Diagnostic Value of Risk of Malignancy Algorithm (ROMA) in Adnexal Masses

Background

Differentiating malignancy from benign diseases is the key to successful management of adnexal masses. Risk of malignancy algorithm (ROMA) has been used for this purpose. We have prospectively studied the diagnostic value of ROMA in patients presented with adnexal masses.

Methods

We prospective calculated ROMA values prior to surgery for adnexal masses. The risk calculated was then correlated with the histological findings, and results were analyzed according to menopausal status. ROMA cutoff value was determined using ROC curve, and sensitivity, specificity and predictive values were calculated. Statistics were performed on SPSS software (version 20.0).

Results

There were 94 patients with adnexal masses included in the study, 65 (69.1%) had epithelial ovarian cancer and 29 (30.9%) were diagnosed benign on histopathology. In both pre- and postmenopausal patients, ROMA values were significantly higher in patients with malignancy compared to those with benign disease (p?<?0.05). ROMA score was of a significant diagnostic value in both premenopausal (AUC?=?0.914, Z?=?10.81, p?<?0.001) and postmenopausal patients (AUC?=?0.975, Z?=?21.51, p?<?0.001). In premenopausal females, ROMA?>?13.3% was able to discriminate malignant from benign patients with 97.06% sensitivity and 85.00% specificity. The positive and negative predictive values were 91.7% and 94.4%. Similarly, in postmenopausal females, ROMA value of?>?76% achieved 87.10% sensitivity and 100.00% specificity in discriminating malignant from benign patients with 100% positive and 69.2% negative predictive value. The overall accuracy of ROMA in pre- and postmenopausal patients was 87.0% and 85%, respectively.

Conclusions

ROMA is a useful and accurate test for differentiating epithelial ovarian cancer from benign ovarian masses. Further studies are needed to compare performance of ROMA with the Risk of Malignancy Index (RMI), CA 125 and HE4. Such comparative studies will be helpful to the clinician in deciding the best diagnostic tool for women with adnexal masses.

     

Advanced ovarian cancer and cytoreductive surgery: Independent validation of a risk-calculator for perioperative adverse events

ObjectiveTo independently validate a published risk-calculator for adverse perioperative outcomes in patients with epithelial ovarian cancer undergoing debulking surgery at a high-volume surgical center.MethodsUsing our institution's curated prospective ovarian cancer database, we identified patients with epithelial ovarian cancer who underwent a debulking procedure from 7/2015 to 5/2019, to be used as the validation cohort. Variables used in the published nomogram were collected. These included American Society of Anesthesiology classification, preoperative albumin, history of bleeding disorder, presence of ascites on preoperative imaging, designation of elective or emergent surgery, age of the patient, and a procedure score. Patients were included if they had information available for all the variables used in the nomogram, and 30-day follow-up within our institution. The primary outcome was Clavien-Dindo Class IV with specific conditions (postoperative sepsis, septic shock, cardiac arrest, myocardial infarction, pulmonary embolism, ventilation >48 h, or unplanned intubation) and 30-day mortality. The combination of these endpoints is called the combined complication rate.ResultsA total of 700 patients who underwent debulking surgery for epithelial ovarian cancer during the timeframe met inclusion criteria. The combined complication rate was 11.7%; 9.9% of patients were readmitted; 2.7% required reoperation. Sepsis was the most common primary endpoint complication (4.4%), followed by septic shock (1.4%). There was no 30-day mortality in our cohort. The nomogram performed well, with a c index of 0.715 (95% CI 0.66–0.768), which was comparable to the published nomogram.ConclusionsWe independently validated a complication nomogram at a high-volume surgical center. This nomogram performs well at predicting a lower likelihood of serious postoperative complications. An enhanced nomogram would help identify patients at higher risk for serious complications.     

A nomogram for estimating the probability of ovarian cancer

Objective

Accurate preoperative estimates of the probability of malignancy in women with adnexal masses are essential for ensuring optimal care. This study presents a new statistical model for combining predictive information and a graphic decision support tool for calculating risk of malignancy.

Methods

The study included 153 women treated with definitive surgery for adnexal mass between 2001 and 2007 with preoperative ultrasound testing and a serum CA125. Multivariable logistic regression was used to develop a statistical model for estimating the probability of ovarian cancer as a function of age, ultrasound score, and CA125 value, with adjustments for nonlinear and interactive relationships.

