Are serum HE4 or ROMA scores useful to experienced examiners to improve characterization of adnexal masses after transvaginal ultrasonography?

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1 See discussions, stats, and author profiles for this publication at: Are serum HE4 or ROMA scores useful to experienced examiners to improve characterization of adnexal masses after transvaginal ultrasonography? Article in Ultrasound in Obstetrics and Gynecology January 2014 Impact Factor: 3.85 DOI: /uog Source: PubMed CITATIONS 5 READS authors, including: Toon Van Gorp Maastricht University 103 PUBLICATIONS 1,446 CITATIONS Elisabeth Epstein Karolinska Institutet 81 PUBLICATIONS 1,084 CITATIONS SEE PROFILE SEE PROFILE Thomas Bourne Imperial College London 505 PUBLICATIONS 8,523 CITATIONS Ben Van Calster University of Leuven 259 PUBLICATIONS 3,125 CITATIONS SEE PROFILE SEE PROFILE Available from: Ahmad Sayasneh Retrieved on: 09 May 2016

2 Ultrasound Obstet Gynecol 2014; 43: Published online 4 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography? J. KAIJSER, T. VAN GORP, M.-E. SMET, C. VAN HOLSBEKE, A. SAYASNEH, E. EPSTEIN, T. BOURNE, I. VERGOTE, B. VAN CALSTER and D. TIMMERMAN KU Leuven Department of Development and Regeneration, Leuven, Belgium; Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals, KU Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, MUMC +, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands; Department of Obstetrics and Gynecology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Cancer and Surgery, Imperial College London, London, UK; Department of Obstetrics and Gynecology, Karolinska Institute, Stockholm, Sweden KEYWORDS: CA 125 protein; diagnostic test; HE4 protein, human; ovarian neoplasms; ultrasonography ABSTRACT Objective To determine whether serum humanepididymis protein-4 (HE4) levels or Risk of Ovarian Malignancy Algorithm (ROMA) scores are useful second-stage tests for tumors thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced examiners, and to investigate whether adding information on serum HE4 levels or ROMA scores to ultrasound findings improves diagnostic performance. Methods This was a prospective cross-sectional diagnostic accuracy study conducted in a tertiary referral center that enrolled consecutive women with a known adnexal mass scheduled for surgery. Experienced level III examiners classified each mass as certainly or probably benign, difficult to classify, or probably or certainly malignant after preoperative ultrasound examination. Serum HE4 and CA 125 levels were measured before surgery. Results The final database comprised 360 women, of whom 216 (60%) had benign and 144 (40%) had malignant disease. Examiners were highly confident in 196 cases (54%), moderately confident in 135 (38%) and completely uncertain about their diagnosis in 29 (8%) cases. With a sensitivity of 67% and specificity of 70%, subjective assessment outperformed HE4 and ROMA in the subgroup of difficult tumors. Both tests had low discriminatory capacity with poor areas under the receiver operating characteristics curve of (95% CI, ) and (95% CI, ), respectively. A strategy that incorporates sequential testing of serum HE4 or ROMA scores after transvaginal ultrasonography resulted in a deterioration in overall test performance. Conclusion Measurement of serum HE4 or calculating scores using the ROMA as secondary tests does not seem useful for classifying adnexal tumors after subjective assessment with transvaginal ultrasonography. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION Measurement of serum biomarkers is still advocated in many guidelines relating to ovarian cancer diagnostics 1 3. Biomarkers are currently incorporated into different approaches to classify adnexal pathology such as the Risk of Malignancy Index (RMI) 4 or the Risk of Ovarian Malignancy Algorithm (ROMA) 5, licensed in 2011 to combine results of both serum CA 125 and human-epididymis protein-4 (HE4) 6. None of these diagnostic tools nor single serum CA 125 measurement alone has been shown to outperform test performance by an experienced examiner with a special interest in gynecologic ultrasound 7,8. In general expert subjective assessment has been regarded as the optimal approach for diagnosing cancer in women with adnexal pathology. However, diagnostic studies have shown that there is a considerable proportion of tumors (10%) that still prove difficult to classify even for expert operators 9 12.The overall accuracy of subjective assessment in this group of difficult tumors is of the order of 68%, with rather poor sensitivities ranging from 57 to 70% and specificities of Correspondence to: Prof. D. Timmerman, University Hospital KU Leuven, Herestraat 49, 3000 Leuven, Belgium ( dirk.timmerman@ uzleuven.be) Accepted: 11 June 2013 Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

