Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

The INTERNATIONAL MISSION study: minimally invasive surgery in ovarian neoplasms after neoadjuvant chemotherapy.

OBJECTIVES: The aim of this retrospective multicenter study was to investigate the extent, feasibility, and outcomes of minimally invasive surgery at the time of interval debulking surgery in different gynecological cancer centers. METHODS/MATERIALS: In December 2016, 20 gynecological cancer centers were contacted by e-mail, to participate in the INTERNATIONAL MISSION study. Seven centers confirmed and five were included, with a total of 127 patients diagnosed with advanced epithelial ovarian cancer after neoadjuvant chemotherapy and minimally invasive interval surgery. Only women with a minimum follow-up time of 6 months from interval surgery or any cancer-related event before 6 months were included in the survival analysis. Baseline characteristics, chemotherapy, and operative data were evaluated. Survival analysis was evaluated using the Kaplan-Meier method. RESULTS : All patients had optimal cytoreduction at the time of interval surgery: among them, 122 (96.1%) patients had no residual tumor. Median operative time was 225 min (range 60 - 600) and median estimated blood loss was 100 mL (range 70 - 1320). Median time to discharge was 2 days (1-33) and estimated median time to start chemotherapy was 20 days (range 15 - 60). Six (4.7%) patients experienced intraoperative complications, with one patient experiencing two serious complications (bowel and bladder injury at the same time). There were six (4.7%) patients with postoperative short-term complications: among them, three patients had severe complications. The conversion rate to laparotomy was 3.9 %. Median follow-up time was 37 months (range 7 - 86): 74 of 127 patients recurred (58.3%) and 31 (24.4%) patients died from disease. Median progression-free survival was 23 months and survival at 5 years was 52 % (95% CI: 35 to 67). CONCLUSIONS: Minimally invasive surgery may be considered for the management of patients with advanced ovarian cancer who have undergone neoadjuvant chemotherapy, when surgery is limited to low-complexity standard cytoreductive procedures.

Conservative management of endometrial cancer: a survey amongst European clinicians.

OBJECTIVE: To investigate differences and similarities in the clinical approach of young clinicians managing women with endometrial cancer (EC) conservatively. METHODS: A web-based survey was carried out. A platform of the European Network of Young Gynaecological Oncologists (ENYGO) database was used. A 38-item multiple-choice questionnaire was used to evaluate current practice in fertility-sparing management of EC. The survey covered investigations, treatment options, follow-up and management of recurrence and future family planning. Descriptive statistics were used. RESULTS: Overall, 116 out of 650 (17.84%) ENYGO members responded to the survey. In 92 (79.3%) centres, the caseload of early stage EC treated conservatively was less than 10 per year. One hundred and seven responders (93.8%) believe that treatment with progestins could be offered in grade 1 EC without myometrial invasion, but a minority would recommend it even for grade 2 tumours with no myometrial invasion or grade 1 with superficial invasion. The diagnostic tool for establishing grade of tumour was hysteroscopy with dilatation and curettage in 64 (55%) centres. Medroxyprogesterone acetate represents the most commonly prescribed progestogen (55, 47.4%). In 78 (67.2%) centres, a repeat endometrial biopsy was offered after 3 months of treatment commencement. Recurrences are treated mostly with hysterectomy (81, 69.9%) with only a small number of responders recommending to repeat progestin treatment. Lynch syndrome is a contraindication for conservative management in half of the responders (57, 49.1%). Most clinicians agree that patients should be referred promptly for assisted reproductive techniques once complete response has been achieved (68, 58.6%). CONCLUSIONS: Our study shows that conservative management is increasingly offered to women affected by early stage EC wishing to preserve their fertility. Further studies and joint registries are required to evaluate safety and effectiveness of this approach in this probably growing number of patients.

Carcinoma of the recto-vaginal septum. Comprehensive literature review.