Results

A total of 20 cases of pathologically confirmed cancer (13 invasive malignancies, and 7 tumors of low malignant potential) were identified (20/153 = 13%). The model obtained excellent discrimination (ROC area = 0.87), explained nearly half of the observed variation in the risk of malignancy (R² = 0.43), and was well calibrated across the full range of malignancy probabilities. The model equation is represented in the form of a nomogram, which can be used to calculate preoperative probability of malignancy. At a 5% risk of malignancy threshold, the model has a sensitivity of 90% and a specificity of 73%.

Conclusions

Statistical models for estimating the probability of adnexal mass malignancy are substantially improved by including adjustments for non-linear relationships among key variables. A clinically relevant nomogram provides an objective tool to further aid clinicians in counseling patients and ensuring proper referral to surgical sub-specialists when indicated.     

Combination of serum biomarkers to differentiate malignant from benign ovarian tumours

ObjectiveTo investigate biomarkers and clinical parameters to distinguish ovarian cancers from benign ovarian tumours.MethodsSerum biomarkers (CA 125, human epididymis protein 4 [HE 4], interleukin-18 [IL-18], leptin, macrophage migration inhibitory factor [MIF], fibroblast growth factor 2 [FGF-2], insulin-like growth factor, osteopontin, prolactin) and the risk of malignancy indexes I &; II (RMI-I and RMI-II) scores were obtained prior to surgery in 52 patients with ovarian tumours (37 malignant and 15 benign). ROC curves were built for each individual marker, for logistic regression models using all markers, and for models combining both biomarkers and RMI scores.ResultsThe model with nine biomarkers performed well (specificity 93%, sensitivity 84%) and was more reliable than the RMI-I or RMI-II alone. A regression model combining RMI-II and six of the biomarkers (CA 125, HE 4, IL-18, leptin, MIF, and FGF-2) allowed differentiation between the cancer and non-cancer cases in this pilot studyConclusionThe regression models using biomarkers combined with clinical scoring systems warrant further investigation to improve triage of patients with ovarian tumours to enhance utilization of resources and optimize patient care.     

Ovarian malignancy in breast cancer patients with an adnexal mass

OBJECTIVE: The objectives of this study were to estimate ovarian malignancy rate in breast cancer patients with an adnexal mass and to identify variables predictive of malignancy. METHODS: This was a review from 1990-2002 including women with breast cancer diagnosed with an adnexal mass who subsequently underwent oophorectomy. Ovarian pathology was classified as benign, primary malignancy, or metastatic breast cancer. Women with preoperative evidence of malignancy were excluded. RESULTS: Of 129 cases reviewed, benign ovarian cysts were found in 113 cases (88%) and malignant ovarian neoplasms were found in 16 cases (12%). Univariate logistic regression analyses were performed to determine predictors of malignancy. Complex masses were 29 times more likely to be malignant (P < .001). Women with estrogen-receptor-negative breast cancer had an increased risk for malignant adnexal masses (44%; OR 12.4, 95% confidence interval 2.4-65.1; P = .003). Patients with an elevated CA 125 had a 6.3-fold increased risk of malignancy, P = .02. Adnexal mass size greater than 5 cm also increased the risk of malignancy (18.8%; OR 4.6, 95% confidence interval 1.2-17.3; P = .02). Malignant adnexal masses had a greater likelihood of being primary ovarian cancer than metastatic breast cancer by 7:1. CONCLUSION: An isolated adnexal mass in the breast cancer patient is most commonly a benign ovarian cyst. Adnexal masses associated with an increased CA 125, complex architecture by ultrasonography, or size greater than 5 cm are significant predictors of malignancy and are indications for referral to a gynecologic oncologist.     

Initial Evaluation and Referral Guidelines for Management of Pelvic/Ovarian Masses

ObjectivesTo optimize the management of adnexal masses and to assist primary care physicians and gynaecologists determine which patients presenting with an ovarian mass with a significant risk of malignancy should be considered for gynaecologic oncology referral and management.OptionsLaparoscopic evaluation, comprehensive surgical staging for early ovarian cancer, or tumour debulking for advanced stage ovarian cancer.OutcomesTo optimize conservative versus operative management of women with possible ovarian malignancy and to optimize the involvement of gynaecologic oncologists in planning and delivery of treatment.EvidencePublished literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified by searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.Recommendations

