In Canada in 2010, an estimated 2600 new cases of ovarian cancer will be diagnosed and, of those cases, 1750 women will die, making ovarian cancer the seventh most prevalent form of cancer in Canadian women and their fifth leading cause of cancer death (1). Women with ovarian cancer typically have subtle, non-specific symptoms such as abdominal pain, bloating, changes in bowel frequency, and urinary and/or pelvic symptoms (2), making early detection difficult. Thus, the majority of ovarian cancer cases are diagnosed at an advanced stage when the cancer has spread outside the pelvis (3). Due to the late diagnosis of this disease, the five-year relative survival ratio for ovarian cancer in Canada is only 40% (1). Unfortunately, due to the low-positive predictive values of potential screening tests (CA-125 and ultrasound), there is currently no screening strategy for ovarian cancer (4). Palpation using a bimanual pelvic examination or by radiological imaging (3) can identify an adnexal mass, which is defined as an enlarged lump near the uterus, usually in the ovary or fallopian tube. Adnexal masses include both benign (ovarian cysts, fibroids, and endometriomas) and malignant tumours.
There are numerous methods that have been tested in the preoperative identification of adnexal masses suspicious for malignancy. These methods include CA-125, transvaginal and transabdominal ultrasound, MRI, CT scans and the risk of malignancy index (RMI). However, the most appropriate identification method has yet to be determined, mainly due to poor positive and negative predictive values associated with each test in differentiating a benign from a malignant mass.
Once the diagnosis of ovarian cancer is confirmed, the patient must undergo surgical staging or debulking. However, which surgical staging and debulking procedure should be used to improve overall survival, progression-free survival, and quality of life in women with ovarian cancer is also unknown. The purpose of this document is to identify evidence that would inform optimal recommended protocols for the identification and surgical management of adnexal masses suspicious for malignancy.
The evidence-based series (EBS) guidelines developed by the CCO PEBC use the methods of the Practice Guidelines Development Cycle (5). For this project, the core methodology used to develop the evidentiary base was an update of two previously published systematic reviews: the Agency for Healthcare Research and Quality (AHRQ) report, 2006 (3) and Australian Cancer Network (ACN) Clinical Practice Guideline, 2004 (6). Evidence was selected and reviewed by five members of the PEBC Gynecology Cancer DSG and one methodologist.
The systematic review is a convenient and up-to-date source of the best available evidence on the management of an adnexal mass suspicious for malignancy. The body of evidence in this review is primarily comprised of prospective and retrospective cohort studies. That evidence forms the basis of the recommendations developed by the Gynecology Cancer DSG and published in Section 1. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source.

# Literature Search Strategy Environmental Scan
As a first step, an internet search of Canadian and international health organizations and the National Guidelines Clearinghouse (see Appendix 1 for full list) was conducted for existing guidelines and systematic reviews relevant to our research question. Guidelines were included if they were published since 1999 in English. This initial environmental scan yielded 11 practice guidelines; however, one guideline was excluded because the full guideline was available only in French, and another guideline was excluded because only the National Guidelines Clearinghouse summary was available. One evidence report/technology assessment and one clinical practice guideline identified through this environmental scan were deemed to be the most appropriate to answer the guideline questions. The 2006 AHRQ report (3) addressed the identification of an adnexal mass suspicious for malignancy question. The 2004 ACN Clinical Practice Guideline (6) addressed the surgical management of an adnexal mass suspicious for malignancy question.

# Update Literature Search Strategy
The literature search from the AHRQ report was updated (Appendix 2) using MEDLINE (OVID: January 2004 through week 3, March 2009). In addition, as an exact search strategy for the Australian Cancer Network report was not available, an update of that literature search (Appendix 2) was approximated using the keywords provided in the report using MEDLINE (OVID: January 2004 through week 3, April 2009). This literature search combined diseasespecific terms ('pelvic mass,' 'adnexal mass,' 'pelvic neoplasms,' 'ovarian cancer,' 'ovarian neoplasm,' 'ovarian carcinoma,' 'epithelial ovarian cancer,' 'borderline ovarian tumours' and 'tumours of low malignant potential') with surgical specific terms ('intraoperative pathological examination,' 'frozen section,' 'debulking surgery,' 'fertility sparing,' 'surgical staging,' 'bilateral salpingo-oophorectomy,' 'total hysterectomy,' 'node or nodal dissection,' 'surgical management,' 'treatment,' 'cytoreduction,' 'secondary cytoreduction,' 'interval cytoreduction,' 'laparotomy,' and laparoscopy') for all study designs.
Relevant articles and abstracts were selected and reviewed by two reviewers. The reference lists of included studies along with the personal reference lists of the guideline working group were searched for additional studies.

# Study Selection Criteria
Articles were eligible for inclusion in this systematic review if they were systematic reviews, meta-analyses, clinical practice guidelines, randomized trials, or comparative cohort studies. Studies indentified in the update of the AHRQ report literature search were included based on the same inclusion criteria put forth in the AHRQ report (3).
For studies investigating single modality identification of an adnexal mass, the inclusion criteria were:
1) comparison of the test (e.g., bimanual pelvic exam or ultrasound, to histology or negative surgery 2) greater than 20 patients included in study 3) able to construct a 2-by-2 table, which compares the results of the diagnostic test with the definitive histological diagnosis.
For studies investigating the use of multi-modality scoring systems (i.e., RMI), the inclusion criteria were:
1) patients with suspicion of cancer 2) studies with scoring, risk score, combined modality approach 3) assesses predictive value of two or more variables using multivariable model 4) greater than 50 patients included in study.
Studies identified in the update of the Australian Cancer Network (6) guideline were based on the following selection criteria:
1) greater than 20 patients included in study 2) patients with an adnexal mass suspicious for early stage (I-II) malignancy, 3) two-armed (or greater) study design with a comparison of surgical procedures/techniques/approaches 4) report on at least one of the following outcomes: optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, quality of life.

# Synthesizing the Evidence
A bivariate, random-effects meta-regression model was used to produce summary estimates of sensitivity and specificity and to plot summary receiver operating characteristic (ROC) curves with 95% confidence regions. This model, described in detail elsewhere (7)(8)(9), has several advantages over the standard summary ROC approach. Chief among these is the preservation of the two-dimensional nature of the data and the incorporation of any correlation that might exist between sensitivity and specificity (8). The model assumes that the logit sensitivities and specificities are normally distributed and makes use of the variance estimates to compute study weights (7). Heterogeneity in the current review was assessed visually. Given that between-study heterogeneity is widespread for measures of diagnostic accuracy (10), a random-effects model was used for all pooling. This bivariate, randomeffects model takes into account the difference in precision by which sensitivity and specificity have been measured within and across studies, and it incorporates and estimates the amount of between-study variability (8). Statistical analyses were executed with the statistical software package STATA version 11 (11) using the metandi command. The outcomes of the meta-analyses were plotted as summary ROC curves and can be seen in Figures 2A-D.
The Gynecology Cancer DSG decided not to pool the surgical studies, but rather to present the results of each study individually in a descriptive fashion.

# Quality Appraisal and Data Extraction
The Appraisal of Guidelines Research and Evaluation (AGREE) tool (12) was used to evaluate the quality of identified evidence-based guidelines. While all scoring domains of the AGREE tool were considered in the evaluation of guidelines, the Rigour of Development domain, describing the rigour of systematic methods in identifying and evaluating evidence, was considered to be most relevant in application for this systematic review. Systematic reviews and meta-analyses were assessed for quality using the AMSTAR tool (13). The quality of primary studies included assessments for study design, type of data collection, sampling method, and blinding.

# Updated Literature Search Results

# Identification of an adnexal mass literature
Four meta-analyses (14-17) and 67 primary studies (Table 1), pertaining to the identification of an adnexal mass suspicious for malignancy, met the inclusion criteria and are included in this review. 

# Surgical procedures literature
A total of 1809 articles were identified in the updated search for the most appropriate surgical procedure, of which 16 met the inclusion criteria (85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100).

