Superparamagnetic iron oxide (SPIO) for sentinel lymph node detection in vulvar cancer.

OBJECTIVES: Sentinel lymph node (SLN) detection with superparamagnetic iron oxide (SPIO) nanoparticles has been widely studied and standardized for breast and prostate cancer, but there is scarce evidence concerning its use in vulvar cancer. The objective of this study was to compare SLN detection using a SPIO tracer injected at the time of the surgery detected by a magnetometer, with the standard procedure of using a technetium 99 radioisotope (Tc99) detected by a gamma probe, in patients with vulvar cancer. METHODS: The SPIO vulvar cancer study was a single-center prospective interventional non-inferiority study of SPIO compared to Tc99, conducted between 2016 and 2021 in patients who met the GROINSS-V study inclusion criteria for selective sentinel lymph node dissection in vulvar cancer. RESULTS: We included 18 patients and a total of 41 SLNs. The level of agreement between tracers was 92.7% (80.6%-97.4%), corresponding to 38 out of 41 SLNs, which confirms the non-inferiority of SPIO compared to Tc99. The SLN detection rate per groin was 96.3 (81.7%-99.3) using Tc99 and 100% (87.5%-100%) using SPIO. Both tracers had a detection rate of 100% for positive lymph nodes. CONCLUSIONS: The use of SPIO as a tracer for detecting SLNs in patients with vulvar cancer has shown to be non-inferior to that of the standard radiotracer, with the advantages of not requiring nuclear medicine and being able to inject it at the time of surgery after induction of anesthesia.

Impact of Hospital Case Volume on Uterine Sarcoma Prognosis: SARCUT Study Subanalysis.

BACKGROUND: High-complexity and low-prevalence procedures benefit from treatment by referral centers. The volume of cases necessary to maintain high training in the treatment of gynecologic sarcoma is currently unknown. This study aimed to determine differences in survival and recurrence as a function of the volume of patients treated per center. METHODS: The multicentric cross-sectional SARComa of the Uterus (SARCUT) study retrospectively collected cases of uterine sarcomas from 44 centers in Europe from January 2001 to December 2007. The survival of patients treated in high case-volume (HighCV) centers was compared with the survival of patients treated in low case-volume (LowCV) centers. RESULTS: The study enrolled 966 patients: 753 in the LowCV group and 213 in the HighCV. Overall survival (OS) was 117 months, and cancer-specific survival (CSS) was 126 months. The difference was significant (respectively p = 0.0003 and 0.0004, log rank). After adjustment for other confounding factors, the remaining significant factors were age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03-1.05), histology (HR, 1.19; 95% CI, 1.06-1.34), extrauterine involvement (HR, 1.61; 95% CI, 1.24-2.10) and persistent disease after treatment (HR, 3.22; 95% CI, 2.49-4.18). The cytoreduction performed was significantly associated with the CSS and OS in both groups. The log rank for surgical cytoreduction was a p value lower than 0.0001 for OS, lower than 0.0001 for the LowCV centers, and 0.0032 for the HighCV centers. CONCLUSIONS: The prognosis for patients with uterine sarcoma is directly related to complete tumor cytoreduction, histologic type, and FIGO stage, with significant differences between low and high case-volume centers. Patients with uterine sarcomas should be centralized in HighCV centers to improve their oncologic outcomes.

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.

Prognostic factors in young women with epithelial ovarian cancer: the Young Ovarian Cancer-Care (YOC-Care) study.