Carcinoma of the recto-vaginal septum is an extremely rare entity. We performed a MEDLINE-based search on recto-vaginal septum carcinoma, focussing on its management, in order to clarify which are the best treatment options for this disease. In addition an unpublished case report has been added to the review. 34 case reports were included in our review. Surgery and adjuvant chemoradiation therapy seem to be the most common treatment option. However, since primary surgical treatment leads to mutilation by removing a large portion of the vagina and the anal sphincter with a permanent terminal colostomy, primary platinum-based chemoradiation therapy could be considered. In case of extragastrointestinal stromal tumours primary surgical treatment seems to be the best option. Due to the rarity of this entity only limited data is available. Therefore further investigation is necessary.

Intravascular leiomyomatosis: an exceptional entity.

Intravenous leiomyomatosis (IVL) is a rare benign condition characterized by the proliferation of smooth muscle cells originating from either the uterine venous wall or a uterine myoma. This leiomyomatosis extends most frequently to pelvic vessels, but also occasionally into the inferior vena cava and right cardiac chambers. Preoperative diagnosis is difficult and it should be suspected in the presence of cardiac or pelvic masses in women who have undergone hysterectomy or myomectomy previously. The treatment is hysterectomy, normally associated with a bilateral oophorectomy and removing the mass or metastasis if any. The post-surgical follow-up should be performed at long-term and include exploration and imaging, either ultrasound or MRI. The association of antiestrogenic drugs can be useful for disease control, especially in cases where oophorectomy is not performed and the tumor cannot be removed completely.

[Meigs' syndrome caused by bilateral ovarian fibroma mimicking ovarian cancer]. / Síndrome de Meigs por fibroma ovárico bilateral parecido al cáncer de ovario.

CASE REPORT: We report the case of a 55-year-old patient who pre- sented a pelvic mass, ascites and elevated serum CA125. Suspecting a malignant process she underwent surgery and a total hysterectomy with bilateral salpigo-oforectomy was performed. Pathologic report revealed a bilateral ovarian fibroma and non-tumoral ascites. The presence of elevated serum CA125 levels in a postmenopausal woman with a pelvic mass and ascites suggest an ovarian malignant disease. However, in case of Meigs'syndrome, all symptoms will diappear after removal of the pelvic tumor, so a fast surgical management of the patients is mandatory.

Granular cells tumor of the vulva: an exceptional entity.

INTRODUCTION: Granular cells tumor (GCT) is a rare tumor that develops on skin and soft tissues. Only 1-2% of these tumors present malignant behavior. MATERIAL AND METHODS: The authors report three cases of GCT and review the management of these tumors. CASE REPORT: The first case is a 73-year-old woman who was diagnosed with an atypical GCT. She was treated with local excision and then presented a local recurrence 21 months after the surgery. The other two cases are 60- and 58-year-old women diagnosed with a benign GCT. They were treated with single excision; both patients underwent second surgery due to margin affectation. CONCLUSION: Management of GCT is not clear nowadays. The careful selection of patients with poor prognostic factors is very important. Follow-up for early diagnosis of local recurrence and metastases of these tumors is of utmost importance.

Experience and results of office hysteroscopy at a primary hospital.

Our aim was to analyse, retrospectively, the perioperative outcomes of 3,488 office hysteroscopies. Age, menopausal status, parity, medical indications, use or not of anaesthesia, incidents, presence of pathology in the cavity, endometrial pathology, type of surgery and pain assessment details were collected. The mean age of patients was 52.1 years. The most common medical indication was suspicious ultrasound for endometrial disease, and the most frequent symptom was metrorrhagia. We did not use any type of anaesthesia in 89.5% of patients and we could access the uterine cavity in 99.4% of cases. The complication rate was very low though 12% of patients reported severe pain while performing the test. Although office hysteroscopy in outpatients is fully established and is usually well tolerated, there is a group of patients who could benefit from analgesic treatment prior to the test, to improve their tolerance.

The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO).

BACKGROUND: Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. PATIENTS AND METHODS: A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbach's-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. RESULTS: One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5% were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH = 47.35) differed mainly by accredited training (P = 0.003). The training-satisfaction score (TSS) had high reliability (Cronbach's alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P = 0.001) and salary (P = 0.002). The TSS was independent of age (P = 0.360), working hours (P = 0.620), overtime-pay (P = 0.318), annual leave (P = 0.933), gender (P = 0.545) and marital status (P = 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. CONCLUSIONS: Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology training within Europe.