# Study Design and Quality
The ACN evidence-based guideline (6) earned 80.2% for the Rigour of Development domain of the AGREE tool. Since the role of AGREE in the assessment of health technology assessments has not yet been formally evaluated, the AHRQ report was not rated with AGREE but with AMSTAR for systematic reviews. It received an overall quality score of 90%. The meta-analyses by Geomini et al (14), Liu et al (15), Medieros et al (17), and Geomini et al (16) received scores of 73%, 55%, 82%, and 82% respectively.
Given that, at the time of inclusion, all patients either have ovarian cancer or they do not, diagnostic accuracy studies are, in principle, cross-sectional in nature (101). The diagnostic tests under study are intended to reduce the clinical uncertainty about their status (101). As such, the terms "cohort-type" or "case-control-type" accuracy studies have been proposed depending on the method of patient recruitment. Using such terminology, two casecontrol type studies and 65 cohort-type accuracy studies were included in this review (Figure 1). Data collection occurred prospectively in 64% of the studies, retrospectively in 33%, and not described in 3%. The sampling method was consecutive in 42% of the studies and not reported in the remaining 58%. Pathologists were blinded to the preoperative index test findings in only 4% of studies and not blinded in 1% of studies, with the remaining 94% of studies not describing any such blinding. In general, the quality of evidence for studies identified for the surgical question was poor. No meta-analyses or systematic reviews were identified. Only one of the 16 eligible surgical studies was an RCT (89), and another was designed as a "historically controlled trial" (95), defined as per the Cochrane Collaboration definition of study designs (102). The remaining 14 eligible studies were all retrospective in nature. As the quality of data collection in a retrospective study is often compromised, it is important to take the inherent limitations of such retrospective review designs into consideration. Furthermore, with the exception of 2 large SEER database reviews, the studies tended to be small and were likely underpowered to detect statistically significant differences in survival outcomes.

# Outcomes 1. Identification of an adnexal mass suspicious for malignancy
Ultrasonography is the most common diagnostic imaging technique for the noninvasive assessment of adnexal masses and is believed to be both a reliable and reproducible method for preoperative discrimination between malignant and benign pelvic masses (103)(104).

# 2D versus 3D
In addition to the four studies considered in the AHRQ report that analyzed both 2D and 3D ultrasonography, two new prospective studies were identified through the updated literature search (38,48). Analyzing the 2D ultrasonography data from the six studies using a bivariate random effects model yielded an overall sensitivity of 85.3% and specificity of 87.4% (Table 2, Figure 2A). When the data were pooled from the six 3D ultrasonography studies, the estimates improved to an overall sensitivity of 93.5% and specificity of 91.5% (Table 2, Figure 2A). Morphological scoring systems, based on parameters observed from gray-scale sonography, were developed to overcome limitations with operator subjectivity and tumour variability (3). These scoring systems assign and then sum up the score for established sonographic variables. A predetermined specific cutoff value classifies the mass as either malignant or benign.

# Sassone Scoring System
The model originally described by Sassone et al ( 105) is based on a weighted sum of the following four morphological features: inner wall structure, wall thickness, septa, and echogenicity. A score of greater than 9 is suggestive of malignancy. The AHRQ report identified and conducted a meta-analysis of 15 studies that explicitly used Sassone's criteria. The meta-analysis by Geomini et al ( 16) included 18 studies with cutoffs that ranged from 4 to 15, although 9 was the most common cutoff as in the original report. While our updated literature search did not identify any additional studies reporting on the Sassone et al model, we elected to conduct a meta-analysis of studies from both the AHRQ report and the Geomini et al meta-analysis that met our inclusion criteria, because neither report alone captured all the available data. A bivariate random effects model of these 22 studies generated a pooled sensitivity of 90.4% and specificity of 76.4%. Limiting our analysis to the 17 studies (42,62,67,71,(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117) reporting a cutoff point of 9, yielded an overall sensitivity of 88.6% and specificity of 77.5% (Table 3, Figure 2B).

# Lerner Scoring System
Lerner et al (118) devised a scoring system based on a modification to the Sassone model. The Lerner model differs from Sassone's in several ways, including weighted point value assignments, fewer point values per variable studied, the deletion of one variable found not to be significant (wall thickness), and the inclusion of a new variable called shadowing. A cutoff of 3 was determined to best differentiate benign from malignant masses. The AHRQ report did not separately evaluate the Lerner model. Geomini et al (16) reported eight studies that evaluated the Lerner model, in addition to the original, and found a pooled sensitivity of 90% and specificity of 63% (Table 3). Our updated literature search identified one additional study by Lee et al (49) where 137 masses were evaluated in 123 women, and a sensitivity of 82.1% and specificity of 69.7% were reported. We do not believe that the addition of this one study would change the overall estimates reported by Geomini et al and, thus, did not rerun the analysis.

# DePriest Scoring System
The model described by DePriest et al (119) uses the weighted sum of cystic wall structure, volume, and septum structure. The score ranges from 0 to 12, with the most common cutoff set at 5. The AHRQ report identified six studies that made use of the DePriest scoring system. Geomini et al (16) evaluated 10 studies and reported a pooled sensitivity of 91% and specificity of 69% (Table 3). Our literature search identified an additional study (49) not included in either the AHRQ report or the meta-analysis by Geomini et al. In 123 women with 137 masses, Lee and colleagues reported a sensitivity of 92.9% and specificity of 59.6%. We do not believe the addition of this one study to the Geomini et al meta-analysis would have changed the overall estimates and, therefore, did not repeat the analysis.

# Ferrazzi Scoring System
Ferrazzi et al (109) developed their model to include four morphological features: wall structure, septa, vegetations and echogenicity. The weighted sum can range from 4 to 18, with 9 used as a cutoff to suggest malignancy. The AHRQ report identified three studies explicitly using the Ferrazzi et al criteria and the meta-analysis by Geomini et al (16) pooled seven studies. An updated search of the literature identified 1 additional study reporting on the Ferrazzi et al scoring system (58). Pooling the nine available, qualifying studies generated an overall sensitivity of 85.2% and specificity of 85.9% (Table 3, Figure 2B).

# Finkler Scoring System
Finkler et al (120) developed a 10-point scoring system, where scores of 7 or more indicate malignancy. The AHRQ report identified three studies that evaluated the Finkler system, as did Geomini et al (16). However, Geomini et al found that the summary estimates varied widely in the ROC curve. Despite not having identified any additional studies, we felt it was worthwhile to combine all available data in overall summary estimates. Our bivariate random-effects analysis of the five studies (120-124) allowed in our model generated an overall sensitivity of 83.5% and specificity of 78.2% (Table 3, Figure 2B).

# Other Scoring Systems
The meta-analysis by Geomini et al ( 16) also considered a model developed by Alcazar and Jurado that made use of the Sassone score as a variable in a logistic regression. Although the model was evaluated in four studies, there was too much variability in the sensitivity and specificity to pool the summary estimates. The AHRQ report identified 53 studies that evaluate ultrasonography in the assessment of adnexal mass morphology. These publications included unique, modified, or unclear scoring systems that did not fit into the other scoring system categories. While there was significant heterogeneity in the criteria used for diagnosis, the report did go ahead and pool sensitivity and specificity. The resulting summary estimates were 86% for sensitivity and 83% for specificity. 

# Explicit Scoring Systems
The AHRQ report considered scoring systems that included data combined from the following categories: 1) imaging, including ultrasound, CT, and MRI; 2) patient risk factors, such as age and menopausal status; and 3) laboratory data, primarily CA-125.

# Risk of Malignancy Index (RMI)
The RMI, first published by Jacobs and colleagues (125), is based on scores from ultrasound (U), menopausal status (M), and CA-125 data in the following manner: RMI = U x M x CA-125. A cutoff of 200 was used to differentiate between malignant and benign masses in the original study. The AHRQ report (3) identified 11 studies in addition to the original that assessed the diagnostic performance of RMI. The meta-analysis by Geomini et al (16) identified 16 studies in which the RMI was evaluated but considered only the 13 studies that used the original cutoff of 200.
An updated literature search identified two new studies (21,32) that considered the diagnostic accuracy of RMI. When a bivariate random effects model was used to pool the data from the 13 studies, with 15 data sets, employing a cutoff of 200 to be indicative of malignancy, the summary sensitivity and specificity were 79.2% and 91.7%, respectively (Table 4, Figure 2B). When the analysis was extended to the 23 studies considering a cutoff level of 50, the summary estimates were 82.1% for sensitivity and 87.8% for specificity.
Several years after the RMI was published, improvements to the model were attempted. Tingulstad et al (126) proposed the RMI2, which gives new weights to the ultrasound and menopause components of the original model. The same cutoff level of 200 was recommended for the RMI2 model.
The AHRQ report identified four studies in addition to the Tingulstand et al original, while Geomini et al ( 16) evaluated seven studies and, at a cutoff level of 200, reported pooled estimates for sensitivity and specificity of 79% and 81%, respectively (Table 4). The updated literature search indentified only one additional study evaluating the diagnostic accuracy of RMI2. In 194 women, Bensaid et al ( 21) reported a sensitivity of 92% (95% CI, 65 to 100%) and specificity of 80% (95% CI, 75 to 84%) at a cutoff of 125. Because data were not available at the recommended cutoff of 200, we did not repeat the analysis to include the data from Bensaid et al.
In 1999, Tingulstad et al (127) suggested a further refinement to the two previous RMI models, again with suggested new weights given to the ultrasound and menopause components. Two hundred was once again the recommended cutoff level for this third model.
Both the AHRQ report and the meta-analysis by Geomini et al identified only one additional study (128) that evaluated the RMI3 and reported that this validation study found a sensitivity of 74% and specificity of 91%. These results were very similar to the original RMI3 report, which found a sensitivity of 71% and specificity of 92%. We did not identify any additional literature evaluating RMI3.

