Oncological outcomes among young women with non-epithelial ovarian cancer: the YOC-Care study (Young Ovarian Cancer - Care).

OBJECTIVE: To determine oncological outcomes and associated prognostic factors in women younger than 45 years diagnosed with non-epithelial ovarian cancer. METHODS: A retrospective, multicenter Spanish study was performed including women with non-epithelial ovarian cancer younger than 45 years between January 2010 and December 2019. All types of treatments and stages at diagnosis with at least 12 months of follow-up were collected. Women with missing data, epithelial cancers, borderline or Krukenberg tumors, and benign histology, as well as patients with previous or concomitant cancer, were excluded. RESULTS: A total of 150 patients were included in this study. The mean±SD age was 31.45±7.45 years. Histology subtypes were divided into germ cell (n=104, 69.3%), sex-cord (n=41, 27.3%), and other stromal tumors (n=5, 3.3%). Median follow-up time was 58.6 (range: 31.10-81.91) months. Nineteen (12.6%) patients presented with recurrent disease with a median time to recurrence of 19 (range: 6-76) months. Progression-free survival and overall survival did not significantly differ among histology subtypes (p=0.09 and 0.26, respectively) and International Federation of Gynecology and Obstetrics (FIGO) stage (I-II vs III-IV) with p=0.08 and p=0.67, respectively. Univariate analysis identified sex-cord histology with the lowest progression-free survival. Multivariate analysis showed that body mass index (BMI) (HR=1.01; 95% CI 1.00 to 1.01) and sex-cord histology (HR=3.6; 95% CI 1.17 to 10.9) remained important independent prognostic factors for progression-free survival. Independent prognostic factors for overall survival were BMI (HR=1.01; 95% CI 1.00 to 1.01) and residual disease (HR=7.16; 95% CI 1.39 to 36.97). CONCLUSIONS: Our study showed that BMI, residual disease, and sex-cord histology were prognostic factors associated with worse oncological outcomes in women younger than 45 years diagnosed with non-epithelial ovarian cancers. Even though the identification of prognostic factors is relevant to identify high-risk patients and guide adjuvant treatment, larger studies with international collaboration are essential to clarify oncological risk factors in this rare disease.

One-Step Nucleic Acid Amplification (OSNA) of Sentinel Lymph Node in Early-Stage Endometrial Cancer: Spanish Multicenter Study (ENDO-OSNA).

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 µm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/µL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial.

BACKGROUND: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. METHODS: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02494063). RESULTS: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. INTERPRETATION: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

Central Pathology Review in SENTIX, A Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2).

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.

Prognostic classification of endometrial cancer using a molecular approach based on a twelve-gene NGS panel.

Endometrial Cancer (EC) is one of the most common malignancies in women in developed countries. Molecular characterization of different biotypes may improve clinical management of EC. The Cancer Genome Atlas (TCGA) project has revealed four prognostic EC subgroups: POLE, MSI; Copy Number Low (CNL) and Copy Number High (CNH). The goal of this study was to develop a method to classify tumors in any of the four EC prognostic groups using affordable molecular techniques. Ninety-six Formalin-Fixed Paraffin-embedded (FFPE) samples were sequenced following a NGS TruSeq Custom Amplicon low input (Illumina) protocol interrogating a multi-gene panel. MSI analysis was performed by fragment analysis using eight specific microsatellite markers. A Random Forest classification algorithm (RFA), considering NGS results, was developed to stratify EC patients into different prognostic groups. Our approach correctly classifies the EC patients into the four TCGA prognostic biotypes. The RFA assigned the samples to the CNH and CNL groups with an accuracy of 0.9753 (p < 0.001). The prognostic value of these groups was prospectively reproduced on our series both for Disease-Free Survival (p = 0.004) and Overall Survival (p = 0.030).Hence, with the molecular approach herein described, a precise and suitable tool that mimics the prognostic EC subtypes has been solved and validated. Procedure that might be introduced into routine diagnostic practices.

Relevance of minor discrepancies at second pathology review in gynaecological cancer.

