometrioid endometrial adenocarcinoma: is there a role of traditional hospital follow-up in the detection of cancer recurrence in women after treatment?

OBJECTIVE: To investigate the rate of asymptomatic recurrence of stage 1 endometrioid endometrial cancer and assess the role of routine hospital follow-up after treatment. METHODS: We performed a retrospective case-note review study of women who were diagnosed with stage 1 endometrioid endometrial adenocarcinoma at Queen's Hospital, Romford, between January 2008 and December 2016. RESULTS: We included 299 patients with a median follow-up period of 44.4 months. All the patients underwent total hysterectomy and bilateral salpingo-oophorectomy. Adjuvant radiotherapy was offered to the patients subsequent to discussions in the multidisciplinary team meeting in accordance with the risk stratification criteria. There was no significant correlation between the risk factors and disease recurrence. In total, 11 patients presented with recurrent disease with original staging: 1a, n=6/199; and 1b, n=5/100. Four patients presented with vaginal bleeding due to vault recurrence and one patient with abdominal pain due to pelvic mass. Locoregional recurrence was an incidental finding in two other patients. Four patients presented with symptomatic distant metastases to the lung (n=2), liver (n=1), and bone (n=1). No asymptomatic recurrences were identified on routine follow-ups, despite several hospital appointments and clinical examinations. The recurrence rate for patients with stage 1a and 1b, grade 1, and grade 2 disease was 3.53%, and that for patients with stage 1a, grade 1, and grade 2 disease was 2.7%. CONCLUSION: Routine clinical examinations have a low yield in finding recurrence in asymptomatic women and should be questioned for their value, considering the limited resources of the National Health Service (NHS). Larger studies are required to support a stratified follow-up, which will include telephone and patient-initiated follow-up.

Medically unfit women with early-stage endometrial cancer treated with the levonorgestrel intrauterine system.

OBJECTIVE: To assess the clinical efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the treatment of early-stage endometrial cancer in elderly morbidly obese women, whose multiple co-morbidities made the standard surgical treatment too risky to undertake. METHODS: A retrospective review was conducted and case series reports were prepared of all women diagnosed with endometrial cancer, from April 2011 to December 2016 at the Queen's Hospital, London, to identify women unfit for surgery and treated with the LNG-IUS. RESULTS: Out of 438 women with endometrial cancer, Eight women with early-stage endometrial cancer were deemed unfit for surgery and underwent treatment with the LNG-IUS. All had grade 1 endometrioid endometrial adenocarcinoma, radiologically staged as 1a. Four women died of their co-morbidities, not related to endometrial cancer. One of them had 68 months of progression-free survival before death due to co-morbidities. One patient required a hysterectomy after 32 months of treatment with LNG-IUS and oral progestogens due to heavy vaginal bleeding. Three women have continued the LNG-IUS treatment with no evidence of progressive disease symptoms till date at a mean follow-up of 35.7 months. CONCLUSION: For women with multiple co-morbidities, the LNG-IUS offers an effective and safe treatment for early-stage, low-grade endometrial cancer, with no cases of symptomatic progression reported in our case series. In the frail and elderly, where the quality of life is of paramount importance, surgical treatment may not offer additional long-term survival benefits.

Post-coital bleeding: What is the incidence of significant gynaecological pathology in women referred for colposcopy?

OBJECTIVE: To evaluate the incidence of underlying serious gynaecological pathology in women referred to colposcopy with post-coital bleeding. MAIN OUTCOME MEASURES: Incidence of precancer and cancer. METHODS: A retrospective cohort study of women referred to colposcopy at a London hospital from January 2008-March 2015. Inclusion criteria are women with post-coital bleeding and the following cervical cytology history: negative; inadequate; never had. Multinomial logistic regression was used to assess for significant risk factors for cervical dysplasia and cancer. RESULTS: Overall, 635 women with either negative cytology (n = 436/68.7%), no previous cytology (n = 175/27.6%), or inadequate cytology (n = 24/3.8%) were referred to colposcopy for post-coital bleeding. The median age is 35 years (S.D. = 9.7 years). In 256 (40.3%) women, no cause was detected, and 322 (50.7%) women had a benign cause. Overall, 42 (6.6%) women had low-grade dysplasia, and eleven women had high-grade dysplasia (1.7%). Four women (0.6%) had cervical cancer; clinically evident cancer on speculum examination (n = 3); micro-invasive cancer (n = 1). Current smokers were significantly more likely to have HPV atypia (p = 0.015) or cervical intraepithelial neoplasm grade 1 (CIN1) p = 0.003. Advancing age was a significant risk factor for cervical cancer (p = 0.037). CONCLUSION: All women with post-coital bleeding need an urgent speculum examination to rule out frank cervical cancer. Although most women had a benign cause for post-coital bleeding, around 2% had a colposcopy-aided diagnosis of either cervical precancer or cancer; therefore, referral of symptomatic women deserves consideration. HPV testing may reduce referrals to colposcopy for post-coital bleeding due to non-significant pathology in the future.