# Tailor's Model
Tailor et al ( 129) developed a scoring system based on an artificial neural-network analysis that incorporates age, menopausal status, morphological features, and Doppler indices. The AHRQ report found four additional studies that evaluated this model but did not pool the data sets. They did note, however, that the subsequent studies each reported poorer performance than did the original publication. Geomini et al (16) found five publications that evaluated the original Tailor model. At a suggested cutoff of 50%, the pooled sensitivity and specificity of four data sets were 60% and 93%, respectively (Table 4). Our updated search of the literature did not identify any other studies that evaluated the diagnostic performance of the Tailor et al model.  (130) in the late 1990s to predict the malignancy of an adnexal mass. Through complex modelling techniques, the ANN models investigate the possible existence of non-linear interactions or correlation between variables. The ANN1 model combines the predictive value of menopausal status, serum CA-125, presence/absence of papillary structures, and colour score, and uses a cutoff of 45%. The ANN2 model includes, in addition to menopausal status, serum CA-125, and papillary structures as in ANN1, the following set of morphological parameters: smoothness of internal walls, unilocularity, presence of ascites, and whether the mass is bilateral. A cutoff of 60% was used. Timmerman et al found the sensitivity and specificity of ANN1 to be 94% and 90%, respectively. ANN2 performed slightly better with a sensitivity of 96% and specificity of 94%. Two separate studies validated the models (77,115) and also reported a better performance with ANN2 over ANN1, although performance in subsequent replications was poorer. Mol et al (115) reported ANN2 to have a sensitivity and specificity of 90% and 46%, respectively, while Van Holsbeke et al ( 77) reported 98% and 34%, respectively. Our updated literature search did not identify any additional studies that validated the Timmerman ANN models. While other artificial neural networks have been developed over the years, external validation of these additional models is scarce, and they will not be discussed further.

# Logistic Regression Models (LR) 1 and 2
The development of algorithms through statistical modeling that assess the probability of malignancy can also be used to distinguish malignant from benign masses preoperatively. One such logistic regression model (LR1) (131), developed in the late 1990s by Timmerman et al, included the following variables in the analysis: menopausal status, CA-125 level, presence of 1 papillary growth (>3mm in length), and a colour score indicative of tumour vascularity and blood flow. At a cutoff of 25%, the sensitivity of the LR1 was 95.9% and specificity was 87.1%. Two external validation studies (77,132) found lower estimates upon replication, where sensitivity was found to be 62% by Valentin et al and 78.1% by Van Holsbeke et al, and specificity was 79% in both studies.
A second logistic regression model (LR2) developed by the Timmerman group incorporates the same variables as ANN2 (i.e., menopausal status, serum CA-125, papillary structures, smoothness of internal walls, unilocularity, presence of ascites, and whether the mass is bilateral). Timmerman et al (130) reported, at a cutoff of 60%, a sensitivity and specificity of 95.9% and 85.5%, respectively. Again, at external validation, estimates were considerably lower (sensitivity 90% and 84% and specificity 86% and 75% in Mol et al (115) and Van Holsbeke et al (77), respectively).
A number of other logistic regression prediction models are found in the literature, but many are without external validation and will not be considered further in this document.

# Doppler Sonography
Regular gray-scale sonography can be enhanced with Doppler measurements, which assess the direction of blood flow and its relative velocity. Colour Doppler imaging and pulsed Doppler spectral analysis enable evaluation of ovarian tumour blood flow, analysis of the distribution of blood vessels, and quantitative measurement of blood-flow velocity waveforms. These parameters increase the sensitivity and specificity of ultrasound evaluation of ovarian tumours (133).

# 2D Power Doppler (2D PD)
The updated search of the literature identified five qualifying studies that evaluated 2D PD technology in the preoperative discrimination between malignant and benign adnexal masses. The sensitivity in these studies ranged from 49% to 100%, while specificity ranged from 74% to 100% (Table 5). 

# 3D Power Doppler (3D PD)
The evaluation of 3D PD technology in the differential assessment of adnexal masses was considered in four qualifying studies identified through the updated literature search. The sensitivity in these studies ranged from 68% to 100%, while specificity ranged from 40% to 98% (Table 6). 

# Resistance Index (RI)
Resistance Index (RI), the difference between peak systolic and maximum enddiastolic flow velocity divided by peak systolic flow velocity, is one of the most common flow criteria in colour Doppler scanning. The AHRQ report identified 32 articles that evaluated RI, although one study (134) actually considered a morphology index, not RI, and was excluded from further analyses. Our updated literature search identified five new studies (41,48,(51)(52)55) that assessed the diagnostic accuracy of Doppler scanning using the RI parameter, but the data from Marret et al (52) was not included because this same data was previously published and already included. The analysis of the summary estimates for these four new studies along with the existing qualifying literature included 42 data sets and yielded an overall sensitivity of 77.2% and specificity of 89.8% (Table 7, Figure 2C).

# Pulsatility Index
Pulsatility Index (PI) is defined as the difference between peak systolic and enddiastolic flow velocity, divided by the time-averaged flow velocity. The AHRQ report analyzed the PI from 20 studies, while the updated literature search identified only one additional study (51) looking at PI that met the inclusion criteria. When we analysed the 21 studies with 22 data sets, using a bivariate random effects model, we obtained an overall sensitivity of 80.6% and specificity of 79.9% (Table 7, Figure 2C).

# Peak Systolic Velocity
The peak or maximum systolic velocity (PSV) is the maximum flow recorded in any visualized artery and, along with RI and PI, it is one of the most common flow criteria. Our analysis of the six studies included in the AHRQ report plus one additional identified paper (55) yielded an overall sensitivity of 80.0% and specificity of 84.2% (Table 7, Figure 2C).
The AHRQ report considered Doppler studies that did not measure or calculate waveforms but, rather, looked at the presence of vascularity within the mass or a direct count of the vessels observed. The report identified 10 such studies with sensitivities that ranged from 77% to 100% and specificities that ranged from 30% to 94%. Pooling these studies resulted in an overall sensitivity of 88% and specificity of 78% (Table 7). Our updated literature search did not identify any additional studies investigating Doppler visualization. 

# Combined Morphology and Doppler 2D Ultrasonography plus Doppler
A combination of morphological and vascular imaging was developed to try to improve the differentiation of malignant and benign adnexal masses. The AHRQ report identified nine studies that described such a combined modality. An additional three studies were identified through our updated search of the literature. When a bivariate random effect model was used to analyses all 12 studies, an overall sensitivity of 91.0% (95% CI, 84.8% to 94.8%) and specificity of 91.7% (95% CI, 81.1% to 96.6%) was obtained. (Figure 2C).

# 3D Ultrasonography plus Doppler
The updated search of the literature identified two qualifying studies that evaluated 3D ultrasonography plus Doppler technology in the differential assessment of adnexal masses (Table 8). 