3 90 Kaijser et al. only 60 77% This suggests an urgent need for a reliable second-stage test. Difficult tumors mainly consist of borderline tumors, cystadenofibromas, cystadenomas, fibromas and rare benign tumors Serum CA 125 is often not very reliable as a diagnostic tool with these histological subtypes 13. Levels are frequently normal in borderline tumors and early-stage invasive disease 14,15, while frequently showing false-positive elevations in numerous benign tumors, or conditions that irritate the pelvic peritoneum 16. Serum CA 125 therefore has not proved to be a useful secondary test in ovarian masses that are difficult to classify with ultrasound 9. A promising novel epithelial biomarker used to indicate malignancy of the reproductive tract is HE4 17. Compared to CA 125, HE4 is less frequently elevated in those benign tumors that are commonly difficult to differentiate from ovarian cancer, particularly in premenopausal women 18.Other studies have concluded that serum HE4 is a better single marker for the detection of ovarian cancer 19,20. This increased specificity of serum HE4 in contrast to that of CA 125 might also explain the improved accuracy observed in some validation studies of the ROMA over single serum CA 125 measurement alone 5,19. However, controversy exists, as subsequent studies have been unable to demonstrate a diagnostic advantage for the ROMA or serum HE4 over CA 125 alone The primary aim of this study was to investigate the diagnostic accuracy of serum HE4 and ROMA as candidate second-stage tests in a subgroup of tumors thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced ultrasound examiners. Furthermore, we evaluated whether adding information on serum HE4 or risk scores produced by ROMA after subjective assessment by transvaginal ultrasonography improves the preoperative characterization of adnexal masses. METHODS Design and setting From August 2005 to March 2009 we enrolled 389 consecutive patients with a pelvic mass of suspected ovarian origin who were already scheduled for surgical intervention in a prospective cross-sectional diagnostic accuracy study conducted at the University Hospitals KU Leuven, Belgium. The study was approved by the Ethics Committee of UZ Leuven (reference: OG032/ML3132). Written informed consent was obtained from all patients. Women with a previous bilateral oophorectomy were not eligible. To be considered for inclusion patients had to undergo preoperative standardized gray-scale and color Doppler imaging by transvaginal ultrasound using high-quality equipment (Voluson E8 or 730 Expert, GE Medical Systems, Zipf, Austria) in accordance with previously published standardized guidelines of the International Ovarian Tumor Analysis (IOTA) collaborative group, with documented presence of an adnexal (ovarian, tubal, paraovarian) mass 25. The ultrasound information obtained did not influence the decision-making process when planning surgery. Subjective assessment Experienced ultrasound examiners classified each mass as benign, borderline or invasive malignant, using their subjective assessment at the time of a real-time ultrasound examination, irrespective of their level of diagnostic certainty regarding malignancy. When examiners were completely uncertain they were still obliged to provide a probable diagnosis. All examiners were level III examiners who had a high level of ultrasound expertise and a special interest in the use of ultrasound imaging to characterize adnexal tumors 26. Their degree of diagnostic certainty was scored as certainly benign, probably benign, completely uncertain (benign or malignant), probably malignant or certainly malignant. The ultrasound examiner had no prior knowledge of the patient s serum CA 125, HE4 or ROMA scores when suggesting a diagnosis. Biomarkers Serum samples were obtained for biomarker analysis prior to surgery. Serum CA 125 levels were measured using the CanAg CA 125 EIA assay (Fujirebio Diagnostics Inc., Göteborg, Sweden) 27 and serum HE4 levels using the HE4 EIA assay (Fujirebio Diagnostics Inc.) 28. For CA 125, we considered 35 U/mL as a cut-off to indicate cancer for both pre- and postmenopausal women, while for HE4 we used both 70 pmol/l and 150 pmol/l as cut-offs in both menopausal age groups, as given in the package insert for the HE4 EIA kit 18,28. Postmenopausal status was defined as more than 1 year of amenorrhea, or age 50 years or older if the woman had had a prior hysterectomy. Since both cut-offs (70 pmol/l, 150 pmol/l) for HE4 do not take into consideration age or menopausal status, they may lead to inaccurate patient evaluation. In view of this limitation we also introduced age-dependent cut-offs for HE4 based on new normative curves for the upper limits of normal using the 95 th percentile for HE4 in premenopausal (89 pmol/l) and postmenopausal women (128 pmol/l), or 114 pmol/l for both groups combined when using the HE4 EIA kit 29. The ROMA classifies patients as being at low or high risk for malignant disease using the following algorithms and thresholds according to the manufacturer s insert: for premenopausal women the linear predictor z equals: ( 2.38 ln (HE4) ) + ( 626 ln (CA 125) ) ; for postmenopausal women z equals: ( 1.04 ln (HE4) ) + ( ln (CA 125) ). The probability of malignancy then equals 1/(1 + e z ). The cut-off used to indicate high risk of finding epithelial ovarian cancer was 12.5% (probability 0.125) in premenopausal women and 14.4% (probability 0.144) in postmenopausal women.