• 1.Primary care physicians and gynaecologists should always consider the possibility of an underlying ovarian cancer in patients in any age group who present with an adnexal or ovarian mass. (II-2B)
• 2.Appropriate workup of a perimenopausal or postmenopausal woman presenting with an adnexal mass should include evaluation of symptoms and signs suggestive of malignancy, such as persistent pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty eating. In addition, CA125 measurement should be considered. (II-2B)
• 3.Transvaginal or transabdominal ultrasound examination is recommended as part of the initial workup of a complex adnexal/ovarian mass. (II-2B)
• 4.Ultrasound reports should be standardized to include size and unilateral/bilateral location of the adnexal mass and its possible origin, thickness of septations, presence of excrescences and internal solid components, vascular flow distribution pattern, and presence or absence of ascites. This information is essential for calculating the risk of malignancy index II score to identify pelvic mass with high malignant potential. (IIIC)
• 5.Patients deemed to have a high risk of an underlying malignancy should be reviewed in consultation with a gynaecologic oncologist for assessment and optimal surgical management. (II-2B)

     

Risk of Malignancy Index in the Evaluation of Patients With Adnexal Masses

ObjectiveTo determine if the risk of malignancy index (RMI) can distinguish between benign and malignant adnexal masses in a population of women referred to a department of gynaecologic oncology for surgical resection of an adnexal mass.MethodsWe performed a retrospective review of the medical of charts of 259 consecutive patients. Ninety-six charts did not have data available to calculate the RMI, leaving a total of 163 for review. Three definitions of RMI were compared; each incorporated menopausal status of the patient, ultrasound characteristics of the adnexal mass, and serum CA-125 level.ResultsOf the masses resected, 105 were benign and 58 were malignant. The area under the ROC curve for all three definitions of RMI was 0.87. Using a cut-off of 120, the first RMI definition (RMI 1) had a sensitivity of 72% and a specificity of 87%; the second (RMI 2) had a sensitivity of 76% and a specificity of 81%; and the third (RMI 3) had a sensitivity of 74% and a specificity of 84%. These results are generally in agreement with published values.ConclusionWe have validated the use of RMI to predict the risk of malignancy in a Nova Scotia population of women with adnexal masses. This will aid in more selective referral of patients to specialized oncology centres for cancer surgery, allowing for appropriate management of health care resources and optimization of treatment for women with gynaecological malignancies.     

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

Objective

Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes.

Methods

Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI.

Results

809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI = 200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI).

Conclusion

HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.     

浆液性卵巢癌治疗后远期生存列线图预测模型的构建和验证

目的:构建并验证浆液性卵巢癌远期生存概率的列线图,为卵巢癌患者提供个性化的治疗建议和随访策略.方法:共有6957例来自SEER数据库的患者被纳入训练组;外部验证组数据来自于1244例患者的临床资料.基于Cox回归模型构建列线图,使用一致性指数、受试者操作特征曲线、校准图进行验证.绘制Kaplan-Meier曲线比较不同...     

Guideline No. 404: Initial Investigation and Management of Benign Ovarian Masses

ObjectiveTo provide recommendations for a systematic approach to the initial investigation and management of a benign ovarian mass and facilitate patient referral to a gynaecologic oncologist for management.Intended UsersObstetricians, gynaecologists, family physicians, internists, nurse practitioners, radiologists, general surgeons, medical students, medical residents, fellows, and other health care providers.Target PopulationWomen ≥18 years of age presenting for evaluation of an ovarian mass (including simple and unilocular cystic masses, endometriomas, dermoids, fibromas, and hemorrhagic cysts) who are not acutely symptomatic and without known genetic predisposition to ovarian cancer.OutcomesThis guideline aims to encourage conservative management and help reduce unnecessary surgery and long-term health complications, maintain fertility, and decrease operative costs and improve overall patient care and outcomes by providing criteria for referral of patients with ultrasound imaging findings suggestive of a malignant mass to a gynaecologic oncologist.EvidenceDatabases searched: Medline, Cochrane, and PubMed. Medical terms used: benign asymptomatic and symptomatic ovarian cysts, adnexal masses, oophorectomy, ultrasound diagnosis of cysts, simple ultrasound rules, surgical and medical therapies for cysts, screening for ovarian cancer, ovarian torsion, and menopause. Initial search was completed by 2017 and updated in 2018. Exclusion criteria were malignant ovarian cystic masses, endometriosis therapies, and other adnexal pathologies unrelated to the ovary.Validation MethodsThe content and recommendations were drafted and agreed upon by the authors. The Society of Obstetricians and Gynaecologists of Canada's Board of Directors approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation methodology framework.Benefits, Harms, CostsImplementation of the recommendations could reduce costs due to unnecessary surgeries and hospitalizations and reduce lost work days and the risk of loss of fertility, early menopause, and surgical complications.SUMMARY STATEMENTS (GRADE ratings in parentheses)