Histopathologic response to neoadjuvant chemotherapy as a prognostic biomarker in tubo-ovarian high-grade serous carcinoma: updated Chemotherapy Response Score (CRS) results.

OBJECTIVE: The Chemotherapy Response Scoring (CRS) system was developed to enable reproducible reporting of histologic tumor response in interval debulking specimens following neoadjuvant chemotherapy in advanced stage tubo-ovarian high-grade serous carcinoma. This prognostic biomarker has been included in ovarian cancer pathology reporting guidelines (International Collaboration on Cancer Reporting, College of American Pathologists) and in the upcoming European Society for Medical Oncology-European Society of Gynaecological Oncology (ESMO-ESGO) guidelines for ovarian cancer management. We present follow-up data on the CRS validation initiatives and suggest research with novel therapeutic agents incorporating this biomarker. METHODS: The cohort on whom CRS was originally developed was analyzed after an extended follow-up of an additional 36 months. The CRS histopathologic scoring system was applied to omental sections obtained at interval surgery from all 80 patients. Progression-free and overall survival were re-calculated. RESULTS: After a median follow-up of 4.3 years the CRS score predicted progression-free survival with an HR of 0.39 (95% CI 0.21 to 0.70), p = 0.002 adjusted for age, stage, and debulking status (median 1.08 vs 2.27 years for CRS1/2 vs CRS3). CRS was also predictive of overall survival with an HR of 0.17 (95% CI 0.07 to 0.44), p = 0.0002 adjusted for age, stage, and debulking status (median 2.55 vs 5.47 years for CRS1/2 vs CRS3). CONCLUSION: CRS3 is a reproducible prognostic biomarker for improved progression-free and overall survival in stage 3C or 4 tubo-ovarian high-grade serous carcinoma after neoadjuvant chemotherapy. The score, obtained at interval debulking surgery, can help facilitate research and biomarker driven first-line treatment of patients with advanced ovarian cancer.

Conservative management of cervical intraepithelial neoplasia grade 2 (CIN2) in women under 30 years of age: A cohort study.

OBJECTIVE: To assess the safety of conservative management of cervical intraepithelial neoplasia grade 2 (CIN2) in women aged under 30 years. STUDY DESIGN: A retrospective cohort study at Queen's Hospital, London, UK. We reviewed patient records and 'Open Exeter' cytology results of 178 women aged less than 30 years with histologically proven CIN2 between 1st April 2014 and 31st March 2016. Analysis included rates of spontaneous regression of CIN2, the persistence of abnormality, the progression to CIN3 and cancer, duration of conservative management, and the number of patients that defaulted follow-up. RESULTS: Of 178 women, 69 women underwent primary treatment of CIN2 with large loop excision of the transformation zone (LLETZ). Nine women defaulted follow-up after their first appointment. One hundred women were managed conservatively with colposcopy, cytology and cervical biopsy. Overall 57% had successful conservative management with regression of high-grade lesion on colposcopy and negative cytology; 32% had failed conservative management and LLETZ, and 11% of women defaulted follow-up with abnormal cytology. Only 13% of women managed conservatively progressed to CIN3, with no woman developing cancer at a median follow-up of 22 months. In women with successful conservative management features of high-grade dysplasia on colposcopy resolved in a significantly shorter time-period compared to normalisation of their cytology (p = 0.021). CONCLUSION: Conservative management of CIN2 appears reasonable and safe in women under the age of 30 years, with 57% showing regression to negative cytology. There is a significant time lag before cytology becomes negative, so early recourse to treatment based on cytology alone is not advised where colposcopy is satisfactory and reassuring.