4 HE4 or ROMA after ultrasound 91 Final outcome All patients underwent surgical removal of the adnexal mass, and complete surgical staging was performed in the case of ovarian cancer. The reference test used in this study was the final histological diagnosis. Histology of the tumors was classified according to the World Health Organization classification of ovarian tumors 30. For statistical analysis borderline ovarian tumors were classified as malignant tumors. The pathologist was blinded to the diagnosis suggested by subjective assessment of the ultrasound examiner and serum concentrations of both CA 125 and HE4. Statistical analysis All statistical analysis was performed with Medcalc version (MedCalc Software, Mariakerke, Belgium) and SAS 9.2 (SAS Institute, Cary, NC, USA). The diagnostic performance of subjective assessment, serum HE4 and the ROMA was expressed as sensitivity, specificity and positive (LR + ) and negative (LR ) likelihood ratios, and was stratified according to the level of diagnostic confidence and reported according to the Standards for Reporting of Diagnostic Accuracy 31. Receiver operating characteristics (ROC) points for subjective assessment and ROC curves for serum HE4 and the ROMA were constructed with their corresponding areas under the curve (AUC) for the different levels of diagnostic certainty. In addition, using the six levels of diagnostic confidence of subjective assessment as different cut-offs, a ROC curve was constructed for subjective assessment for all tumors, and binomial exact 95% CIs for single AUCs were calculated. To illustrate the effect of sequential testing of serum HE4 or calculating the risk of cancer with the ROMA after transvaginal ultrasonography we conducted a posthoc descriptive analysis including evaluation of the overall test performance of a two-step strategy that required both subjective assessment and serum HE4 or ROMA scores to be concordant for either a benign or malignant diagnosis to be made (Figure S1). Median overall time difference between ultrasonography and blood sampling for HE4 and CA 125 in all tumors was 8 (95% CI, ) days. For presumed malignant and benign masses after subjective assessment the median time difference was 3 (95% CI, 1 6) days and 29 (95% CI, ) days, respectively. RESULTS In total 389 women were recruited to the study. Twentynine cases (7%) were excluded as either transvaginal ultrasonography had not been performed or there was absence of measurable pathology in the adnexal region on ultrasound evaluation. The final database for analysis therefore comprised 360 women. Slightly more malignant cases (n = 18) were excluded than benign cases (n = 11). The overall rate of malignancy was 40% (n = 144). The majority of malignant tumors were epithelial ovarian cancers (n = 116). We included 32 cases of borderline ovarian tumors. Most epithelial cancers were serous or mucinous and over half were diagnosed with advanced International Federation of Gynecology and Obstetrics (FIGO) stage and highgrade differentiation (II III) (61%). There were 52% postmenopausal patients, and more malignant tumors were diagnosed in postmenopausal women (57%) than in premenopausal women (22%). The histological diagnoses stratified for the level of diagnostic certainty of the ultrasound examiner are presented in Table 1. In 196 (54%) of all included cases the ultrasound examiners were certain about their classification. Examiners were less confident about 135 adnexal tumors (37%) and were completely uncertain in only 29 cases (8%). Most of these unclassifiable cases were benign tumors (n = 23, 79%); four (14%) were borderline tumors and two (7%) were invasive cancers. Endometriomas, teratomas, follicular, functional or parasalpingeal cysts and advanced-stage serous epithelial ovarian cancer were the most common tumors where examiners showed complete confidence. Fibromas and borderline tumors were over-represented among tumors when examiners were less confident or completely uncertain. Preoperative serum