OBJECTIVE: To determine oncological outcomes and to identify prognostic factors in women aged <45 years with epithelial ovarian cancer. METHODS: A multicenter retrospective study was performed of patients treated for epithelial ovarian cancer aged <45 years between January 2010 and December 2019. RESULTS: A total of 998 patients with epithelial ovarian cancer from 55 different institutions in Spain were collected. The median age of the study population was 40.8 years (range 35.6-43.4). The grouped International Federation of Gynecology and Obstetrics (FIGO) stage distribution was 508 (50.9%) patients in initial stages (I and II) and 490 (49.1%) with advanced stages (III and IV). Three hundred and twenty-five (32.6%) patients presented with recurrent disease after a median follow-up of 33.1 months (range 16.1-66.4). The type of staging surgery (incomplete vs complete), type of initial treatment modality (primary cytoreduction vs interval surgery), and amount of residual disease were all significantly associated with overall survival. Tumor rupture was noted in 288 (27.9%) cases, but it was not associated with oncologic outcomes (p=0.11 for overall survival). In the multivariate analysis, the response based on radiological findings (HR 3.24, 95% CI 2.14 to 4.91 for partial response; HR 6.93, 95% CI 4.79 to 10.04 for progression), neoadjuvant chemotherapy (HR 1.42, 95% CI 1.04 to 1.94), and FIGO stage (HR 1.68, 95% CI 1.40 to 2.02) were identified as independent prognostic factors associated with worse oncologic outcomes (p<0.001). CONCLUSION: The partial and progression radiology-based response after chemotherapy, neoadjuvant chemotherapy, and advanced FIGO stage are independent prognostic factors associated with worse oncological outcomes in women aged <45 years with epithelial ovarian cancer.

SUCCOR quality: validation of ESGO quality indicators for surgical treatment of cervical cancer.

OBJECTIVE: To evaluate whether compliance with European Society of Gynaecological Oncology (ESGO) surgery quality indicators impacts disease-free survival in patients undergoing radical hysterectomy for cervical cancer. METHODS: In this retrospective cohort study, 15 ESGO quality indicators were assessed in the SUCCOR database (patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage 2009 IB1, FIGO 2018 IB1, and IB2 cervical cancer between January 2013 and December 2014), and the final score ranged between 0 and 16 points. Centers with more than 13 points were classified as high-quality indicator compliance centers. We constructed a weighted cohort using inverse probability weighting to adjust for the variables. We compared disease-free survival and overall survival using Cox proportional hazards regression analysis in the weighted cohort. RESULTS: A total of 838 patients were included in the study. The mean number of quality indicators compliance in this cohort was 13.6 (SD 1.45). A total of 479 (57.2%) patients were operated on at high compliance centers and 359 (42.8%) patients at low compliance centers. High compliance centers performed more open surgeries (58.4% vs 36.7%, p<0.01). Women who were operated on at centers with high compliance with quality indicators had a significantly lower risk of relapse (HR=0.39; 95% CI 0.25 to 0.61; p<0.001). The association was reduced, but remained significant, after further adjustment for conization, surgical approach, and use of manipulator surgery (HR=0.48; 95% CI 0.30 to 0.75; p=0.001) and adjustment for adjuvant therapy (HR=0.47; 95% CI 0.30 to 0.74; p=0.001). Risk of death from disease was significantly lower in women operated on at centers with high adherence to quality indicators (HR=0.43; 95% CI 0.19 to 0.97; p=0.041). However, the association was not significant after adjustment for conization, surgical approach, use of manipulator surgery, and adjuvant therapy. CONCLUSIONS: Patients with early cervical cancer who underwent radical hysterectomy in centers with high compliance with ESGO quality indicators had a lower risk of recurrence and death.

Role of fluorescence imaging for intraoperative intestinal assessment in gynecological surgery: a systematic review.

BACKGROUND: Our aim was to review the current knowledge of the role of fluorescence imaging for intraoperative intestinal assessment in gynecological surgery. MATERIAL AND METHODS: A computer-based systematic review was performed from 2000 to 2020. All articles describing the use of indocyanine green (ICG) applied to bowel assessments in gynecology or endometriosis surgery were considered for review. RESULTS: ICG is an effective tool for assessing bowel vascularization, potentially preventing anastomotic leakage and recto-vaginal fistula and can therefore be useful for endometriosis surgery or bowel assessment in gynecological oncology procedures. Real-time characterization of the hypovascular pattern of endometriotic nodules has been associated with a larger nodule size and lower microvessel density, helping surgeons choose the best transecting line and the most appropriate technique. ICG angiography allows for a laparoscopic and intrarectal bowel assessment, which can act as a double check of bowel perfusion, enabling the assessment of mucosa vascularization. ICG fluorescence can guide intraoperative decision-making after intestinal anastomosis, discoid resection, and rectal shaving, preventing anastomotic leakage and postoperative recto-vaginal fistula in low anterior resections. CONCLUSIONS: ICG angiography provides a better intestinal assessment. Larger, prospective, randomized controlled studies are needed to validate the technique and confirm these encouraging results.