Nodal involvement evaluation in advanced cervical cancer: a single institutional experience.

PURPOSE: To assess the usefulness of different imaging techniques in the detection of nodal involvement in patients with advanced cervical carcinoma. Moreover, to analyze the correlation between the presurgical (FIGO) and postsurgical (pTNM) staging classifications. MATERIALS AND METHODS: All patients diagnosed with advanced cervical cancer (FIGO Stages IIB-IV) from 2005 to 2012 were selected. The medical charts of 51 patients that underwent presurgical assessment with posterior surgical staging by means of para-aortic lymphadenectomy, were reviewed. Nodal status assessment by computed tomography scan (CT scan), magnetic resonance imaging (MRI), positron emission tomography (PET), and sonography was compared, as well as the size given in imaging techniques compared to the final pathologic report information. RESULTS: Presurgical analysis by CT scan, MRI, PET, and sonography showed pelvic nodal involvement in 51.3% of patients, and para-aortic involvement in 30.8% of cases. CT scan showed positive pelvic nodes in 35% of cases, but pathologic confirmation was observed in just 17.6% of cases. However, MRI resulted in higher rates of up to 48.8% of cases. Concerning para-aortic nodal involvement, CT scan showed positive nodes in 25% of cases, MRI in 3.2% of cases, and the pathologic report in 15.6% of cases. The authors found significant differences between staging groups among both classifications (FIGO vs. pTNM; p < 0.001). Eight cases (15.7%) were understaged by FIGO classification. CONCLUSIONS: Despite all imaging techniques available, none has demonstrated to be efficient enough to avoid the systematic study of para-aortic nodal status by means of surgical evaluation.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new?: A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new? A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Evaluation of endometrial and subendometrial vascularization and endometrial volume by 3-D power Doppler ultrasound and its relationship with age and pregnancy in intrauterine insemination cycles.

AIMS: To measure endometrial volume and endometrial-subendometrial vascularization by 3-D power Doppler ultrasound in patients undergoing cycles of artificial insemination with ovarian stimulation, to evaluate their relationship with patients' age and pregnancy development. METHODS: We included patients with primary and secondary infertility of one year of evolution. We measured vascular indexes and endometrial volume by 3-D power Doppler ultrasound. RESULTS: Seventy-nine consecutive cycles were studied. Endometrial volume average was 4.7 ± 2.66 ml. We did not find any difference between the endometrial volumes in women who did versus did not become pregnant (9 vs. 70 women, respectively). The endometrial vascular index was significantly higher in patients aged between 31 and 33 years old. In patients between the ages of 31 and 33, both the endometrial flow index (FI; p = 0.017) and the endometrial vascular FI (p = 0.013) were higher. At the subendometrial area, the vascular FI was lower in women older than 33 years old (p = 0.024), while the FI was higher in patients that achieved pregnancy (p = 0.047). CONCLUSIONS: Endometrial volumes were independent of pregnancy development. Endometrial and subendometrial vascularization FIs were significantly higher in younger women. The subendometrial FI was significantly higher in patients who achieved pregnancy.

Bax expression in untreated breast cancer: an immunocytometric study of 255 cases.

BACKGROUND: Bax is one of the main effectors of apoptosis in breast cancer. However, in contrast with the antiapoptotic protein Bcl-2, which has been extensively studied in this tumor, there are relatively few clinical studies on the biological role of Bax in breast cancer. MATERIALS AND METHODS: The expression of the apoptosis-related Bax gene was studied in a series of 255 previously untreated breast cancers by means of immuno-flow cytometry. Additionally, and by the same method, the expression of the Bcl-2, VEGF and Nup88 genes were also studied. As variables of the study for the final statistical analysis, the histological variety of the tumors, histological and nuclear grade, the expression of hormone receptors, p53, Ki-67 or c-erb-B2, axillary node invasion, tumor size and DNA-ploidy were also included. RESULTS: The expression of the proapoptotic Bax protein was significantly associated with the expression of Nup88 (p<0.0001), VEGF (p=0.0014) and Bcl-2 (p=0.0063), all measured by the same method. An inverse correlation with c-erb-B2 expression, which almost attained statistical significance (p=0.058) was also registered. CONCLUSION: This study adds evidence to the little explored link between apoptosis and angiogenesis. Furthermore, it discloses a previously unreported relationship between Bax and Nup88 expression.