HE4 and CA 125 levels differed depending on benign or malignant histology (Figure 1). HE4 serum levels were 70 pmol/l or higher in only 16 out of 32 (50%) borderline tumors, whereas CA 125 serum levels were elevated ( 35 U/mL) in 18 out of 32 (56%) borderline tumors. Both biomarkers were elevated in 87% of all cases of invasive epithelial ovarian cancer. In Stage I invasive disease serum HE4 levels were elevated in 69% compared to 50% for serum CA 125. In benign tumors serum HE4 showed less frequent false elevations than did serum CA 125. Table 2 shows the diagnostic performance of subjective assessment of ultrasound findings, serum HE4 and ROMA for each level of diagnostic certainty where serum HE4 values 70 pmol/l and ROMA cut off values 12.5 and 14.4% were used to indicate malignancy. For all masses, experienced ultrasound examiners achieved better sensitivity (97%) and specificity (90%) than serum HE4 (74 and 85%, respectively) and ROMA (84 and 80%, respectively). Even when including the borderline tumors (n = 32) in the benign group, subjective assessment was superior to serum HE4 or ROMA in the detection of cancer. The sensitivity of subjective assessment, HE4 and ROMA was 99% (111/112), 81% (91/112) and 88% (99/112), and the specificity 79% (197/248), 80% (199/248) and 74% (183/248), respectively. Subjective assessment of ultrasound findings by an experienced examiner outperformed serum HE4 and the ROMA when experienced examiners were highly or moderately confident. In the event that they were completely uncertain about the histologic nature of an adnexal mass, subjective assessment tended to be more sensitive but less specific than serum HE4, but did not suggest strong differences with ROMA on this

5 92 Kaijser et al. Table 1 Histology groups in 360 women with an adnexal mass stratified by confidence level of ultrasound examiner Histological diagnosis Certainly benign or malignant (n = 196) Probably benign or malignant (n = 135) Uncertain (n = 29) Total (n = 360) All benign tumors 113 (52) 80 (37) 23 (11) 216 Serous cystadeno(fibro)ma 19 (43) 18 (41) 7 (16) 44 Mucinous cystadeno(fibro)ma 11 (44) 12 (48) 2 (8) 25 Cystadeno(fibro)ma, other 1 (100) 1 Endometriosis 42 (67) 16 (25) 5 (8) 63 Fibroma/thecoma 3 (21) 10 (71) 1 (7) 14 Follicular/ functional/ parasalpingeal cyst 9 (69) 2 (15) 2 (15) 13 Teratoma 20 (69) 8 (28) 1 (3) 29 Hydrosalpinx/abscess 2 (50) 2 (50) 4 Rare benign tumor (Brenner, struma ovarii) 2 (50) 2 (50) 4 Other 7 (37) 10 (52) 2 (10) 19 All malignant tumors 83 (58) 55 (38) 6 (4) 144 Borderline tumors 6 (19) 22 (69) 4 (13) 32 Primary invasive Stage I 6 (38) 9 (56) 1 (6) 16 Primary invasive Stage II 3 (60) 2 (40) 5 Primary invasive Stage III 45 (85) 8 (15) 53 Primary invasive Stage IV 5 (50) 5 (50) 10 Invasive serous EOC 42 (78) 12 (22) 54 Invasive non-serous EOC 17 (57) 12 (40) 1 (3) 30 Non-ovarian primary tumor 2 (67) 1 (33) 3 Sex cord stromal tumor 2 (100) 2 Metastatic disease 14 (61) 8 (35) 1 (4) 23 Data presented as number (percentage of row total). Includes mixed types of benign histology, normal ovaries and one torted ovarian cyst. EOC, epithelial ovarian cancer. Hydrosalpinx/abscess Rare benign tumor Teratoma Histological subtype Follicular/functional/parasalpingeal cyst Fibroma Endometriosis Mucinous cyst(fibro)adenoma Serous cyst(fibro)adenoma Metastatic Non-serous primary invasive EOC Serous primary invasive EOC Invasive EOC FIGO Stage IV Invasive EOC FIGO Stage III Invasive EOC FIGO Stage II Invasive EOC FIGO Stage I Borderline tumor CA 125 (U/mL) or HE4 (pmol/l) Figure 1 Box plots showing CA 125 ( ) and human-epididymis protein-4 (HE4) ( ) serum levels according to histological subsets of benign and malignant adnexal masses. Boxes show range of middle 50% of CA 125 and HE4-levels; lines in box are median and whiskers are 5 th and 95 th percentiles. Data points that lie outside whiskers., HE4 cut-off (70 pmol/l);, CA 125 cut-off (35 U/mL). EOC, epithelial ovarian cancer. FIGO, International Federation of Gynecology and Obstetrics.