Utility of Intraoperative Fluorescence Imaging in Gynecologic Surgery: Systematic Review and Consensus Statement.

BACKGROUND: This study aimed to review the current knowledge on the utility of intraoperative fluorescence imaging in gynecologic surgery and to give evidence-based recommendations to improve the quality of care for women who undergo gynecologic surgery. METHODS: A computer-based systematic review of the MEDLINE, CENTRAL, Pubmed, EMBASE, and SciSearch databases as well as institutional guidelines was performed. The time limit was set at 2000-2019. For the literature search, PRISMA guidelines were followed. A modified-Delphi method was performed in three rounds by a panel of experts to reach a consensus of conclusions and recommendations. RESULTS: Indocyanine green (ICG) is used primarily in gynecology for sentinel node-mapping. In endometrial and cervical cancer, ICG is a feasible, safe, time-efficient, and reliable method for lymphatic mapping, with better bilateral detection rates. Experience in vulvar cancer is more limited, with ICG used together with Tc-99 m as a dual tracer and alone in video endoscopic inguinal lymphadenectomy. In early ovarian cancer, results are still preliminary but promising. Indocyanine green fluorescence imaging also is used for ureteral assessment, allowing intraoperative ureteral visualization, to reduce the risk of ureteral injury during gynecologic surgery. CONCLUSIONS: For most gynecologic cancers, ICG fluorescence imaging is considered the tracer of choice for lymphatic mapping. The use of this new technology expands to a better ureteral assessment.

Fertility preservation treatment of gynecological cancer patients in Spain: a national survey (GOFER study).

PURPOSE: To analyze the current management and use of fertility preservation (FP) treatments among different gynecologic oncology centers in Spain METHODS: From March to April 2019, a transversal study was conducted using a national online survey to consultants registered in the section of Gynecologic Oncology of the Spanish Society of Obstetrics and Gynecology. The survey contained 30 questions that assessed the perceptions and attitudes towards fertility-sparing strategies as well as its management in each participating center. RESULTS: A total of 51 responders from 12 out of 17 geographical regions of Spain answered the survey. According to 35 responders (68.63%), the age limit for offering FP was 40 years. In most of the centers, an ovarian reserve study is carried out prior to a FP procedure (34 responders, 66.67%). In cervical cancer size, limit for offering trachelectomy is 2 cm (40 responders, 78.43%), with LVSI as an exclusion factor for 26 (51%). Twenty-four (48.98%) responders reported that FP only in ovarian cancer stages IA, 12 (24.49%) also in stages IB, and an additional 13 (26.53%) up to stages IC. Most responders perform FP only in the absence of myometrial infiltration (30, 58.82%) in patients with g1-g2 endometrial cancer. CONCLUSIONS: The performance of professionals at the national level is uneven, demonstrating the need for referral centers to ensure optimal management. International guidelines should be more widely extended throughout Spain to homogenize the treatment of young oncology patients who wish to have children.

Prevention of lymphorrhea in aortic lymphadenectomy.

The objective of this video 1 is to describe the technique to avoid postoperative lymphorrhea after a lumboaortic lymphadenectomy. All procedures were performed at Donostia University Hospital, a tertiary referral and educational center in San Sebastián, Spain. Lumboaortic extra-peritoneal lymphadenectomy was performed for several gynecological malignancies (endometrial and cervical cancer). During the procedure, afferent lymphatic capillaries were identified at the infra-renal aortic level and clipped to avoid retrograde lymphorrhea at this level. Numerous strategies have been described to reduce the likelihood of lymphorea and lymphocele formation.1 Harmonic scalpel and other sealing advanced devices are not useful to secure lymphatic leakage at this level, although some authors have published a clinical benefit in their use,2 while clips have been found useful to prevent leakage in other lymphatic locations.3 The use of harmonic scalpel, biological agents or surgical patch has been ineffective in our experience, but sealing clips and peritonization (marsupialization),4 once the procedure is concluded, could be an effective approach. Performing simple gestures during lumboaortic lymphadenectomy can help to reduce the appearance of posterior lymphorrhea.