Luteinising hormone releasing hormone (LHRH) agonists for the treatment of relapsed epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is seventh most common cancer in women worldwide. Approximately 1.3% of women will be diagnosed with ovarian cancer at some point during their life time. The majority of tumours arise from surface of the ovary (epithelial). Two thirds of these women will present with advanced disease, requiring aggressive treatment, which includes debulking surgery (removal of as much disease as possible) and chemotherapy. However, most women (75%) with advanced epithelial ovarian cancer (EOC) will relapse following surgery and chemotherapy. Patients who relapse are treated with either platinum or non-platinum drugs and this is dependent on the platinum-sensitivity and platinum-free interval. These drug regimens are generally well-tolerated although there are potential severe side effects. New treatments that can be used to treat recurrence or prevent disease progression after first-line or subsequent chemotherapy are important, especially those with a low toxicity profile. Hormones such as luteinising hormone releasing hormone (LHRH) agonists have been used in the treatment of relapsed EOC. Some studies have shown objective remissions, while other studies have shown little or no benefit. Most small studies report a better side-effect profile for LHRH agonists when compared to standard chemotherapeutic agents used in EOC. OBJECTIVES: To compare the effectiveness and safety of luteinising hormone releasing hormone (LHRH) agonists with chemotherapeutic agents or placebo in relapsed epithelial ovarian cancer (EOC). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group trials register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase up to January 2016. We also searched registers of clinical trials and abstracts of scientific meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared LHRH agonists with chemotherapeutic agents or placebo in relapsed EOC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether relevant studies met the inclusion criteria, retrieved data and assessed risk of bias. MAIN RESULTS: Two studies, including 97 women, met our inclusion criteria: one assessed LHRH agonist (leuprorelin) use in relapsed (platinum-resistant and platinum-refractory) EOC in comparison with a chemotherapeutic agent (treosulfan) (Du Bois 2002); the other examined LHRH agonist (decapeptyl) versus a placebo (Currie 1994). Since both studies had different control groups, a meta-analysis was not possible.There may be little or no difference between treatment with leuprorelin or treosulfan in overall survival (OS) (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.58 to 1.67; very low-quality evidence) or progression-free survival (PFS) at six and 12 months (risk ratio (RR) 0.61, 95% CI 0.22 to 1.68, and RR 0.65, 95% CI 0.12 to 3.66; very low-quality evidence), respectively (Du Bois 2002). The duration of follow-up was 2.5 years and quality of life (QoL) was not reported in this study.Alopecia and fatigue were probably more common with treosulfan than leuprorelin (alopecia RR 0.32, 95% CI 0.12 to 0.91 (very low-quality evidence)). There may be little or no difference in other Grade 3/4 side effects: nausea and vomiting (RR 0.65, 95% CI 0.12 to 3.66 (very low-quality evidence)); neurotoxicity (RR 0.32, 95% CI 0.01 to 7.71 (very low-quality evidence)) and neutropenia (RR 0.97, 95% 0.06 to 14.97 (very low-quality evidence)),The Currie 1994 study, which compared decapeptyl treatment with placebo, reported mean PFS of 16 weeks verus 11.2 weeks, respectively. No relative effects measures or P value at a particular time point were reported. Overall survival (OS) and QoL outcomes were not reported. In addition, adverse events were only mentioned for the decapeptyl group.Adverse events were incompletely reported (no adverse events in decapeptyl group, but not reported for the placebo group). AUTHORS' CONCLUSIONS: Based on this review of two small RCTs, there is not enough evidence to comment on the safety and effectiveness of LHRH agonists in the treatment of platinum-refractory and platinum-resistant (relapsed) EOC. Overall, the quality of evidence for all outcomes (including OS, PFS, QoL and adverse events) is very low.

Location of Sentinel Lymph Node in Cervical Carcinoma and Factors Associated With Unilateral Detection.