6 HE4 or ROMA after ultrasound 93 Table 2 Diagnostic performance of subjective assessment (SA), human-epididymis protein-4 (HE4) and the Risk of Ovarian Malignancy Algorithm (ROMA), depending upon confidence level of ultrasound examiner, in 360 women with an adnexal mass Test performance SA HE4 ROMA Certainly benign (n = 113) or malignant (n = 83) Sensitivity 82/83 70/83 74/83 Specificity 112/ / /113 Probably benign (n = 80) or malignant (n = 55) Sensitivity 54/55 36/55 44/55 Specificity 66/80 64/80 58/80 Uncertain benign (n = 23) or malignant (n = 6) Sensitivity 4/6 1/6 3/6 Specificity 16/23 18/23 15/23 Data given as n/n. Serum HE4 values 70 pmol/l and ROMA scores 12.5/14.4% were used to indicate a malignant tumor. (a) 1.0 (b) Sensitivity Sensitivity HE4: AUC ( ) ROMA: AUC ( ) 0.2 HE4: AUC ( ) ROMA: AUC ( ) Specificity Specificity (c) 1.0 (d) Sensitivity Sensitivity HE4: AUC ( ) ROMA: AUC ( ) 0.2 HE4: AUC ( ) ROMA: AUC ( ) SA: ( ) Specificity Specificity Figure 2 Receiver operating characteristics (ROC) curves and corresponding areas under the curve (AUCs) for the Risk of Ovarian Malignancy Algorithm (ROMA, ) and serum human-epididymis protein-4 (HE4, ) and ROC point for subjective assessment ( ) stratified by category of confidence level of ultrasound examiner: (a) certainly benign or malignant; (b) probably benign or malignant; (c) uncertain; (d) all tumors, with ROC curve for subjective assessment (SA, ). Reference line is indicated ( ).

7 94 Kaijser et al. limited sample. Adopting other cut-off levels for serum HE4 (114 pmol/l or 150 pmol/l for all women, or 89 pmol/l for premenopausal and 128 pmol/l for postmenopausal women) did not alter our findings (data not shown). Figures 2a c show the ROC points for subjective assessment and ROC curves with corresponding AUCs and 95% CIs for serum HE4 and ROMA, categorized by level of diagnostic confidence. The AUCs of serum HE4 and ROMA in difficult tumors were (95% CI, ) and (95% CI, ), respectively. ROC curves with corresponding AUCs and 95% CIs of both subjective assessment and serum HE4 and ROMA for all tumors are displayed in Figure 2d. In Table 3 we illustrate the effect of sequential testing of a single measurement of serum HE4 or use of ROMA scores after experienced examiners had suggested a benign or malignant diagnosis irrespective of their diagnostic confidence. A two-step strategy requiring both subjective assessment and serum HE4 or ROMA scores to be in agreement to diagnose a benign tumor resulted in a slight gain in sensitivity at the expense of a sharp decrease in specificity. The additional measurement of serum HE4 (cut-off 70 pmol/l) after experienced sonographers suggested a benign diagnosis led to the detection of only one extra ovarian cancer in a postmenopausal patient, at the cost of 22 false-positive test results. Using the ROMA as a secondary test also resulted in the diagnosis Table 3 Overall diagnostic performance using serum human-epididymis protein-4 (HE4) or the Risk of Ovarian Malignancy Algorithm (ROMA) as a second-stage test in masses presumed benign or malignant after ultrasound examination, irrespective of confidence level Strategy Sensitivity (%) Specificity (%) LR + LR TP FP Presumed benign masses All women (n = 360) SA NA NA SA + HE4 < 70 pmol/l SA + HE4 < 114 pmol/l SA + HE4 < 150 pmol/l SA + ROMA Premenopausal (n = 173) SA NA NA SA + HE4 < 70 pmol/l SA + HE4 < 89 pmol/l SA + HE4 < 150 pmol/l SA + ROMA < 12.5% Postmenopausal (n = 187) SA NA NA SA + HE4 < 70 pmol/l SA + HE4 < 128 pmol/l SA + HE4 < 150 pmol/l SA + ROMA < 14.4% Presumed malignant masses All women (n = 360) SA NA NA SA + HE4 70 pmol/l SA + HE4 114 pmol/l SA + HE4 150 pmol/l SA + ROMA Premenopausal (n = 173) SA NA NA SA + HE4 70 pmol/l SA + HE4 89 pmol/l SA + HE4 150 pmol/l NA SA + ROMA 12.5% Postmenopausal (n = 187) SA NA NA SA + HE4 70 pmol/l SA + HE4 128 pmol/l SA + HE4 150 pmol/l SA + ROMA 14.4% For presumed benign masses, strategy requires results of both subjective assessment (SA) and HE4 or ROMA to be benign to indicate a benign diagnosis, with any other combination of results indicating a malignant diagnosis; the reverse is true for presumed malignant masses. FP, difference in false positives between SA and a strategy combining SA and HE4 or ROMA; TP, difference in true positives between SA and a strategy combining SA and HE4 or ROMA; LR +, positive likelihood ratio; LR, negative likelihood ratio; NA, not applicable; SA + HE4 (or ROMA) cut-off, requiring results of both subjective assessment and HE4 (or ROMA) to indicate a malignant diagnosis for a malignant diagnosis to be made; SA + HE4 < cut-off, requiring results of both subjective assessment and HE4 (or ROMA) to indicate a benign diagnosis for a benign diagnosis to be made.