Accessory polar renal artery not pre-operatively visualized at extra-peritoneal para-aortic lymphadenectomy.

The objective of this video is to describe the technique of extra-peritoneal para-aortic laparoscopic lymphadenectomy and emphasize potential vascular risks that should be taken into account during the procedure.The procedure was performed at Donostia University Hospital, a tertiary referral and educational center in San Sebastián, Spain.A 58-year-old woman, body mass index 25.4 kg/m2, G2P2, with a diagnosis of intermediate-risk endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) IBG2 based on pre-operative endometrial histology and pre-operative magnetic resonance imaging (MRI), but upstaged to high-risk endometrial adenocarcinoma on final report (IBG3). In our hospital, risk stratification is based on pelvic MRI (myometrial invasion, cervical invasion) and biopsy (histology and grade) to tailor surgery. Computed tomography (CT) scan pre-operatively is only performed for type 2 endometrial carcinoma and grade 3 histologies.The local institutional review board was consulted, which confirmed that the study was exempt from requiring approval.The patient underwent an extra-peritoneal para-aortic laparoscopic lymphadenectomy, trans-peritoneal bilateral pelvic lymphadenectomy, and a total hysterectomy and bilateral salpingo-oophorectomy.It is mandatory to check pre-operative imaging studies in order to identify vascular anomalies that are not uncommon and may increase the risk of vascular complications.1 Frequently these vascular anomalies, such as a retro-aortic left renal vein, or a double vena cava or left vena cava, may be a casual finding in the pre-operative study, and often such findings are not reported by the radiologist. It is vitally important that the surgeon checks for and identifies any such anomolies, as the risk of complications may be decreased if anomalies of this type are detected pre-operatively.In addition, in the case of existing polar renal arteries, these are frequently not identified in the pre-operative study,2 leading to a risk of injury and partial renal necrosis. There are several anatomical variations of the renal arteries, with an aortic lower polar artery found in 3% of cadavers and 1% of patients on CT, more frequently on the right side.3 Renovascular hypertension4 secondary to an injury of an accessory polar renal artery (APRA) has also been described.Although vascular anomalies, especially venous ones, are more frequently found at the infra-renal left level, in this video we show access to the right side of the dissection and the care that needs to be taken in order not to damage a vascular structure at this level. Special caution is required with the right side of the dissection so as not to injure any perforating veins, including Fellow's vein, when pushing all the nodes to the roof of the dissection.The dissection maneuvers are fine and blunt, establishing bridges of tissue to be sectioned, and thus identifying vascular structures, such as a right APRA that is to be identified and preserved.The surgeon must have a good knowledge of retro-peritoneal vascular anatomy, they should examine pre-operative imaging studies to check for vascular anomalies, and they need to possess an accurate surgical technique to avoid potential vascular injury during laparoscopic para-aortic lymphadenectomy.

Maximizing Sentinel Lymph Node Detection: Aortic Sentinel Lymph Node Detection in Endometrial Cancer.