AIM: To determine the incidence of discrepancy rate between the initial pathology diagnosis and referral diagnosis in women with gynaecological cancer. METHODS: A retrospective observational study was performed including all consecutive patients with gynaecological cancer referred and who underwent pathologic review between January 2013 and May 2017. Discrepancies were minor when future treatment was not altered or major when the treatment was modified. RESULTS: A total of 259 patients were included. The original diagnosis was ovarian cancer (n = 126, 48.6%), endometrial cancer (n = 84, 32.4%), cervical cancer (n = 43, 16.6%) and vulvar cancer (n = 6, 2.3%). Eighteen women (6.9%) had major discrepancies and 69 patients (26.6%) had minor discrepancies. The main reason for the minor discrepancy was tumour grade or histology subtype. Regarding ovarian cancer, 13 out of 16 patients had minor discrepancies at histology subtype among serous, endometrioid, mucinous or undifferentiated tumours. The main issue for the minor discrepancy in patients with cervical cancer was among different subtype of cervical adenocarcinoma. Minor discrepancies due to tumour grade were also observed in 14, 19, 8 and 3 patients with endometrial, ovarian, cervical and vulvar cancer, respectively. CONCLUSIONS: A second pathology review also adds valid information in those cases with minor discrepancies leading to a difference in patients´ counselling regarding follow-up and prognosis.

A different surgical approach for cardiophrenic lymph node resection in advanced ovarian cancer.

OBJECTIVE: To describe the surgical technique of a subxiphoid approach to remove cardiophrenic lymph nodes in women with advanced ovarian cancer. MATERIALS AND METHODS: The first step is to dissect and separate the anterior insertions of the diaphragm at the xiphoid appendix. Thus, the parietal peritoneum and the upper fibres of the transversus abdominis muscle are incised. Then, the anteroinferior mediastinum is identified and dissected. Diaphragmatic deinsertion may be extended 5-7 cm laterally to the xiphoid appendix following the inferior costal margin according with the localization of the enlarged lymph nodes. Thus, the dissection of the anterolateral cardiophrenic space allows the identification of both pleura. In addition, the vertical dissection of the anterior cardiophrenic space allows the removal of enlarged lymph nodes. However, it is important to bear in mind at this time that the unintentional opening of the pleura is possible. To reduce this risk, a careful dissection of the anterior cardiophrenic fat tissue is essential. Moreover, a careful dissection will avoid damage at the left phrenic nerve as well as the left pericardiophrenic artery and vein. After removing the cardiophrenic fat tissue, the diaphragm is sutured at the lower costal margin by using separated stiches of absorbable 2-0 suture. CONCLUSION: The subxiphoid approach to resect cardiophrenic lymph nodes is a feasible surgical technique. In addition, it reduces the possibility of opening the pleural cavity, while avoiding a diaphragmatic incision, in comparison with the standard trans-diaphragmatic surgical approach.

Malignant Bowel Obstruction in Relapsed Ovarian Cancer With Peritoneal Carcinomatosis: An Occlusive State.

OBJECTIVE: The aim of this study was to describe the clinical and oncological outcomes of women with malignant bowel obstruction (MBO) for relapsed ovarian cancer and peritoneal carcinomatosis. METHODS: A retrospective cohort study was performed in all consecutive patients admitted at Instituto Valenciano de Oncología, Valencia, Spain, between July 2013 and July 2016 with MBO for relapsed ovarian cancer and peritoneal carcinomatosis. All patients underwent the same protocol of conservative management. Surgical treatment was indicated only in selected cases. RESULTS: There were a total of 22 patients presenting 59 episodes of MBO; 17 (77.2%) of those patients presented more than 1 episode of MBO. All patients had serous epithelial ovarian cancer; 18 (81.8%) were high grade, and 4 (18.2%) low-grade tumors. The median (range) number of episodes per patient was 3 (range, 1-7) with a mean length of hospitalization of 13 (SD, 13.6) days. The median time interval between episodes of MBO (54 episodes in 17 patients) was 17 days (range, 1-727 days). Twenty of 22 patients died with a median overall survival time from the first episode of MBO of 95 days (95% confidence interval, 49-124 days). CONCLUSIONS: Patients with MBO due to relapsed epithelial ovarian cancer in the peritoneal carcinomatosis setting have a short life expectancy, presenting a median of 3 episodes of MBO until death, with a short time interval between episodes. These findings show that bowel obstruction can represent a constant status over time until death.