8 HE4 or ROMA after ultrasound 95 of this extra ovarian cancer, but at an even higher misclassification cost of 30 additional false-positive cases. The effect of sequential use of serum HE4 or use of ROMA scores after experienced examiners suggested a malignant diagnosis, again irrespective of their certainty, led to an unacceptable loss of sensitivity in both pre- and postmenopausal women, but an increase in specificity. DISCUSSION In this study we have shown that subjective assessment of ultrasound findings by an experienced examiner still offers a better diagnostic performance than do methods based on serum HE4 level alone or ROMA for the preoperative characterization of adnexal masses, irrespective of their level of diagnostic certainty. To our knowledge no published study has evaluated the test performance of serum HE4 or ROMA for the characterization of ovarian masses that experienced ultrasound examiners find difficult to classify. Our data indicate that both serum HE4 and its combination with CA 125 in the ROMA have very low discriminatory capacity with poor sensitivities, and thus are not useful as second-stage tests to improve diagnostic test performance in this group of difficult tumors. This is probably explicable by the histological case-mix of malignant tumors that are difficult to characterize on ultrasound. Borderline ovarian tumors and Stage I invasive tumors are frequently over-represented, and our data clearly show that both biomarkers show normal values in up to 50% of such cases, thereby compromising sensitivity. These findings are comparable with those of previous reports on serum CA 125 levels in these histological subtypes 14,15. Our results further indicate that sequential testing in all ovarian masses, requiring either serum HE4 or ROMA scores and subjective evaluation of ultrasound findings to be concordant for a definite diagnosis of benignity or malignancy to be made, leads to a deterioration in overall diagnostic performance for both pre- and postmenopausal patients. We must also acknowledge that adopting a strategy using biomarkers (CA 125, HE4) to overrule experienced ultrasound examiners after diagnosing cancer seems very unlikely to be taken up in clinical practice. This strategy will only increase specificity at the expense of a markedly reduced sensitivity for cancer because of the frequent finding of normal values of both biomarkers in patients with ovarian cancer 14,15,whereas high sensitivities ( > 90%) are generally accepted to be a prerequisite in ovarian cancer diagnostics 32. Experienced examiners might consider using serum HE4 or ROMA scores as a secondary test to confirm a benign diagnosis. However, our data suggest that this will lead to an additional increase in patients with benign tumors undergoing unnecessary staging procedures or extensive surgery. In daily clinical practice it might seem more reasonable for experienced ultrasound examiners to classify all uncertain cases as malignant. We assessed the net benefit of this strategy compared to a situation in which an examiner was obliged to provide a diagnosis irrespective of their uncertainty. Our data then suggest that for every additional malignant tumor detected with this reclassification there will be eight extra false-positive test results. The present study does have some limitations. One is the low absolute number of cases thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced examiners (n = 29). However, the case-mix, relative percentage of difficult tumors (8%) and diagnostic test performance of subjective assessment by level III examiners in this subgroup are consistent with the results of four