# Other Imaging Modalities MRI
The AHRQ report identified 15 articles investigating the performance of MRI in the diagnosis of adnexal masses. An updated search of the literature since the AHRQ report was published identified a meta-analysis ( 15) evaluating, among other things, the MRI modality. Liu et al considered 10 studies reporting 13 data. In addition to this meta-analysis, six primary studies, not included in the Liu et al meta-analysis or the AHRQ report, were also identified during the updated literature search. Again, using a bivariate random effects model, we conducted a meta-analysis of the 15 studies from the AHRQ report, the one study exclusive to the Liu et al meta-analysis that qualified for the current analysis, and the six additional primary studies identified. This analysis of 22 studies with 24 data sets yielded an overall sensitivity of 91.9% and a specificity of 88.4% (Table 9, Figure 2A).
The AHRQ report described three studies that looked at the performance of CT in diagnosing adnexal masses. Liu et al (15) evaluated a total of four studies, two of which also appeared in the AHRQ report and two that did not meet the AHRQ inclusion criteria. Our updated search identified an additional four studies evaluating CT in the diagnosis of adnexal masses. A bivariate random effects analysis of these four studies, along with the three studies (with four data sets) considered in the AHRQ report yielded an overall sensitivity of 87.2% and specificity of 84.0% (Table 9, Figure 2A).
Three studies investigating positron emission tomography (PET) were evaluated in the AHRQ report. Our updated search identified two additional studies, both investigating the accuracy of the combined PET/CT modality. Since results for PET alone were not available, no further PET analyses were undertaken. The AHRQ report found a pooled sensitivity of 67% and specificity of 79% in the diagnosis of adnexal masses with PET technology (Table 9). 

# Serum Marker CA-125
The AHRQ report identified 66 studies that investigated the use of CA-125 serum marker in the evaluation of an adnexal mass. An updated literature search identified 11 new studies, with 14 data sets, investigating the use of CA-125 in the diagnosis of an adnexal mass that met our inclusion criteria. In keeping with the AHRQ report and the most commonly used threshold of 35 U/mL, we conducted a meta-analysis of the 51 studies, with 52 data sets, that used a threshold of 35 U/mL. Eight of these studies (20,(31)(32)(33)53,57,58,135) were published since the AHRQ report. The addition of these newer studies to the analysis did little to change the AHRQ summary estimates. We calculated an overall sensitivity of 78.7% and a specificity of 77.9% (Table 10, Figure 2D). Since many of the studies reported a threshold other than 35 U/mL, we re-ran the analysis using 50 U/mL as the cutoff point. The analysis included 66 studies with 72 data sets, including 10 studies published since the AHRQ report. This yielded an overall sensitivity of 79.0% and specificity of 78.3%.

# Frozen Section
While considered an intraoperative assessment rather than a preoperative one, frozensection diagnosis can help to guide further surgical management of ovarian tumours. Accordingly, the accuracy of this technique is of great consequence and, as such, this method of diagnosing a suspicious adnexal mass was deemed valuable for consideration in this report.
The updated search of the literature identified two systematic reviews and 15 primary studies (19,(23)(24)(25)35,37,39,43,56,61,65,66,79,81,82) published in or since 2004 that considered the diagnostic accuracy of frozen-section diagnosis and were not included in either systematic review. All 15 studies were retrospective cohort-like in design, with seven reporting the selection of consecutive patients. Only one study reported the blinding of pathologists from the final histopathologic diagnosis when interpreting results of frozen sections. One study specifically reported that pathologists were not blinded, and the remaining 13 studies made no reference to blinding status.
Geomini et al considered the accuracy of frozen-section diagnosis in a 2005 systematic review (14). The literature search ranged from 1966 to mid-2003, with 18 primary studies qualifying for inclusion. When borderline tumours were classified as malignant, the sensitivity of frozen-section diagnosis ranged from 65% to 97% and the specificity between 97% and 100%. Classifying borderline tumours as benign resulted in a sensitivity of 71% to 100% and a specificity of 98.3% to 100%.
Medeiros and colleagues (17) also conducted a systematic review and meta-analysis on the accuracy of frozen-section analysis that included 14 primary studies. The literature search period in this review ranged from 1984 to the end of 2003. The pooled sensitivity and specificity of frozen-section diagnosis distinguishing between benign and borderline or malignant ovarian tumours was 99% (95% CI, 89 to 99%) and 88% (95% CI, 86 to 90%), respectively.
In our analysis of the 15 primary frozen section studies published since 2004, borderline tumours were considered malignant and counted as such in the 2x2 tables. Furthermore, any deferred cases reported were excluded from the 2x2 tables and, consequently, from the analysis. A bivariate random effects analysis of these 15 studies yielded an overall sensitivity of 89.2% (95% CI, 86.3 to 91.5%) and specificity of 97.9% (95% CI, 96.6 to 98.7%) (Table 10, Figure 2D). 

# ACOG/SGO Referral Guidelines
The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) jointly published guidelines for the referral of women with pelvic masses that are suspicious for ovarian cancer to gynecologic oncologists (136). The referral guidelines are based on patient age, CA-125 level (>200 U/mL for premenopausal, >35 U/mL for postmenopausal), physical findings, imaging results, and a family history of breast or ovarian cancer in a first-degree relative.
The referral guidelines were validated, and their role in distinguishing benign from malignant masses was tested in a multicentre setting with 1035 patients (44). In premenopausal women, the sensitivity and specificity of the referral guidelines in differentiating benign and malignant masses was 70% and 69%, respectively. Sensitivity was 

# D. CA125 and Frozen Section SROC Curves
Sensitivity enhanced in postmenopausal women, where the guideline correctly identified 94% of ovarian cancer patients. Specificity in this group was reported to be 58%. The predictive value of the referral guidelines was further evaluated in a prospective cohort study of 837 consecutive patients (30). In premenopausal women, the sensitivity and specificity were 79.2% and 69.8%, respectively. In postmenopausal women, sensitivity was found to be 93.2% and specificity was 59.9%. In considering early-versus late-staged disease, the referral guidelines performed better in terms of sensitivity in late-staged disease, especially in postmenopausal women where sensitivity reached 98.3%. In premenopausal women, the referral guidelines were 92.3% sensitive in distinguishing malignant from benign cases.

# Surgical procedures for an adnexal mass suspicious for malignancy
The Australian Cancer Network (ACN) 2004 guideline ( 6) on the management of women with epithelial ovarian cancer made recommendations on, among other things, the most appropriate surgical approach to take in such patients. Eight studies were included in the surgery for pelvic mass section of the guideline and are not discussed further here. An updated search of the literature identified an additional 16 studies (Table 11) published since the 2004 ACN guideline that met our inclusion criteria. 
A randomized controlled trial (RCT) ( 89) of patients undergoing a systematic aortic and pelvic lymphadenectomy versus those undergoing lymph node sampling reported no statistically significant difference in five-year progression-free (p=0.16) or overall survival (p=0.56). However, this RCT was underpowered to detect an effect of systematic lymphadenectomy on survival. The sample size calculation in this study was undertaken to detect a difference in prevalence of lymph node positivity, the study's primary outcome. The targeted sample size required to detect an effect of lymphadenectomy on survival, the secondary outcome, was deemed unattainable by the researchers. Despite the reduced power to detect a statistical difference in the secondary outcomes, the study reported a trend favouring lymphadenectomy in terms of progression-free (HR, 0.72; 95% CI, 0.46 to 1.14) and overall (HR, 0.85; 95% CI, 0.49 to 1.47) survival.
Eight additional studies (85-88,90-93) investigated the survival impact of comprehensive surgical staging in women diagnosed with early-stage ovarian cancer. In two large population-based studies (85)(86), consisting exclusively of over 6600 early-stage epithelial ovarian cancer patients, Chan et al found that surgical staging with lymphadenectomy was associated with improved three-year (p<0.001) (86) and five-year disease-specific survival (p<0.001) (85) compared to staging procedures without lymphadenectomy. Similarly, Oksefjell et al reported a statistically significant improvement in 5-year overall survival rates in patients undergoing a lymphadenectomy versus those that did not (87% vs. 64%, respectively; p=0.02). Survival analyses performed by both Skirnisdottir et al ( 91) and Hornung et al ( 88) also demonstrated a statistically significant benefit in disease-free survival (p=0.004 and p=0.0007, respectively) for patients undergoing a lymphadenectomy versus those that did not. Hornung and colleagues also considered overall survival and reported a statistically significant difference (p=0.0008) in the two patient groups in favour of the lymphadenectomy group. Conversely, in 205 patients with pTI-IIb clear cell carcinoma, Suzuki et al (92) found that patients who underwent systemic lymphadenectomy did not show a significant improvement in disease-free (p=0.353) or overall survival (p=0.645) compared to those that did not. Similarly, Cho et al (87) report no significant difference between groups in progression-free and overall survival rates in patients with stage I mucinous epithelial ovarian tumours undergoing complete staging versus those whose staging was incomplete.
In an attempt to determine the benefit of surgically staging ovarian low malignant potential (LMP) tumours, Wong and colleagues (93) retrospectively reviewed the records of 247 patients with tumours of borderline malignancy and found no statistically significant difference in rates of recurrence or mortality between patients surgically staged and those who were unstaged.
Six studies (94-99, 137) compared laparoscopy versus laparotomy for the surgical management of women with apparent early ovarian cancer or borderline tumours. Patient sample sizes in these studies ranged from 34 to 360. In the three studies (95-97) that considered patients with early epithelial ovarian cancer (EOC), no statistical difference in survival rates was detected between patients undergoing a laparoscopy versus laparotomy. Similarly, in the management of patients with early borderline ovarian tumours, Romagnolo et al (98), Park et al (99), and Desfeux et al (94) found that a laparoscopic versus laparotomic surgical approach did not appear to influence survival rates, although Desfeux et al acknowledged that the number of events was too small to allow for proper statistical testing.
Fertility-preserving treatments are often desirable for women of reproductive age who are diagnosed with borderline ovarian tumours (BOT). Two studies compared the impact of conservative fertility-sparing surgeries versus more extensive surgical approaches. Yinon et al (100) specifically compared rates of recurrence in 40 patients who underwent unilateral salpingo-oophorectomy versus 22 patients who underwent cystectomy only. No statistical difference in recurrence rates was detected (27.5% vs. 22.7%, p=0.8). Similarly, in a larger study of 360 women with BOT, Park et al (99) found no difference in disease-free survival between patients that underwent radical or fertility-sparing surgery (p=0.651).