STUDY OBJECTIVE: To determine the importance of a dual (cervical and fundal) indocyanine green (ICG) injection and thorough dissection for the detection of sentinel lymph nodes (SLNs). DESIGN: Description and step-by-step demonstration of the surgical procedure using video (Canadian Task Force classification III). SETTING: Hospital Universitario Donostia, San Sebastián, Spain. PATIENTS: A 60-year-old woman with a diagnosis of IAG1 endometrial adenocarcinoma (EC). INTERVENTIONS: The patient received a cervical and transcervical fundal ICG injection for para-aortic and pelvic SLN detection in the setting of a research protocol, followed by a total hysterectomy and bilateral salpingo-oophorectomy with a frozen section of the uterus as a standard approach [1]. Institutional Review Board approval was obtained for the research protocol of this study. MEASUREMENTS AND MAIN RESULTS: Dual ICG injection [2] adds the benefit of a cervical injection (that best evaluates the pelvic region [3]) to the fundal injection, with better spread to the lumboaortic pathway [4] so as not to lose the aortic drainage and aortic SLN, whose relevance is still discussed due to its low incidence of metastasis [5]. This search does not add to the associated morbidity but is associated with increased operative time. For pelvic SLN dissection, patience and good training are key; the surgeon must always be on the lookout for uncommon pathways if no SLN is detected in the classical areas. The final histological classification was upgraded to a grade IIIC2 (ie, micrometastasis in the aortic and pelvic-right pararectal space) EC, 3 cm G1 with no lymphovascular invasion. CONCLUSION: Dual ICG injection allows comprehensive mapping not only of pelvic SLNs, but also of para-aortic SLNs, in EC, maximizing the identification of all possible affected areas. Nonetheless, the relevance of its added benefit requires further evaluation.

Efficacy of a Fibrin Sealant (Tissucol Duo) for the Preventionof Lymphocele after Laparoscopic Pelvic Lymphadenectomy:A Randomized Controlled Trial.

STUDY OBJECTIVE: To assess the efficacy of Tissucol Duo (Baxter AG, Vienna, Austria) fibrin sealant in decreasing the incidence of lymphocele (LC) after pelvic laparoscopic lymph node dissection using harmonic shears. DESIGN: Randomized controlled trial (Canadian Task Force classification level I). SETTING: Tertiary referral and educational center. PATIENTS: Seventy-four patients randomized to the use of sealant per hemipelvis. INTERVENTION: Fibrin sealant. MEASUREMENTS AND MAIN RESULTS: After bilateral pelvic lymphadenectomy a fibrin sealant was used in 1 hemipelvis but not the other, applied in 41 patients (55.4%) to the left and 33 patients (44.6%) to the right hemipelvis. The primary outcome was the incidence of LC after surgery in symptomatic and asymptomatic patients. Imaging (ultrasound, computed tomography, and magnetic resonance) was performed to detect LC at 3, 6, and 12 months after surgery. Overall, 26 patients (35.1%) developed LC, and 4 were symptomatic (5.4%). Allowing patients to serve as their own treatment group and control, the hemipelvis treated with Tissucol Duo corresponding to the treatment group and that not treated to the control group, LCs were found in 17 (23%) and 14 (19%) cases, respectively, but the difference was not significant. The mean initial LC maximum diameter was 27.1 mm (standard deviaiotn, 35.2), and LCs tended to decrease in size during the first year to a mean of 8.7 mm. CONCLUSION: Application of Tissucol Duo fibrin sealant after laparoscopic pelvic lymphadenectomy using ultrasonic shears does not decrease the occurrence of symptomatic or asymptomatic LC.

Sentinel Node Biopsy in Endometrial Cancer With Dual Cervical and Fundal Indocyanine Green Injection.

PURPOSE: The aim of this study was describe a novel sentinel lymph node (SLN) tracer injection procedure featuring dual cervical and fundal indocyanine green (ICG) injection for endometrial cancer and results of SLN biopsy. METHODS: Between June 26, 2014 and October 31, 2016, 111 patients underwent laparoscopic surgery for endometrial cancer at our institution. In all cases, we performed SLN biopsy with dual cervical and fundal ICG injection. All SLNs were processed with an ultrastaging technique. A total of 69 patients also underwent total pelvic and paraaortic lymphadenectomy. RESULTS: The detection rates were as follows: 92.79% (103/111) overall for SLNs; 89.19% (99/111) overall for pelvic SLNs; 61.26% (68/111) for bilateral SLNs; 59.46% (66/111) for paraaortic SLNs, and 4% (4/111) for isolated paraaortic SLNs. We found macroscopic lymph node metastasis in 11 patients (9.9%) and microdisease in lymph nodes in another 10 patients, raising the overall rate of lymph node involvement to 18.92%. There was 1 false-negative (negative SLN biopsy but positive aortic lymphadenectomy) and another positive case in 1 undetected SLN. The sensitivity of detection was 94.44%, specificity 100%, negative predictive value 97.83%, and negative likelihood ratio 0.06 for intermediate and high-risk endometrial cancer groups. CONCLUSIONS: The SLN biopsy with both cervical and fundal ICG injection offers good overall detection rates and improved mapping of the aortic area. The SLN ultrastaging increases the number of nodes considered positive.