OBJECTIVE: The aims of this study were to assess locality of the sentinel lymph node (SLN) in cervical carcinoma and examine factors affecting bilateral SLN detection. METHODS: This was a retrospective review of SLN data (anatomical location, count and laterality) in patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA1 with lymphovascular space invasion to stage IIA) using intraoperative gamma probe and blue dye. The preoperative single-photon emission computed tomography with computed tomography was used to detect laterality, number of the SLNs, and rare locations. Patients were treated between January 2005 to January 2015 at the West Kent Gynaecological Oncology Centre, Maidstone Hospital, Maidstone, United Kingdom. RESULTS: A total of 132 women were investigated. The most common SLN location was the external iliac (38.6%) followed by obturator (25.3%) and internal iliac (23.6%) regions. A small percentage was identified in presacral (1.4%) and para-aortic regions (0.7%). Older age (P = 0.01) and an elevated body mass index (P = 0.03) were associated with decreased SLN count by preoperative single-photon emission computed tomography with computed tomography, and only age affected SLN count by gamma probe (P = 0.01). Initial surgery, large loop excision of the transformation zone, or cone biopsy of the cervix had no effect on SLN count. There was no difference observed in bilateral detection with respect to surgical approach (open: n = 48/laparoscopic: n = 84). However, older age was independently associated with a decrease in bilateral SLN detection (P = 0.003). In these patients who underwent unilateral full pelvic lymphadenectomy, all the nonsentinel nodes were negative. CONCLUSIONS: The majority of SLNs were located in the external iliac, obturator, and internal iliac regions. Both older age and an elevated body mass index were associated with a reduced SLN count. Unilateral detection of SLN was independently associated with older age, which may be due to sclerosis in the lymphatic vessels or reduced perfusion in the pelvis in these women. If no SLN is detected on one side, the consensus is to perform a full pelvic lymphadenectomy on that side of the pelvis.

Women with high BMI: should they be managed differently due to antagonising action of leptin in labour?

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. There is evidence that leptin may be responsible for various complications in obese and morbidly obese women in labour by its effect on the myometrium causing uterine smooth muscle relaxation (causes less Ca(2+) flux in myometrium). By doing this, we believe it opposes oxytocin effect on the myometrium which in fact promotes uterine smooth muscle contractions (causes more Ca(2+) flux in myometrium). The opposing action of these two hormone may contribute to the dysfunctional labour process, prolonged first stage of labour, increase in operative vaginal delivery in second stage of labour and increase in caesarean section rate both in first and second stage of labour in obese women. Also, there is increased incidence of postdated pregnancy, induction of labour and atonic postpartum haemorrhage in obese and morbidly obese women. Does this mean labour should be managed differently in women with high BMI?

Pregnancy outcomes after treatment for cervical intraepithelial neoplasia in a single NHS hospital.

OBJECTIVE: The objective of this study was to assess the adverse pregnancy outcomes in women who had treatment for cervical intraepithelial neoplasia. METHODS: This was a retrospective cohort using data linkage. Pathology databases from Whipps Cross University Hospital were used to identify women with a histological sample taken at colposcopy between 1995 and 2009. Births for these women were identified through the hospitals' obstetric database. A total of 876 births (from 721 women) were identified. Logistic regression was used to assess the relationship between adverse pregnancy outcomes and treatment for cervical intraepithelial neoplasia before delivery. Results were adjusted by ethnicity, deprivation, and parity. RESULTS: After taking into account parity, socioeconomic status, and ethnicity, receiving any type of excisional treatment (single or multiple) before birth increased the risk of preterm labor compared with having a punch biopsy only (adjusted relative risk, 1.61; 95% confidence interval, 1.11-2.32). Preterm deliveries that occurred after a spontaneous onset of labor were found to be more likely after treatment for cervical disease (adjusted relative risk, 1.68; 95% confidence interval, 1.11-2.52). CONCLUSIONS: Women receiving any type of excisional treatment before delivery are at increased risk of preterm delivery when compared with women attending colposcopy but not treated. Although we took into account the effects of parity, socioeconomic status, and ethnicity, residual confounding factors may be unidentified.

Are oestrogens and genetic predisposition etiologic factors in the development of clear cell carcinoma of the peritoneum?

A literature search was carried out for clinical observations that could explain the possible aetiology of primary peritoneal clear cell carcinoma (CCC) including diagnostic dilemmas, various theories of origin, oestrogen dependence and genetic association. It was found to be an extremely rare tumour (CCC) arising in the peritoneum and is often misdiagnosed as mesothelioma or serous carcinoma or metastatic adenocarcinoma due to overlapping morphological features. The awareness of such dilemmas is important even before making a diagnosis. Clinicopathological features and immunohistochemical studies like WT1, CK20 and calretinin are usually helpful in differentiating CCC from serous carcinoma, metastatic carcinoma from bowel and mesothelioma. (CK7 is common to all epithelial tumours, CEA can be expressed in clear cell carcinoma, WT1 is normally expressed in serous carcinoma, calretinin is expressed in mesothelioma and CK20 in colon carcinoma). The distinction between the above tumours is important as correct diagnosis is required in initiating appropriate treatment. Less than ten cases have been reported in the English language medical literature. Mullerian metaplasia and malignant transformation in endometriosis are two theories proposed for its existence. Peritoneal CCC can be oestrogen dependent in view of association with oestrogen dependent conditions which include endometriosis, adenomyosis and endometrial carcinoma. A genetic ascertain is difficult to be associated and needs further evaluation in a research setting in the familial cancer genetic clinics.