# Adverse Events
While the surgical technique did not appear to impact patient survival, there were differences detected in surgical outcomes and complication rates. Cho et al (87) found a statistically significant difference in complication rates, with 12.9% experiencing a complication in the completely staged group versus 1.0% in those incompletely staged (p<0.001). Ghezzi et al (95) reported a statistically significant difference in the rates of minor postoperative complications, with 6.7% of patients in the laparoscopy group experiencing such an event compared to 42.1% of patients in the laparotomy group (p=0.047). Romagnolo et al (98) reported a difference in the cases of tumour rupture or spilling during surgery, with 34.6% ruptures recorded in the laparoscopic group compared to 6.6% in patients undergoing a laparotomy (p<0.0001). Similarly, Lecuru et al (96) found 31% of laparoscopic patients experienced intraoperative tumour rupture versus 16% in the laparotomy group. However, this difference did not reach statistically significance. In patients with borderline tumours, the difference in the occurrence of intraoperative tumour rupture was found not to be statistically associated with the surgical approach according to Desfeux et al. ( 94)
The basic diagnostic work-up of patients with a suspicious adnexal mass involves a gynecological exam, ultrasound imaging and testing of serum tumour markers. While this approach is often sufficient in detecting advanced disease, the diagnosis of early-staged ovarian cancer is more challenging. In an attempt to determine the best method for the identification and diagnosis of a suspicious adnexal mass, we systematically reviewed existing guidelines and the literature.
The intention and necessity of preoperative diagnosis of an adnexal mass is to both triage the patient and better define the surgical options. Recent Canadian guidelines on the evaluation and referral of ovarian masses (138) recommend that patients with a high-level risk of underlying malignancy be reviewed in consultation with a gynecologic oncologist. Indeed, studies considering the impact of physician's specialty on the survival of patients with early stage ovarian cancer have shown a trend towards improved survival when gynecologic oncologists perform the surgery (139)(140). Along with triaging appropriate patients to subspecialists, the preoperative diagnosis of an adnexal mass provides the anatomic details necessary to inform the surgical options. For patients with clearly benign masses, or likely benign masses with health issues, observation only is the usual management. Such preoperative diagnostic information can also help to distinguish patients who require extensive surgery over those for whom a more conservative surgical approach is adequate.
Statistical comparisons between diagnostic techniques could not be performed in this review. Instead, the assessment of various modalities in differentiating benign from malignant masses is based on inspection of the summary data obtained from the meta-analyses conducted. These results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each system with equivalent diagnostic competence. Explicit scoring systems did not appear to perform as well as other diagnostic testing methods. Not only was external validation of the models lacking in many cases, where results were available, but performance was often poorer upon subsequent replication. Assessment of an adnexal mass by colour Doppler technology, using the RI, PI, and PSV indices, was neither as sensitive nor as specific as simple ultrasonography. Furthermore, because of overlap of vascular parameters between malignant and benign masses, a firm diagnosis based on Doppler evaluation alone can be problematic (141). Summary estimates from studies considering combined morphology and Doppler assessment were higher than the estimates for either modality alone. Both sensitivity and specificity of this combined approach were high. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT as determined by overlapping confidence intervals. PET did not appear to perform as well as either MRI or CT, although only three studies were considered in the analysis. The measurement of the CA-125 tumour marker appears to be less reliable than other available assessment methods; however, results were not stratified by menopausal status. It is widely reported that differences exist in CA-125 levels between premenopausal and postmenopausal women, even with the same histological diagnosis (75). Finally, frozen-section analysis has both a high sensitivity and an especially high specificity in the assessment of adnexal masses.
In the treatment of ovarian cancer, the importance of surgical management is universally recognized. Clearly, complete surgical resection is required to improve a patient's prognosis. However, it is not clear how aggressive a surgical approach is necessary in earlystaged ovarian cancer. The included evidence suggests that systematic lymphadenectomy improves survival, as does proper surgical staging. There is an exception to this benefit, however, with tumours of low malignant potential. In such tumours, conservative fertilitypreserving surgical approaches appear to have no adverse survival effect (99).
The accuracy and adequacy of surgical staging by laparotomy or laparoscopic approaches appears to be comparable, with neither approach conferring a survival advantage compared to the other. In spite of this, many surgeons are unwilling to perform laparoscopic surgical staging in early-staged ovarian cancer due to the potential risks of intraoperative tumour rupture, port-site metastasis, and dissemination of the tumour (97). Intraoperative tumour rupture was indeed reported to occur more frequently in patients undergoing laparoscopy versus laparotomy in two retrospective cohort studies (96,98). However, unequivocal prospective comparative data supporting the existence of an increased occurrence of intraoperative tumour rupture in ovarian cancer patients managed by laparoscopy is still lacking (95).
The evidence included in this systematic review is not without significant limitations. In the identification of an adnexal mass literature, the population of patients often included women with a suspicious mass undergoing surgery. This inclusion of operative patients could escalate the prevalence of malignancy in comparison to what would be expected in a primary care population of women presenting with a suspicious adnexal mass. This has implications for the generalizability of the results, and it can inflate the test's sensitivity. Furthermore, the included studies did not often allow for stratification by menopausal status. Given the lower likelihood of ovarian malignancy in premenopausal patients, the accuracy of a diagnostic test can be reduced in a sample that includes a high proportion of premenopausal patients.
In addition to these methodological issues, the quality assessment of the included literature revealed several further shortcomings, especially in study design and reporting. Blinding is a crucial issue in diagnostic accuracy studies, as it is necessary to prevent information bias (142). While the index test always preceded surgery in the included studies, thereby by nature blinding the outcome, the reference test should also be interpreted without knowledge of the index test results (142). The vast majority of studies considered in the identification of a suspicious adnexal mass did not report such blinding.
One third of the diagnostic studies had data collection that occurred retrospectively or was not reported. Retrospective study designs are inherently more prone to bias than are prospective studies and can be more difficult to interpret, especially if the sampling did not include consecutive patients. The reporting of consecutive patient sampling occurred in less than half the included studies.
Many of the surgical studies were also prone to biases inherent in their retrospective designs. Moreover, the small sample of included patients meant many studies were underpowered to detect statistically significant results. There is an obvious need for improvement in the quality of primary research in this area. Ideally, future research would consist of randomized clinical trials with a non-inferiority design where survival outcomes are considered.
Despite these limitations, the best available evidence with respect to the questions posed was collected and included. A rigorous systematic review and meta-analysis, planned a priori, provided an abundant evidentiary base and the context and direction for the development of recommendations.
There are numerous methodologies that have been considered in the preoperative identification of adnexal masses suspicious for malignancy. Results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each morphological system with equivalent diagnostic competence. Explicit scoring systems did not perform as well as other diagnostic testing methods. Assessment of an adnexal mass by colour Doppler technology, using the RI, PI, and PSV indices, was neither as sensitive nor as specific as simple ultrasonography. Summary estimates from studies considering combined morphology and Doppler assessment were higher than the estimates for either modality alone. Both sensitivity and specificity of this combined approach were high. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT. PET did not perform as well as either MRI or CT. The measurement of the CA-125 tumour marker appears to be less reliable than do other available assessment methods. Finally, frozen section analysis has both a high sensitivity and especially high specificity in the assessment of adnexal masses.
The evidence suggests that systematic lymphadenectomy and proper surgical staging improve survival. Conservative fertility-preserving surgical approaches are an acceptable option in women with low malignant potential tumours. The accuracy and adequacy of surgical staging by laparotomy or laparoscopic approaches appears to be comparable, with neither approach conferring a survival advantage.