• 1The following ovarian masses typically demonstrate classic benign features on ultrasound: simple or unilocular cystic mass, hemorrhagic cyst, endometrioma, mature cystic teratoma (dermoid), and fibroma (high).
• 2The risk of malignancy for simple ovarian cystic masses is low (<1%) for <10 cm in diameter (high).
• 3Patients with an ovarian mass ≥5 cm in diameter are at increased risk for ovarian torsion (moderate).
• 4Laparoscopy is the recommended approach for surgical management of symptomatic benign ovarian masses because it not only is technically feasible and safe but also provides the advantages of shorter hospital stays, faster recovery times, and less pain and bleeding compared with laparotomy (high).
• 5Comprehensive preoperative evaluation is necessary in order to determine the risk of malignancy of an ovarian mass before deciding on the appropriate surgical management (high).
• 6Electrocautery for hemostasis should be used sparingly in order to reduce the risk of damage to healthy ovarian tissue and minimize adhesion formation (high).

RECOMMENDATIONS (GRADE ratings in parentheses)

• 1In the asymptomatic patient, masses characterized as benign on ultrasound can be followed initially by repeat ultrasound in 8 to 12 weeks, preferably in the proliferative phase of the menstrual cycle for premenopausal women. Follow-up ultrasound can then be done yearly for masses that remain stable and do not develop malignant features (strong, moderate).
• 2Most asymptomatic masses <10 cm in diameter and characterized as benign can be managed conservatively (strong, high).
• 3If surgery is performed for a symptomatic mass characterized as benign on ultrasound, unilateral or bilateral oophorectomy can be considered for postmenopausal women (strong, low) and ovarian cystectomy can be considered for premenopausal women if technically feasible (strong, low). For perimenopausal women, the decision to perform a cystectomy with a possible salpingectomy versus an oophorectomy should be part of a shared decision-making discussion between the patient and her health care provider (strong, low).
• 4Laparoscopic ovarian cystectomy is the recommended surgical approach for removal of cystic masses, rather than fenestration and aspiration (strong, moderate).
• 5Laparoscopic management should involve examination of the peritoneal surfaces, appendix, upper abdomen, posterior cul-de-sac, and bladder in addition to uterus, tubes, and ovaries for evidence of disease. In addition to pelvic washing for cytology, a biopsy of peritoneal surfaces should be taken for histopathology only if malignancy is suspected (strong, high).
• 6Peritoneal washing for cytology and frozen section for analysis should be undertaken at the time of surgical management of an ovarian mass if there is a suspicion of malignancy. To improve the diagnostic accuracy, specimens should be interpreted by a pathologist with gynaecologic expertise, if resources permit (strong, high).
• 7When pathology results reveal malignancy in an ovarian mass that had originally been presumed benign, comprehensive surgical staging should be performed by a surgeon with expertise in gynaecologic oncology, if resources permit (strong, high).

     

Development and validation of a nomogram for predicting outcome of patients with vulvar cancer

OBJECTIVE: To construct and validate a nomogram to predict relapse-free survival of patients treated for vulvar cancer. METHODS: Data from 244 patients treated for vulvar cancer at a single institution (Creteil, France) were used as a training set to develop and calibrate a nomogram for predicting relapse-free survival and local relapse-free survival. We used bootstrap resampling for the internal validation and we tested the nomogram on an independent validation set of patients (Torino, Italy) for the external validation. RESULTS: The nomograms were based on a Cox proportional hazards regression model. Covariates for the relapse-free survival model included age, T stage, number of metastatic nodes, bilateral lymph node involvement, omission of the lymphadenectomy, margin status, lymphovascular space invasion, and depth of invasion. The concordance indices were 0.85 and 0.83 in the training set before and after bootstrapping, respectively, and 0.83 in the validation set. The predictions of our nomogram discriminated better than did the International Federation of Gynecology and Obstetrics stage (0.83 compared with 0.78, P = .01). The calibration of our nomogram was good. In the validation set, 2-year and 5-year relapse-free survival were well predicted with less than 5% difference between the predicted and observed survivals for each quartile. A nomogram for predicting local relapse was also developed. CONCLUSION: We have developed nomograms for predicting distant and local relapse of vulvar cancer at 2 and 5 years and validated them both internally and externally. These nomograms will be freely available on the International Society for the Study of Vulvovaginal Disease Web site. LEVEL OF EVIDENCE: III.     

Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay

ObjectiveTo validate the effectiveness of a multivariate index assay in identifying ovarian malignancy compared to clinical assessment and CA125-II, among women undergoing surgery for an adnexal mass after enrollment by non-gynecologic oncology providers.MethodsA prospective, multi-institutional trial enrolled female patients scheduled to undergo surgery for an adnexal mass from 27 non-gynecologic oncology practices. Pre-operative serum samples and physician assessment of ovarian cancer risk were correlated with final surgical pathology.ResultsA total of 494 subjects were evaluable for multivariate index assay, CA125-II, and clinical impression. Overall, 92 patients (18.6%) had a pelvic malignancy. Primary ovarian cancer was diagnosed in 65 patients (13.2%), with 43.1% having FIGO stage I disease. For all ovarian malignancies, the sensitivity of the multivariate index assay was 95.7% (95%CI = 89.3–98.3) when combined with clinical impression. The multivariate index assay correctly predicted ovarian malignancy in 91.4% (95%CI = 77.6–97.0) of cases of early-stage disease, compared to 65.7% (95%CI = 49.2–79.2) for CA125-II. The multivariate index assay correctly identified 83.3% malignancies missed by clinical impression and 70.8% cases missed by CA125-II. Multivariate index assay was superior in predicting the absence of an ovarian malignancy, with a negative predictive value of 98.1% (95%CI = 95.2–99.2). Both clinical impression and CA125-II were more accurate at identifying benign disease. The multivariate index assay correctly predicted benign pathology in 204 patients (50.7%, 95%CI = 45.9–55.6) when combined with clinical impression.ConclusionThe multivariate index assay demonstrated higher sensitivity and negative predictive value for ovarian malignancy compared to clinical impression and CA125-II in an intended-use population of non-gynecologic oncology practices.     

A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer

ObjectiveTo investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients.MethodsWomen at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n = 71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n = 35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (n_total = 71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS).ResultsOf the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12 × 10⁻⁶, CI 2.57–16.71). This model was named the serous high grade ovarian cancer (SHOC) score.ConclusionThe SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur.     

Guideline No. 403: Initial Investigation and Management of Adnexal Masses

ObjectivesTo aid primary care physicians, emergency medicine physicians, and gynaecologists in the initial investigation of adnexal masses, defined as lumps that appear near the uterus or in or around ovaries, fallopian tubes, or surrounding connective tissue, and to outline recommendations for identifying women who would benefit from a referral to a gynaecologic oncologist for further management.Intended UsersGynaecologists, obstetricians, family physicians, general surgeons, emergency medicine specialists, radiologists, sonographers, nurses, medical learners, residents, and fellows.Target PopulationAdult women 18 years of age and older presenting for the evaluation of an adnexal mass.OptionsWomen with adnexal masses should be assessed for personal risk factors, history, and physical findings. Initial evaluation should also include imaging and laboratory testing to triage women for management of their care either by a gynaecologic oncologist or as per SOGC guideline no. 404 on the initial investigation and management of benign ovarian masses.EvidenceA search of PubMed, Cochrane Wiley, and the Cochrane systematic reviews was conducted in January 2018 for English-language materials involving human subjects published since 2000 using three sets of terms: (i) ovarian cancer, ovarian carcinoma, adnexal disease, ovarian neoplasm, adnexal mass, fallopian tube disease, fallopian tube neoplasm, ovarian cyst, and ovarian tumour; (ii) the above terms in combination with predict neoplasm staging, follow-up, and staging; and (iii) the above two sets of terms in combination with ultrasound, tumour marker, CA 125, CEA, CA19-9, HE4, multivariable-index-assay, risk-of-ovarian-malignancy-algorithm, risk-of-malignancy-index, diagnostic imaging, CT, MRI, and PET. Relevant evidence was selected for inclusion in descending order of quality of evidence as follows: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional articles were identified through cross-referencing the identified reviews. The total number of studies identified was 2350, with 59 being included in this review.Validation MethodsThe content and recommendations were drafted and agreed upon by the authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration. The Board of Directors of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework (Table A1 of Online Appendix A). See Table A2 of Online Appendix A for the interpretation of strong and weak recommendations. The summary of findings is available upon request.Benefits, Harms, CostsAdnexal masses are common, and guidelines on how to triage them and manage the care of patients presenting with adnexal masses will continue to guide the practice of primary care providers and gynaecologists. Ovarian cancer outcomes are improved when initial surgery is performed by a gynaecologic oncologist, likely as a result of complete surgical staging and optimal cytoreduction. Given these superior outcomes, guidelines to assist in the triage of adnexal masses and the referral and management of the care of patients with an adnexal mass are critical.SUMMARY STATEMENTS (GRADE ratings in parentheses)