Utility and Actual Use of European and Spanish Guidelines on the Management of Endometrial Cancer Among Gynecologic Oncologists in Spain.

OBJECTIVE: The aim of the study was to analyze the current management of endometrial cancer across Spain and to evaluate the use and applicability of the national and international guidelines. MATERIALS AND METHODS: An electronic 30-question survey was distributed among all Spanish Society of Obstetrics and Gynecology-registered specialists dedicated to gynecologic oncology in Spain by e-mail. Data were collected anonymously and analyzed using SPSS program. RESULTS: One hundred forty-five (17.8%) surveys were collected. Significant differences were observed between tertiary hospitals and secondary or private hospitals in terms of appropriate (according to European Society of Gynaecologic Oncology guidelines) nodal staging in low-risk cases (96 [95%] vs 27 [61.4%], respectively; P < 0.001), appropriate nodal staging in intermediate-risk cases (96 [95%] vs 39 [88.6%], respectively; P = 0.004), appropriate treatment in advanced-stage cases (63 [67.7%] vs 13 [40.6%], respectively; P < 0.001), and surgical treatment of relapses (87 [93.5%] vs 18 [56.3%], respectively; P = 0.004) but nonsignificant in the rate of complete paraaortic lymphadenectomy performance (82 [81.2%] vs 28 [63.6%], respectively; P = 0.056). Similar results have been observed when comparing centers with less than 20 cases per year to centers with more than 40 cases annually, with significant differences in the management of low-risk and intermediate-risk endometrial cancers. CONCLUSIONS: This cross-sectional study demonstrates a broad heterogeneity of care giving between the clinical national and international guidelines and the actual practice in Spain. Although most of the responders refer to base their endometrial cancer management on Spanish and European Society of Gynaecologic Oncology guidelines (64.1%), many discrepancies have been observed, mainly in the management of intermediate-risk cases and follow-up. It may be caused by the lack of consensus on certain points, lack of facilities in lower case load centers, and also due to disagreement or unawareness on the current knowledge.

Utility Serum Marker HE4 for the Differential Diagnosis Between Endometriosis and Adnexal Malignancy.

OBJECTIVE: The aim of the study was to assess the utility of serum human epididymal secretory protein E4 (HE4) biomarker in the differential diagnosis of endometriosis and adnexal malignancies. METHODS: Multicentric prospective observational study between January 2010 and December 2011 in 4 European centers (Italy, Portugal, Latvia, and Spain) was carried out. We collected 981 healthy patients diagnosed with adnexal patology and selected 65 patients diagnosed with endometriosis and analyzed their serum markers CA125, HE4, and Risk of Ovarian Malignancy Algorithm (ROMA) index. We also analyzed all cases of malignant histology and divided them according to CA125 levels (negative, ≤35 U/mL; intermediate, >35-150 U/mL; and highly positive, >150 U/mL). RESULTS: HE4 was positive only in 1.5% of cases, CA125 in 64.6%, and ROMA index in 14.1%. In the subgroup intermediate CA125 values, positive HE4 is very specific (91.2%) correctly classifying patients with benign disease, but with lower sensibility (66.1%); however, ROMA index showed a high sensibility (89.3%), with a false-positive rate of 42.8%. CONCLUSIONS: HE4 can be a very useful biomarker to exclude malignant disease in patients with endometriosis.