# CONFLICT OF INTEREST
No conflicts of interest were declared for J Dodge, A Covens, C Lacchetti, L Elit, T Le, M Devries-Aboud, or M Fung Kee Fung.

# JOURNAL REFERENCE
The following systematic reviews and meta-analysis has been published in Gynecologic Oncology ( 2012 Elsevier Inc.;/):
The Gynecology Cancer Disease Site Group would like to thank J Dodge, A Covens, C Lacchetti, L Elit, T Le, M Devries-Aboud, and M Fung Kee Fung for taking the lead in drafting this systematic review with meta-analysis.  The PEBC supports a network of disease-specific panels, termed Disease Site Groups (DSGs), as well as other groups or panels called together for a specific topic, all mandated to develop the PEBC products. These panels are comprised of clinicians, other health care providers and decision makers, methodologists, and community representatives from across the province.
The PEBC is well known for producing evidence-based guidelines, known as Evidencebased Series (EBS) reports, using the methods of the Practice Guidelines Development Cycle (1,2). The EBS report consists of an evidentiary base (typically a systematic review), an interpretation of and consensus agreement on that evidence by our Groups or Panels, the resulting recommendations, and an external review by Ontario clinicians and other stakeholders in the province for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each document, through the periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original guideline information.

# The Evidence-Based Series
Each EBS is comprised of three sections:
- Section 1: Guideline Recommendations. Contains the clinical recommendations derived from a systematic review of the clinical and scientific literature and its interpretation by the Group or Panel involved and a formalized external review in Ontario by review participants.

# DEVELOPMENT OF THIS EVIDENCE-BASED SERIES Development and Internal Review
This EBS was developed by the Gynecology DSG of the CCO PEBC. The series is a convenient and up-to-date source of the best available evidence on management of a suspicious adnexal mass, developed through review of the evidentiary base, evidence synthesis, and input from external review participants in Ontario.

# Report Approval Panel
Prior to the submission of this EBS draft report for external review, the report was reviewed and approved by the PEBC Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. The key issues raised by the Report Approval Panel and the modifications made by the Gynecology DSG are below with the DSG responses bulleted below the comments of the panel members:
- If pathology is still the gold standard, as suggested in your last qualifying statement, what is the role of the other diagnostic technologies? o The need to have clarity in the preoperative diagnosis is to 1) triage the patients to a specialist, and 2) better define the surgical options (e.g., conservative vs. radical). We have now added a paragraph to the discussion regarding the intention and necessity of preoperative diagnosis of an adnexal mass. - The authors' first recommendation, and the one for which the most detailed analysis exists, concludes that 3D US, CT and MRI are "all recommended" with considerations of more "local factors" then suggested as determinants of the modality of choice. The authors should reconsider whether they have missed an opportunity to make a more definitive recommendation that accounts for the "equality" in diagnostic efficacy and what can be reasonably assumed about cost, access, harm (e.g., radiation exposure) and patient inconvenience. o We thank the reviewer for his comments. We have taken this opportunity to add further recommendations based on the Working Group's expert consensus opinion that takes into consideration availability, access, and harm. - The authors consider various diagnostic tools separately (e.g., imaging, CA-125). Is there a risk that, in practice, these modalities are used in combination and in doing so, diagnostic properties are changed? Related to this theme, are there important differences in the eligibility of patients included in any analysis of a single modality, in which a second modality criterion was required for inclusion? The bolded text was removed from the recommendations section, and it was further delineated that the recommendations were based on expert opinion. Furthermore, the recommendation on PET was moved to indicate that the role of PET in cervical cancer has not been prospectively evaluated. o In many circumstances, we have evaluated the combination of diagnostic tests such as ultrasound and CA-125 - In contrast to the diagnostic efficacy section, the section that deals with "therapy"
(What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for malignancy?) does not include conventional guideline methodology or reporting. As this question is a largely a therapeutic question, standard methodologies would move down a hierarchy of acceptable guidelines, metaanalysis of randomized controlled trials (RCTs), RCTs, non-randomized comparisons, etc. The authors do not provide background in their Methods section about their approach to this question (including literature search criteria). The Results section largely is divided into positive vs. negative studies as opposed to a systematic presentation of the literature. As a result, the juxtaposition of data and conclusions is associated with ambiguity and comes across as potentially representing "expert opinion" as opposed to an evidenced-based recommendation. The authors should reconsider their approach to this question. o We thank the reviewer for these comments. We did indeed use standard methodologies in the development of this section of the guideline but acknowledge that this was not clear in the reporting. As such, we have explained more explicitly in the Methods section what was done. Furthermore, we rearranged the reporting of the results so that the one RCT is discussed first. - The authors might wish to clarify whether the post-diagnostic therapeutic pathway includes multiple modalities that require systematic review in order to assess linkage. Again, while this comment may reflect lack of content expertise, if these patients should be considered for adjuvant therapy using another modality, does the use of that subsequent modality interact with the choice of the surgical approach? In addressing the surgical approach, and especially if best therapy involves sequential use of multiple modalities, the authors may need to carefully dissect out the prognostic importance of patients being able to undergo a more extensive surgical procedure vs. the therapeutic benefit of that intervention. o There is indeed a link between surgery and adjuvant therapy. However, the Working Group viewed these two interventions separately, both in terms of prognosis and as therapeutic approaches. As such, a discussion on adjuvant therapy in patients with a suspicious adnexal mass was deemed beyond the scope of this document.

# External Review by Ontario Clinicians and Other Experts
The PEBC external review process is two-pronged and includes a targeted peer review that is intended to obtain direct feedback on the draft report from a small number of specified content experts and a professional consultation that is intended to facilitate dissemination of the final guidance report to Ontario practitioners.
Following the review and discussion of Section 1: Recommendations and Section 2: Evidentiary Base of this EBS and the review and approval of the report by the PEBC Report Approval Panel, the Gynecology Cancer DSG circulated Sections 1 and 2 to external review participants for review and feedback. Box 1 summarizes the draft recommendations and supporting evidence developed by the working group.

# BOX 1:
DRAFT RECOMMENDATIONS (approved for external review 2011-04-08) QUESTIONS
- What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? 2. What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer?

# TARGET POPULATION
The target population of this guideline is adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic.

# INTENDED USERS
This guideline is targeted for clinicians managing the care of women with a suspicious adnexal mass, specifically general gynecologists and gynecological oncologists.

# RECOMMENDATIONS Identification of an Adnexal Mass Suspicious for Ovarian Cancer
 Sonography, particularly three-dimensional (3D) sonography, magnetic resonance imaging (MRI), and computerized tomography (CT) imaging are each recommended for differentiating malignant from benign ovarian masses. However, the working group offers the following further recommendations, based on their expert consensus opinion and the consideration of availability, access, and harm:
- Transvaginal sonography should be the first modality of choice, where technically feasible, in patients with a suspicious, isolated ovarian mass.

# - MRI is the most appropriate test to help clarify the malignant potential in patients
where ultrasound may be unreliable. - CT is most useful in cases where extra ovarian disease is suspected or needs to be ruled out.

# Key Evidence
- The diagnostic performance of each diagnostic technology was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. - A meta-analysis of six cohort studies that investigated 3D sonography (1-6) indicated an enhanced sensitivity of 93.5% and specificity of 91.5% with 3D technology (Section 2, Figure 2A). - A meta-analysis of 22 cohort studies with 24 data sets that investigated the effectiveness of MRI in the diagnosis of adnexal masses (7-28) found an overall sensitivity of 91.9% and specificity of 88.4% (Section 2, Figure 2A). - A meta-analysis of seven studies with eight data sets considering CT technology (2,10,12,14,22,29,30) yielded an overall sensitivity of 87.2% and specificity of 84.0% (Section 2, Figure 2A).