previously published studies on this topic Second, almost 61% of all cancers included were Stage III IV. For women with advanced stage disease with evident clinical hallmarks of malignant disease (ascites, omental cake, peritoneal metastases), it is very unlikely that biomarkers will improve the diagnosis of cancer. The same holds true for those malignant cases (early-stage invasive disease, or borderline tumors) that present as an isolated pelvic mass without evident signs of malignant disease, as we have demonstrated that CA 125 and HE4 are normal in up to 50% of all cases. Although the current test performance of available biomarkers limits their ability to add clinically to the preoperative diagnosis of ovarian cancer, preoperative testing of biomarkers will continue to be used by clinicians as a measure for the detection of progression during chemotherapy 33. Third, we would like to stress that our findings might only be representative to experienced (level III) ultrasound examiners. The results of this study cannot just be extrapolated to any set of ultrasonographers with a different level of training and experience. As a consequence, we cannot rule out that serum HE4 or ROMA scores may be beneficial in some circumstances to those examiners outside tertiary referral centers with less experience. In a recent paper of Sandri et al. 34 the use of ROMA was recommended as a triaging test for examiners with different levels of training in ultrasonography. However, in this study almost 80% of all malignant disease comprised FIGO Stage III IV, high-grade serous cancer 34. It seems plausible that even examiners with limited experience in gynecological ultrasound examinations would pick up most of these cancers; data are available from IOTA 4 in support of this view 35,36. We feel that it should be possible for most examiners to equal or exceed the current performance of biomarkers with the use of the IOTA models and rules. Focus should be redirected towards better education and training in gynecological ultrasound until more promising biomarkers become available. To conclude, numerous diagnostic studies aiming to characterize accurately ovarian pathology have shown that there is a group of tumors that prove difficult to classify irrespective of the test used; this includes expert ultrasonography. This leaves a considerable proportion

9 96 Kaijser et al. of adnexal tumors that remain a diagnostic challenge. So far no secondary diagnostic test (serum CA 125, logistic regression models, RMI) has proved useful in this group of tumors Unfortunately, our findings demonstrate that measuring serum HE4 or calculating risk scores using the ROMA does not solve this diagnostic problem. ACKNOWLEDGMENTS B.V.C. is a postdoctoral fellow from the Research Foundation Flanders (FWO). D.T. and B.V.C. received a scientific project grant from the FWO (grant G049312N) for the IOTA 5 project. T.V.G. is supported by the academic fund MUMC + (Improving the Diagnosis of Ovarian Cancer). T.B. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. REFERENCES 1. 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Ultrasound Obstet Gynecol 2009; 34: Valentin L, Ameye L, Jurkovic D, Metzger U, Lécuru F, Van Huffel S, Timmerman D. Which extrauterine pelvic masses are difficult to correctly classify as benign or malignant on the basis of ultrasound findings, and is there a way of making a correct diagnosis? Ultrasound Obstet Gynecol 2006; 27: Valentin L, Ameye L, Savelli L, Fruscio R, Leone FP, Czekierdowski A, Lissoni AA, Fischerova D, Guerriero S, Van Holsbeke C, Van Huffel S, Timmerman D. Adnexal masses difficult to classify as benign or malignant using subjective assessment of gray-scale and Doppler ultrasound findings: logistic regression models do not help. Ultrasound Obstet Gynecol 2011; 38: Daemen A, Valentin L, Fruscio R, Van Holsbeke C, Melis GB, Guerriero S, Czekierdowski A, Jurkovic D, Ombelet W, Rossi A, Vergote I, Bourne T, De Moor B, Timmerman D. Improving the preoperative classification of adnexal masses as benign or malignant by second-stage tests. Ultrasound Obstet Gynecol 2011; 37: Van Calster B, Valentin L, Van Holsbeke C, Zhang J, Jurkovic D, Lissoni AA, Testa