Patterns of Lymph Node Metastases in Apparent Stage I Low-Grade Epithelial Ovarian Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to determine oncological outcomes and incidence of lymph node (LN) metastases in women who underwent systematic pelvic and paraaortic lymphadenectomy for surgical staging of apparent stage I low-grade epithelial ovarian cancer (LGEOC). MATERIALS AND METHODS: A retrospective study was performed at nine institutions across Europe and the US, and patients who underwent surgical staging for presumed stage I LGEOC between 2000 and 2016 were included. To ensure surgical quality, a minimum number of ≥10 pelvic and ≥10 paraaortic LNs was required. Patients with preoperative radiologic or clinical evidence of extraovarian or LN disease, and those with nonepithelial histology, were excluded. RESULTS: The overall incidence of LN metastases was 4.3% in the 163 evaluated patients, and the incidence of LN involvement in serous, endometrioid, and mucinous subtypes was 10.7, 1.5, and 0%, respectively. However, Upstaging due to LN involvement alone occurred in only 2.4% of the patients. Eighty-nine (54.6%) patients received adjuvant chemotherapy due to International Federation of Gynecology and Obstetrics stage IC or higher disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 93.2% (95% confidence interval [CI] 89.4-97.1%) and 94.5% (95% CI 90.9-98.0%), respectively. There was no significant difference in PFS or OS between LN-negative and LN-positive patients. However, fewer patients received adjuvant chemotherapy in the LN-negative group. Multivariate analysis did not identify any independent prognostic factor of survival. CONCLUSION: The risk of LN involvement in nonserous apparent stage I LGEOC appears low, with a rate of <1% in this retrospective analysis, raising questions about the value of lymphadenectomy in those patients. Larger-scale prospective studies are warranted to evaluate the oncologic safety of omitting systematic LN staging in apparent stage I nonserous LGEOC.

Robotic Surgery in Women With Ovarian Cancer: Surgical Technique and Evidence of Clinical Outcomes.

Robotic surgery is a new technology that has been progressively implemented to treat endometrial and cervical cancer. However, the use of robotic surgery for ovarian cancer is limited to a few series of cases and comparative studies with laparoscopy or laparotomy. The technical issues concerning robotic surgery, as well as clinical evidence, are described in this review. Robotic surgery in early stage, advanced stage, and relapsed ovarian cancer is discussed separately. In conclusion, evidence regarding the use of robotic-assisted surgical treatment for women with ovarian cancer is still scarce, but its use is progressively growing. Robotic-assisted staging in selected patients with early stage disease has an important role in referral institutions when well-trained gynecologists perform surgeries. However, minimally invasive surgery in patients with advanced stage or relapsed ovarian cancer requires further investigation, even in selected cases.

Selecting the best strategy of treatment in newly diagnosed advanced-stage ovarian cancer patients.

Although it is assumed that the combination of chemotherapy and radical surgery should be indicated in all newly diagnosed advanced-stage ovarian cancer patients, one of the main raised questions is how to select the best strategy of initial treatment in this group of patients, neoadjuvant chemotherapy followed by interval debulking surgery or primary debulking surgery followed by adjuvant chemotherapy. The selection criteria to offer one strategy over the other as well as a stepwise patient selection for initial treatment are described. Selecting the best strategy of treatment in newly diagnosed advanced stage ovarian cancer patients is a multifactorial and multidisciplinary decision. Several factors should be taken into consideration: (1) the disease factor, related to the extension and localization of the disease as well as tumor biology; (2) the patient factor, associated with patient age, poor performance status, and co-morbidities; and (3) institutional infrastructure factor, related to the lack of prolonged operative time, an appropriate surgical armamentarium, as well as well-equipped intensive care units with well-trained personnel.

Laparoscopic extraperitoneal para-aortic lymphadenectomy.

Lymph nodes are the main pathway in the spread of gynaecological malignancies, being a well-known prognostic factor. Lymph node dissection is a complex surgical procedure and requires surgical expertise to perform the procedure, thereby minimising complications. In addition, lymphadenectomy has value in the diagnosis, prognosis, and treatment of patients with gynaecologic cancer. Therefore, a video focused on the para-aortic retroperitoneal anatomy and the surgical technique of the extraperitoneal para-aortic lymphadenectomy is presented.

The Relevance of Gynecologic Oncologists to Provide High-Quality of Care to Women with Gynecological Cancer.

Gynecologic oncologists have an essential role to treat women with gynecological cancer. It has been demonstrated that specialized physicians who work in multidisciplinary teams to treat women with gynecological cancers are able to obtain the best clinical and oncological outcomes. However, the access to gynecologic oncologists for women with suspected gynecological cancer is scarce. Therefore, this review analyzes the importance of specialized care of women with ovarian, cervical, and endometrial cancer. In addition, the role of gynecologic oncologists who offer fertility-sparing treatment as well as their role in assisting general gynecologists and obstetricians is also reviewed.