• 1Information from a detailed personal and family history can guide decisions on further testing and evaluation for women with adnexal masses (low).
• 2The majority of women with ovarian cancer have symptoms in the year prior to their diagnosis, although these symptoms can be vague (low).
• 3Adnexal masses are best evaluated through subjective pattern recognition by an expert sonographer in order to distinguish benign adnexal masses from malignant adnexal masses (moderate).
• 4Ultrasound evaluation of adnexal masses with risk prediction models such as the simple rules, developed by the International Ovarian Tumor Analysis group, allows sonographers with varying degrees of expertise to use uniform terminology and accurately classify these masses as “likely malignant,” “benign,” or “indeterminate” (moderate).
• 5Laboratory testing can aid in the differential diagnosis of an adnexal mass. Testing for sexually transmitted infection with results showing leukocytosis can help identify tubo-ovarian abscesses, while a positive pregnancy test can lead to diagnosis of possible ectopic pregnancies (low).
• 6Cancer antigen 125 is a non-specific glycoprotein that can be elevated in benign and malignant gynaecologic conditions and in non-gynaecologic conditions (moderate).
• 7Only half of all early stage ovarian cancers and 80% of advanced stage ovarian cancers show elevated cancer antigen 125 levels (moderate).
• 8The sensitivity and specificity of cancer antigen 125 as a tumour marker are higher in women who are postmenopausal because many of the benign clinical conditions that can increase the level of cancer antigen 125 occur in the premenopausal population, while most cases of epithelial ovarian, fallopian tube, and peritoneal cancer occur in the postmenopausal population (moderate).
• 9Despite having gone through several iterations, the risk of malignancy index, which uses cancer antigen 125 and sonographic features along with the patient's menopausal status, is outperformed by the more recent International Ovarian Tumor Analysis group's logistic regression model 2 and simple rules. The sensitivity and specificity of version 2 of the risk of malignancy index for distinguishing malignant from benign masses are only 75% and 87%, respectively (moderate).

RECOMMENDATIONS (GRADE ratings in parentheses)

• 1Take a detailed history for a woman presenting with an adnexal mass. For a woman with a personal history of infertility, endometriosis, or cancer or a family history of cancer, refer the patient to a gynaecologic oncologist for further evaluation if possible (strong, low).
• 2Physical examination should include lymph node survey, respiratory examination to rule out pleural effusion or consolidation, breast and axillary examination to rule out breast malignancy, and an abdominal examination to assess for ascites, omental caking, and organomegaly as well as a pelvic examination, including a bimanual and rectovaginal examination, to assess for mass size, contour, mobility, and parametrial, bladder, and rectal abnormality (strong, low).
• 3If a woman presents with an adnexal mass, request an initial ultrasound using either pattern recognition or the risk prediction model developed by the International Ovarian Tumour Analysis group (strong, moderate).
• 4Promptly refer to a gynaecologic oncologist any patient who presents with a mass with any of the following sonographic features, suggestive of malignancy: (i) solid component with strong or central colour flow, (ii) ≥4 papillary projections (defined as >3 mm in height), (iii) thick multiple irregular septations, or (iv) ascites and peritoneal nodularity. While awaiting a gynaecologic oncologist consult, where resources permit, pursue further investigations, including tumour marker levels and computed tomography scan of the chest, abdomen, and pelvis, as appropriate (strong, moderate).
• 5Women with adnexal masses with indeterminate features should be evaluated by ultrasound conducted by an expert sonographer (if available) or by magnetic resonance imaging or be referred to a gynaecologic oncologist (strong, low).
• 6Do not use cancer antigen 125 testing as a screening tool in asymptomatic women without a pelvic or adnexal mass (strong, moderate).
• 7The initial ultrasound characterization can be done using either pattern recognition (best in the hands of an expert sonographer) or risk prediction algorithms, such as simple rules, which have been demonstrated to work well for practitioners with varying degrees of expertise. If the lesion is suspicious for malignancy, prompt referral to a gynaecologic oncologist is recommended (strong, moderate).
• 8In women <40 years of age with an adnexal mass, rare forms of ovarian cancer must be considered and further tumour marker measurements, including human chorionic gonadotropin, lactate dehydrogenase, and alpha-fetoprotein, should be obtained (strong, low).
• 9Further tumour marker testing, including carcinoembryonic antigen, cancer antigen 19-9, and cancer antigen 15-3, along with referral to a gynaecologic oncologist are recommended for women presenting with bilateral masses with features of malignancy (strong, moderate).