#  Evaluation of an adnexal mass by Doppler technology alone is not recommended. Doppler technology should be combined with a morphological assessment.

# Key Evidence
- This recommendation is based on the results of several meta-analyses on Doppler indices but not direct comparisons between them. Rather, the summary data from these meta-analyses were inspected, and reasonable sensitivities and specificities were noted. - A meta-analysis of the resistance index (RI) included 35 cohort studies (2,5,17, with 42 data sets and yielded an overall sensitivity of 77.2% and specificity of 89.8% (Section 2, Figure 2C). - A meta-analysis of 21 cohort studies with 22 data sets that evaluated the Pulsatility Index (PI) found an overall sensitivity of 80.6% and specificity of 79.9% (Section 2, Figure 2C). - A meta-analysis of the peak systolic velocity (PSV) included seven cohort studies (32,33,37,42,50,51,62) and found an overall sensitivity of 80.0% and specificity of 84.2% (Section 2, Figure 2C).

# Qualifying Statement
- Assessment of an adnexal mass by colour Doppler technology, using the RI, PI and PSV indices, was neither as sensitive nor specific as simple ultrasonography. Furthermore, because of the overlap of vascular parameters between malignant and benign masses, a firm diagnosis based on Doppler evaluation alone can be problematic.
 Morphological scoring systems can be used to differentiate benign from malignant adnexal masses. The choice between the scoring systems should be made based on demonstrated accuracy and clinician preference.

# Key Evidence
- The diagnostic performance of each morphological scoring system was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. - A meta-analysis of 17 cohort studies (32,33,46,52,57,63-74) assessing the Sassone model at a cutoff of 9, found an overall sensitivity of 88.6% and specificity of 77.5% (Section 2, Figure 2B). - A meta-analysis of nine studies (33,35,63,65,70,(75)(76)(77)(78) considering the Ferrazzi scoring system reported an overall sensitivity and specificity of 85.2% and 85.9%, respectively (Section 2, Figure 2B). - A meta-analysis of five studies (36,(79)(80)(81)(82) measuring the performance of the Finkler scoring system found an overall sensitivity of 83.5% and specificity of 78.2% (Section 2, Figure 2B). - A meta-analysis of data from 13 RMI studies (70,(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94), with 15 data sets, employing a cutoff of 200 to be indicative of malignancy, reported the summary sensitivity and specificity were 79.2% and 91.7%, respectively (Section 2, Figure 2B).
 As a stand-alone modality, serum CA-125 is not recommended for distinguishing between benign and malignant adnexal masses.

# Key Evidence
- This recommendation is based on a meta-analysis of 49 2D).

# Qualifying Statement
- CA-125 values are of limited use in premenopausal women and elevated in only 50% of early-stage ovarian cancers. Caution should be used in interpreting values in such patients.
 Frozen section for the intraoperative diagnosis of a suspicious adnexal mass is recommended in settings where availability and patient preferences allow.

# Key Evidence
- This recommendation is based on a meta-analysis of frozen section diagnoses that included 15 cohort studies (7,(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145) and yielded an overall sensitivity of 89.2% and specificity of 97.9% (Section 2, Figure 2D).

# Surgical Procedures for an Adnexal Mass Suspicious for Malignancy
 Comprehensive surgical staging with lymphadenectomy is recommended for the surgical management of patients with early-stage ovarian cancer to improve survival. 

# Key Evidence

# QUALIFYING STATEMENTS
The Gynecology Cancer Disease Site Group (DSG) acknowledges that, despite definitions and criteria, it is unrealistic to expect that 100% of ovarian cancers will be identified as suspicious preoperatively. Pathology remains the gold standard.
Targeted Peer Review: During the guideline development process, two targeted peer reviewers from Ontario and one from the USA considered to be clinical and/or methodological experts on the topic were identified by the working group. Several weeks prior to completion of the draft report, the nominees were contacted by email and asked to serve as reviewers.
Three reviewers agreed, and the draft report and a questionnaire were sent via email for their review. The questionnaire consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a guideline. Written comments were invited. The questionnaire and draft document were sent out on April 8, 2011. Follow-up reminders were sent at two weeks (email) and at four weeks (telephone call).
Professional Consultation: Feedback was obtained through a brief online survey of health care professionals who are the intended users of the guideline. Gynecologists and gynecologic oncologists in the PEBC database were contacted by email to inform them of the survey.
Participants were asked to rate the overall quality of the guideline (Section 1) and whether they would use and/or recommend it. Written comments were invited. Participants were contacted by email and directed to the survey website where they were provided with access to the survey, the guideline recommendations (Section 1) and the evidentiary base (Section 2). The notification email was sent on April 13, 2011. The consultation period ended on June 10, 2011. The working group reviewed the results of the survey.
Targeted Peer Review: one reviewer out of the three that were invited provided a response. This reviewer's responses are summarized in Table 1.  No significant barriers or enablers were reported.

# Summary of Written Comments
The reviewer advised that references by L. Cohen and A. Fleischer be added to the evidence base.
The authors were not able to gather more information from this reviewer regarding exactly which publications had been missed. The authors examined whether references by Cohen and/or Fleischer had been considered at any time during the guideline development process. Cohen (2001) was considered by the AHRQ review and reported in Section 2 under "Other Scoring Systems". An additional paper by Cohen and Fleischer was excluded by the AHRQ. One Fleischer paper was included in the evidence base for the guideline. In the end, no modifications to the evidence base were made on the basis of this reviewer comment.
Professional Consultation: Sixty responses were received. Key results of the feedback survey are summarized in Table 2. 3. I would recommend this guideline for use in practice. 0(0) 0(0) 7( 13) 22( 39) 31( 55)

# What are the barriers or enablers to the implementation of this guideline report?
Practitioners listed barriers to the implementation of this guideline and suggested ways that uptake could be enhanced or enabled. The feedback included the following:
Some practitioners mentioned that lack of awareness of the guideline would be a barrier to uptake. They recommended making primary care physicians aware of the guideline, and one reviewer suggested presentation of the guideline at group rounds to make the entire team aware of current literature and recommendations.
Many practitioners reported that lack of resources would be a barrier to implementation of the guideline, especially in smaller communities. Specific resources that were noted as lacking included:
- Gynecologic oncologists (e.g., for staging using lymphadectomy).
- MRI only available in larger communities and delays with MRI booking.
- CT access.
- Patients may not always have easy access to an ultrasound department and quality of reporting is variable. - Pathologists with experience in gynecologic pathology for frozen section diagnoses.
- Regional Minimally Invasive Surgery programs in the community.
In order to enable the implementation of the guideline, practitioners also suggested: - A summary table outlining the sensitivities and specificities of the various diagnostic procedures. - Guidance for referral of patients to a gynecologist or gynecologic oncologist for nongynecologist clinicians who identify an adnexal mass.
- Educating radiologists about appropriate use of ultrasound.
- Boundaries to indicate whether the risk for a specific woman is low or high after being investigated. - A recommendations regarding CA-125 use for post-op women.
- A summary table outlining the sensitivities and specificities of the various diagnostic procedures is presented in Section 2 of the report. - Referral criteria are considered to be outside of the scope of this review and guideline. For more information on referral criteria, readers may refer to a guideline published in 2009 by the Society of Obstetricians and Gynaecologists of Canada: Initial evaluation and referral guidelines for management of pelvic/ovarian masses (138). - Cutoffs for the scoring systems included in the report were added to Appendix 2 in Section 1. - CA-125 use post-op is outside of the scope of this guideline. In the event that the reviewer meant that we should clarify the recommendation regarding CA-125 use as a stand-alone modality in postmenopausal women, we amended the CA-125 recommendation so that it no longer refers only to premenopausal women, but to all women, as there is no evidence for its efficacy as a stand-alone modality for any age group.