Leptin - a novel pharmacological agent for treatment of women with overactive bladder symptoms?

Overactive bladder is a common condition and is significantly known to affect quality of life in both men and women. It is usually associated with urinary urgency, frequency, nocturia with or without urinary incontinence. The exact aetiology of overactive bladder is unknown. The two main theories put forward include (a) disruption of central control of the bladder by excessive suprapontine excitation or reduced suprapontine inhibition (b) Peripheral abnormality due to excessive cholinergic excitation (increases release of acetylcholine which is calcium dependent) or reduced neuropeptidergic inhibition. The other factors which contribute to its cause include increase in caffeine intake and behavioural problems. Therefore the initial treatments are based on excluding pathology and implementing behavioural changes, bladder training and caffeine reduction. Anticholinergic drugs are the main pharmacological agents used in the treatment of overactive bladder and they are usually used in conjunction with the above treatment methods. Recently, an increase in serum leptin levels has been associated with overactive bladder symptoms. This possibly is not true because leptin actually reduces Ca2+ influx in the smooth muscle. The addition of increasing doses of leptin on uterine smooth muscle (in vitro) has shown to inhibit spontaneous as well as induced uterine contractions (myometrial biopsies taken from obese women) by reducing Ca2+ influx in obese women compared to normal weight women. We believe it may have similar action on the bladder and therefore expect inhibition of the bladder detrusor smooth muscle contraction rather than stimulation which may lead to overactive bladder symptoms. This action can be considered anticholinergic rather than cholinergic and therefore should improve overactive bladder symptoms. So could this hormone (leptin) be used as a new novel agent for treating women suffering with overactive bladder symptoms?

Leptin--a tocolytic agent for the future?

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. When biopsies of human myometrium from obese women were exposed to leptin, it showed a cumulative inhibitory effect on spontaneous as well as induced contractions. This lead to the proposed theory that leptin may be the cause of dysfunctional labour in obese women leading to increased caesarean section rates. There is an increased rate of post-dated pregnancies in obese women when compared to normal weight women with a consequent increased induction rate in women with a raised body mass index (BMI). Likewise there a decrease in the rate of spontaneous preterm delivery in obese women. These findings suggest that leptin inhibits uterine contractions in these women and this effect could be considered a tocolytic effect on uterine muscle. So could this hormone (leptin) be used as a tocolytic agent for threatened preterm labour in the future?

An unusual cause of postmenopausal bleeding.

BACKGROUND: Non-Hodgkin lymphoma usually presents with lymphadenopathy, fever, night sweats, and weight loss. Postmenopausal vaginal bleeding is a cardinal symptom of carcinoma of the endometrium or cervix but not one of non-Hodgkin lymphoma. Clinical awareness of this unusual mode of presentation is important. CASE: We report a case of non-Hodgkin lymphoma in a 60-year-old woman, who presented primarily with postmenopausal bleeding. Clinical examination revealed a "thickened" area on the posterior vaginal wall. Repeated vaginal biopsies showed fibrosis and inflammatory tissue only. Immunohistochemistry revealed non-Hodgkin lymphoma. This case highlights the diagnostic challenges such a complex case presents. CONCLUSION: This case not only represents a case of non-Hodgkin lymphoma with genital involvement but also highlights the importance of diagnosis and management of such complex cases.

Interesting case of ovarian sarcoidosis: the value of multi disciplinary team working.

BACKGROUND: Sarcoidosis of the genital tract is a rare condition. Ovarian manifestation of this disease is rarer still. CASE PRESENTATION: The case presented here represents ovarian manifestation of sarcoidosis. At the point of referral to our hospital, based on computerised tomography (CT) ovarian carcinoma was a differential diagnosis. Further magnetic resonance imaging along with CT guided biopsy aided by laboratory study supported a diagnosis of sarcoidosis. Patient responded to medical management by a multidisciplinary team. CONCLUSION: The case shows the importance of FNAC and biopsy in case or ovarian masses and multi disciplinary team approach to management.