     

Risk assessment model for overall survival in patients with locally advanced cervical cancer treated with definitive concurrent chemoradiotherapy

ObjectiveTo develop a nomogram for predicting the probability of 5 year survival after definitive concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC).MethodsBetween 1998 and 2008, 209 patients with LACC were treated with definitive CCRT. Multivariate analysis using Cox proportional hazards regression model was performed. A nomogram based on this Cox model was developed and internally validated by bootstrapping. Its performance was assessed by using the concordance index and a calibration curve.ResultsThe median age was 55 years (range, 26–78). Of the patients, 9, 16, 129, 3, 42 and 10 had FIGO stage IB2, IIA, IIB, IIIA, IIIB, and IVA disease, respectively. Histology revealed that 190, 13, 4, and 2 patients had squamous, adenocarcinoma, adenosquamous, and small cell cervical cancer, respectively. In 91 patients, PET/CT was performed before CCRT. The median follow-up period was 51 months (range, 6–151) and there were 50 (23.9%) disease-related deaths. Multivariate regression analysis revealed that histology, tumor size, and paraaortic lymph node metastasis (defined by MRI), but not PET/CT before CCRT, were independent predictors of overall survival. A nomogram for predicting the 5 year survival incorporating these three significant variables was constructed. The concordance index was 0.69. The predictive ability of the nomogram proved to be superior to that of the FIGO staging system (p < 0.05).ConclusionsThe nomogram was a better predictive model for overall survival than the FIGO staging system. If externally validated, it could be used to counsel patients with LACC who must choose additional treatment modalities after definitive CCRT.     

COH outcomes in breast cancer patients for fertility preservation: a comparison with the expected response by age

PurposeBreast cancer is the most common cancer diagnosed during childbearing age, and fertility preservation is becoming increasingly more essential. However, recent studies indicate a possible poorer response to controlled ovarian hyperstimulation (COH) in cancer patients than in non-cancer controls and a negative impact of BRCA mutations on female fertility. This study aims to evaluate ovarian response and the number of mature oocytes (MII) vitrified in women with breast cancer, with or without BRCA mutation, comparing them to the expected response according to an age-related nomogram.MethodsThis is a retrospective observational study involving sixty-one breast cancer patients who underwent COH for oocyte cryopreservation. The age-specific nomogram was built using 3871 patients who underwent COH due to oocyte donation, fertility preservation for non-medical reasons, or FIVET for male factor exclusively.ResultsThe mean number of oocytes retrieved was 13.03, whereas the mean number of MII oocytes was 10.00. After the application of the z-score, no statistically significant differences were found compared with the expected response in the general population, neither by dividing patients according to the presence or absence of BRCA mutation nor according to the phase in which they initiated stimulation.ConclusionThe results obtained do not support the notion of a negative impact of the BRCA mutation on the ovarian response of women with breast cancer. Women with breast cancer undergoing COH for fertility preservation can expect the ovarian response predicted for their age.     

Comparison of candidate serologic markers for type I and type II ovarian cancer

Objective

To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers.

Methods

Levels of 14 currently promising ovarian cancer-related biomarkers, including CA125, macrophage inhibitory factor-1 (MIF-1), leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II (IGF-II), autoantibodies (AAbs) to eight proteins: p53, NY-ESO-1, p16, ALPP, CTSD, B23, GRP78, and SSX, were measured in the plasma of 151 ovarian cancer patients, 23 with borderline ovarian tumors, 55 with benign tumors and 75 healthy controls.