# Summary of Written Comments
Twenty of the sixty responders to professional consultation provided additional written comments.
The majority indicated that the document was of high quality and would be of use to practitioners. Suggestions for improvements or additions to the document included:
- Mention of specific suspicious features may prove useful for the radiologist colleague accessing this guideline. 2. There is clear operative requirement of staging and lymphadectomy, but the role of tertiary referral is not clear. 3. Several comments were made relating the scoring systems described in the report. The feedback generally indicated that there are many practitioners in the province who are not aware of these scoring systems. A direct link from the recommendations to the scoring systems was requested. It was also suggested that the guideline recommend one scoring system that would be the most reliable. Other comments related to scoring systems include: a. Many practitioners are using the Risk of Malignancy Index (RMI) and it should be available as an appendix to this guideline. Also related to RMI: i.
Recommendation on the use of RMI II and how the general gynecologist should use it for guidance when considering referral to a tertiary care centre. ii. Reference to RMI cutoff of 200 instead of 400 which is what is commonly used. 4. There was also a request for an appendix for ultrasound features of malignancy and definitions of resistance index (RI) pulsatility index (PI), and Peak Systologic (sic) Velocity (PSV).
- As specific suspicious features are described in Section 2 of the report, no changes were made based on this comment. 2. The topic of referral is beyond the scope of this guideline and was therefore not considered for inclusion. As mentioned above, readers may refer to the Society of Obstetricians and Gynaecologists of Canada guideline Initial evaluation and referral guidelines for management of pelvic/ovarian masses (138). 3. Response to comments related to the scoring systems:
a. An appendix was added to Section 1 with descriptions of the Sassone, DePriest, Ferrazzi, Lerner, Finkler, and RMI scoring systems. References to the original publications were also added to Section 2 of the report. Because the sensitivity and specificity are comparable for these scoring systems, it is not possible to recommend one of them as most reliable. Therefore, the wording of the recommendation was adjusted to make this clear and to indicate that the choice of scoring system should be based on clinician preference. b. The recommendation was also reworded to state that choice of version of the RMI should be based on clinician preference as they all have comparable sensitivity and specificity. c. The cutoff value of 200 for the RMI was based on the cutoff used in the initial report by Jacobs et al. The sensitivity and specificity values reported here are based on this cutoff. This was also reported in the AHRQ report as the most common cutoff value, therefore, the group decided to not to include reference to a cutoff of 400. d. Other definitions such as RI, PI, and PSV can be found in Section 2 of the document.
This EBS report reflects the integration of feedback obtained through the external review process with final approval given by the Gynecology Cancer Disease Site Group, and the Report Approval Panel of the PEBC. Updates of the report will be conducted as new evidence informing the question of interest emerges. In September 2015, this document was assessed in accordance with the PEBC Document Assessment and Review Protocol and was determined to require a review. As part of the review, a PEBC methodologist conducted an updated search of the literature. A clinical expert (TL) reviewed and interpreted the new eligible evidence and proposed the existing recommendations could be endorsed. The Gynecology Cancer Disease Site Group (DSG) endorsed the recommendations found in Section 1 (Clinical Practice Guideline) on September 9, 2016.

# DOCUMENT ASSESSMENT AND REVIEW RESULTS

# Questions Considered
- What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer?
- What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer

# Literature Search and New Evidence
The new search (January 2011 to January 2016) yielded 9386 papers. Three hundred and eighty six were retained for full text review. After the full text review, 93 studies were retained. Brief results of these searches are shown in the Document Review Tool.

# Impact on Guidelines and Its Recommendations
The new data supports existing recommendations. Hence, the Gynecology Cancer DSG ENDORSED the 2011 recommendations on management of a suspicious adnexal mass.
A new qualifyling statement was added to the recommendation on ultrasound-based morphological scoring systems. "Ultrasound diagnostic criteria using a set of simple rules to distinguish between benign and malignant masses, and the IOTA (International Ovarian Tumour Analysis) predictive adnexal model had been extensively studied with acceptable sensitivity and specificity. This can serve as potential alternative diagnostic strategy to the RMI score." The following paragraphs are the justification for the inclusion of this qualifying statement.. Inconclusive result can be classified using subjective assessment by an experienced ultrasound operator. This strategy has been recently validated in 4848 patients with adnexal masses against histopathologic diagnosis with a sensitivity of 99.7% and specificity of 33.7%. In addition, the IOTA group also constructed an Assessment of Different Neoplasias in the adneXa (ADNEX) model. This is a risk prediction model to differentiate between benign, borderline tumours, stage I invasive, stage II-IV invasive ovarian cancer and secondary metastatic cancer. The ADNEX model consists of three clinical predictors and six ultrasound predictors. The clinical predictors are age (years), serum CA-125 (U/mL) and type of center to which the patient has been referred for ultrasound examination. Type of center was divided into oncology centers versus other hospitals. The ultrasound predictors are the maximal diameter of the adnexal mass (mm), proportion of solid tissue (%), number of papillary projections (0, 1, 2, 3, > 3), presence of more than 10 cyst locules (yes/no), acoustic shadows (yes/no), and presence of ascites (yes/no). The model performed well in differentiating between benign and malignant masses with the area under the receiver operating characteristic curves (AUC) of the ADNEX model of 0.954 (95% confidence interval 0.947 to 0.961) on the development data and 0.943 (0.934 to 0.952) on the validation data. The sensitivity for diagnosis of malignancy was 96.5% and specificity was 71.3% on the validation data set. 3. What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? 4. What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer?
The target population of this guideline is adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic.

# Study Section Criteria:
Articles were eligible for inclusion in this systematic review if they were systematic reviews, meta-analyses, clinical practice guidelines, randomized trials, or comparative cohort studies. Studies identified in the update of the AHRQ report literature search were included based on the same inclusion criteria put forth in the AHRQ report (3).
For studies investigating single modality identification of an adnexal mass, the inclusion criteria were:
1) comparison of the test (e.g., bimanual pelvic exam or ultrasound, to histology or negative surgery 2) greater than 20 patients included in study 3) able to construct a 2-by-2 table, which compares the results of the diagnostic test with the definitive histological diagnosis.
For studies investigating the use of multi-modality scoring systems (i.e., RMI), the inclusion criteria were:
1) patients with suspicion of cancer 2) studies with scoring, risk score, combined modality approach 3) assesses predictive value of two or more variables using multivariable model 4) greater than 50 patients included in study.
Studies identified in the update of the Australian Cancer Network (6) guideline were based on the following selection criteria:
1) greater than 20 patients included in study 2) patients with an adnexal mass suspicious for early stage (I-II) malignancy, 3) two-armed (or greater) study design with a comparison of surgical procedures/techniques/approaches 4) report on at least one of the following outcomes: optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, quality of life. 
The SUVmax of malignant tumors was significantly higher than that of benign and borderline lesions (mean, 7.8, 1.7, 2.4; P < 0.05). Among malignant tumors, SUVmax was significantly lower in mucinous adenocarcinomas compared with nonmucinous malignant tumors (mean, 3.3, 8.4; P < 0.05) and lower in clear cell adenocarcinomas compared with other subtypes of nonmucinous malignant tumors (mean, 6.0, 9.4; P < 0.05). The SUVmax cutoff that best differentiated malignant lesions from benign/borderline lesions was 2.4 for mucinous and 4.0 for nonmucinous tumors. These cutoffs correctly classified lesions as malignant or not in 88 
The frequency of invasive malignancy was 10% in small tumors, 19% in medium-sized tumors and 40% in large tumors; 11% of the large tumors were borderline tumors vs 3% and 4%, respectively, of the small and medium-sized tumors. The type of benign histology also differed among the three subgroups. For all methods, sensitivity with regard to malignancy was lowest in small tumors (56-84% vs 67-93% in medium-sized tumors and 74-95% in large tumors) while specificity was lowest in large tumors (60-87%vs 83-95% in medium-sized tumors and 83-96% in small tumors. The DOR and the AUC value were highest in medium-sized tumors and the AUC was largest in tumors with a largest diameter of 7-11 cm. 

# Author Study type Comparison N Results
Frozen sections were compared with final paraffin sections 27 cases had a diagnostic discrepancy.

# Rakhshan 2009
Not stated Frozen section diagnosis of adnexal masses was compared with permanent section diagnosis as the gold standard.
The overall accuracy of frozen section diagnosis was 95.7%. The sensitivity of frozen section diagnosis for benign, borderline and malignant lesions was 99, 60, and 92%, respectively. The tumor size in discrepant cases was larger than the concordant cases, however no association between mucinous histology and inaccurate diagnosis was found. 

# OUTCOMES DEFINITIONS
- ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of the Web site and each page is watermarked with the phrase "ARCHIVED".
- ENDORSED -An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way.
- DELAY -A Delay means that there is reason to believe new, important evidence will be released within the next year that should be considered before taking further action.
- UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.