Current situation in gynecological oncology training in Spain: where we are and where we want to go.

BACKGROUND: It is important to know what a young gynecologic oncologist perceives as a need to achieve a good training in gynecologic oncology. OBJECTIVE: This study aims to evaluate the level of training in gynecologic oncology in Spain. METHODS: A Web-based anonymous questionnaire was sent via e-mail to Spanish trainees listed in European Network of Young Gynecological Oncology (ENYGO). The survey was developed in four sections: (1) general training in gynecologic oncology, (2) distribution of current clinical activity, (3) surgical training, and (4) perspective future gynecologic oncology. It contained 51 questions, with multiple-choice answers that had to be answered by the ENYGO members. RESULTS: The questionnaire was sent to 64 people listed in the ENYGO database. Of these, 37 members responded (response rate of 58%). Overall, more training in surgery is necessary, to perform radical oncological surgeries. It is claimed a sub-specialty recognition, to ensure an equalitarian and homogeneous training.

Conservative treatment of early stage ovarian cancer: oncological and fertility outcomes.

BACKGROUND: Ovarian cancer may appear in young women during their reproductive age. As a result of late childbearing nowadays, fertility preservation has become a major issue in young women with gynecological cancer. The aim of this review is to update the current knowledge on conservative treatment and fertility preservation of women affected of early stage epithelial ovarian cancer. MATERIAL AND METHODS: A web-based search in Medline and CancerLit databases on conservative treatment for early stage ovarian cancer has been carried out. All relevant information has been collected and analyzed. RESULTS: Less than 40% of ovarian cancers are diagnosed at early stages. Conservative treatment may be considered in young patients with a relapse rate that ranges from 9% to 29%, and a 5-year survival ranging from 83% to 100%. Recurrences in the controlateral ovary has been reported to be less than 5%, with most of these patients being alive after savage treatments. Moreover, it has been reported good fertility outcomes after conservative treatment with a successful conception rate that ranges from 60% to 100%, with an abortion rate under 30% in all series reported. CONCLUSIONS: Conservative treatment for early epithelial ovarian cancers could be a safe option for women younger than 40 years who wish to preserve their childbearing potential. We need a strict case selection such as FIGO stage I grade 1 and 2, although grade 3 cases could be considered.

Class I versus class III radical hysterectomy in stage IB1-IIA cervical cancer. A prospective randomized study.

OBJECTIVE: The standard treatment for stage IB-IIA cervical cancer over the past three decades has been the Piver-Rutledge type III radical hysterectomy. This surgery implies a high rate of urologic morbidity. The objective was to determine the role of class I radical hysterectomy compared to class III radical hysterectomy in terms of morbidity, overall survival, DFS and patterns of relapse in patients undergoing primary surgery. MATERIALS AND METHODS: 125 patients with stage IB1 and IIA cervical cancer ≤ 4 cm were randomized between type I and type III hysterectomy. Clinical, pathologic and follow-up data were prospectively collected. Adjuvant radiotherapy was administered when indicated. Univariate and multivariate analyses were carried out. RESULTS: Sixty-two patients were randomized to class I surgery and 63 to class III. No significant differences were observed regarding pathologic findings and adjuvant treatment. Morbidity rates were higher after class III surgery (84% versus 45%). Pelvic recurrences were equal in both groups (8 cases each one). Fifteen-year overall survival rate was 90 and 74% respectively (p = 0.11) and 76 and 80% when cervical size is ≤ 3 cm (p = 0.88). CONCLUSIONS: There are no significant differences in terms of both recurrence rate and overall survival among patients with stage IB-IIA cervical cancer undergoing simple extrafascial hysterectomy (class I) or radical hysterectomy (class III). Morbidity is proportional to the extent of radicality. These data confirm the need of tailoring the extent of resection to the characteristics of the cervical neoplasia and open new interesting pathways to upcoming protocols for the conservative management of these tumors.