Results

When examined individually, seven candidate biomarkers (MIF, Prolactin, CA-125, OPN, Leptin, IGF-II and p53 AAbs) had significantly different plasma levels between type II ovarian cancer patients and healthy controls. Based on the receiver operating characteristic (ROC) curves constructed and area under the curve (AUC) calculated, CA125 exhibited the greatest power to discriminate the plasma samples of type II cancer patients from normal volunteers (AUC 0.9310), followed by IGF-II (AUC 0.8514), OPN (AUC 0.7888), leptin (AUC 0.7571), prolactin (AUC 0.7247), p53 AAbs (AUC 0.7033), and MIF (AUC 0.6992). p53 AAbs levels exhibited the lowest correlation with CA125 levels among the six markers, suggesting the potential of p53 AAbs as a biomarker independent of CA125. Indeed, p53 AAbs increased the AUC of ROC curve to the greatest extent when combining CA125 with one of the other markers. At a fixed specificity of 100%, the addition of p53 AAbs to CA125 increased sensitivity from 73.8% to 85.7% to discriminate type II cancer patients from normal controls. Notably, seropositivity of p53 AAbs is comparable in type II ovarian cancer patients with negative and positive CA125, but has no value for type I ovarian cancer patients.

Conclusions

p53 AAbs might be a useful blood-based biomarker for the detection of type II ovarian cancer, especially when combined with CA125 levels.     

Comparison of diagnostic usefulness of predictive models in preliminary differentiation of adnexal masses

The purpose of this study was to compare prognostic models evaluating the probability of an ovarian cancer occurrence based on a number of clinical and ultrasonographic data in women with adnexal masses. A total of 686 women with adnexal masses underwent the examinations between 1994 and 2002. The recorded parameters included: age, menopausal status, body mass index, the grayscale and Doppler ultrasonographic examination, and selected markers concentration levels. In order to find the best combination of features, which significantly influences the probability of malignancy, stepwise logistic regression analysis, as well as artificial neural network, was used. The diagnostic efficiency of received models was estimated and compared using receiver-operating characteristics (ROC) curve. The results indicate that 431 and 255 patients had a benign and malignant ovarian tumor, respectively. Application of stepwise logistic regression analysis revealed statistically significant importance of eight features. The sensitivity and specificity for the received model were 65.71% and 77.59%, respectively. Three-layer perceptron network shows 13 features as significant predictors of malignancy. The network gave a sensitivity of 85.7% and specificity of 93.1%. Comparison of area under ROC curve for received models was 0.9679 vs 0.9716. Prognostic values of the analyzed neural model are not optimal but seem to surpass logistic regression model in terms of the predictive possibilities.     

Use and Accuracy of Intraoperative Frozen Section Analysis for Ovarian Masses in Children and Adolescents

Study ObjectiveDescribe the current practice patterns and diagnostic accuracy of frozen section (FS) pathology for children and adolescents with ovarian massesDesignProspective cohort study from 2018 to 2021SettingEleven children's hospitalsParticipantsFemales age 6-21 years undergoing surgical management of an ovarian massInterventionsObtaining intraoperative FS pathologyMain Outcome MeasureDiagnostic accuracy of FS pathologyResultsOf 691 patients who underwent surgical management of an ovarian mass, FS was performed in 27 (3.9%), of which 9 (33.3%) had a final malignant pathology. Among FS patients, 12 of 27 (44.4%) underwent ovary-sparing surgery, and 15 of 27 (55.5%) underwent oophorectomy with or without other procedures. FS results were disparate from final pathology in 7 of 27 (25.9%) cases. FS had a sensitivity of 44.4% and specificity of 94.4% for identifying malignancy, with a c-statistic of 0.69. Malignant diagnoses missed on FS included serous borderline tumor (n = 1), mucinous borderline tumor (n = 2), mucinous carcinoma (n = 1), and immature teratoma (n = 1). FS did not guide intervention in 10 of 27 (37.0%) patients: 9 with benign FS underwent oophorectomy, and 1 with malignant FS did not undergo oophorectomy. Of the 9 patients who underwent oophorectomy with benign FS, 5 (55.6%) had benign and 4 (44.4%) had malignant final pathology.ConclusionsFSs are infrequently utilized for pediatric and adolescent ovarian masses and could be inaccurate for predicting malignancy and guiding operative decision-making. We recommend continued assessment and refinement of guidance before any standardization of use of FS to assist with intraoperative decision-making for surgical resection and staging in children and adolescents with ovarian masses.