AC, Czekierdowski A, Fischerová D, Domali E, Van de Putte G, Vergote I, Van Huffel S, Bourne T, Timmerman D. A novel approach to predict the likelihood of specific ovarian tumor pathology based on serum CA-125 a multicenter observational study. Cancer Epidemiol Biomarkers Prev 2011; 20: Engelen MJ, de Bruijn HW, Hollema H, ten Hoor KA, Willemse PH, Aalders JG, van der Zee AG. Serum CA 125, carcinoembryonic antigen, and CA 19 9 as tumor markers in borderline ovarian tumors. Gynecol Oncol 2000; 78: Gotlieb WH, Soriano D, Achiron R, Zalel Y, Davidson B, Kopolovic J, Novikov I, Ben-Baruch G. CA 125 measurement and ultrasonography in borderline tumors of the ovary. Am J Obstet Gynecol 2000; 183: Sevinc A, Adli M, Kalender ME, Camci C. Benign causes of increased serum CA-125 concentration. Lancet Oncol 2007; 8: Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol 2006; 7: Moore RG, Miller MC, Steinhoff MM, Skates SJ, Lu KH, Lambert-Messerlian G, Bast RC Jr. Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders. Am J Obstet Gynecol 2012; 206: 351.e Moore RG, Brown AK, Miller MC, Skates S, Allard WJ, Verch T, Steinhoff M, Messerlian G, DiSilvestro P, Granai CO, Bast RC Jr. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol 2008; 108: Yu S, Yang HJ, Xie SQ, Bao YX. Diagnostic value of HE4 for ovarian cancer a meta-analysis. Clin Chem Lab Med 2012; 50: Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, Timmerman D, De Moor B, Vergote I. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer 2011; 104: Montagnana M, Danese E, Ruzzenente O, Bresciani V, Nuzzo T, Gelati M, Salvagno GL, Franchi M, Lippi G, Guidi GC. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? Clin Chem Lab Med 2011; 49: Jacob F, Meier M, Caduff R, Goldstein D, Pochechueva T, Hacker N, Fink D, Heinzelmann-Schwarz V. No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. Gynecol Oncol 2011; 121: Li F, Tie R, Chang K, Wang F, Deng S, Lu W, Yu L, Chen M. Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer a meta-analysis. BMC Cancer 2012; 12: 258.

10 HE4 or ROMA after ultrasound Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H, Vergote I. Terms, definitions and measurements to describe the sonographic features of adnexal tumors a consensus opinion from the International Ovarian Tumor Analysis (IOTA) Group. Ultrasound Obstet Gynecol 2000; 16: Education and Practical Standards Committee, European Federation of Societies for Ultrasound in Medicine and Biology. Minimum training recommendations for the practice of medical ultrasound. Ultraschall Med 2006; 27: CA125 CanAg product insert, version Available from: 25%20EIA% %20Eng,% %20F5048,%20r7.pdf [Accessed May 27, 2013]. 28. HE4 EIA product insert, version Available from: EIA% ,% ,%20r1.pdf [Accessed May 27, 2013]. 29. Moore RG, Miller MC, Eklund EE, Lu KH, Bast RC Jr, Lambert-Messerlian G. Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet Gynecol 2012; 206: 349.e World Health Organization. IARC WHO Classification of tumors, No 4. Pathology and Genetics Tumours of the Breast and Female Genital Organs. IARC Press: Lyon, Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Lijmer JG, Moher D, Rennie D, de Vet HC; Standards for Reporting of Diagnostic Accuracy. Towards complete and accurate reporting of studies of diagnostic accuracy: The STARD Initiative. AnnInternMed2003; 138: Kaijser J, Bourne T, Valentin L, Sayasneh A, Van Holsbeke C, Vergote I, Testa AC, Franchi D, Van Calster B, Timmerman D. Improving strategies for diagnosing ovarian cancer a summary of the International Ovarian Tumor Analysis (IOTA) studies. Ultrasound Obstet Gynecol 2013; 41: Alexandre J, Brown C, Coeffic D, Raban N, Pfisterer J, Mäenpää J, Chalchal H, Fitzharris B, Volgger B, Vergote I, Pisano C, Ferrero A, Pujade-Lauraine E. CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience of the GCIG CALYPSO trial. BrJCancer2012; 106: Sandri MT, Bottari F, Franchi D, Boveri S, Candiani M, Ronzoni S, Peiretti M, Radice D, Passerini R, Sideri M. Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome. Gynecol Oncol 2013; 128: Sayasneh A, Kaijser J, Preisler J, Johnson S, Stalder C, Husicka R, Guha S, Naji O, Abdallah Y, Raslan F, Drought A, Smith AA, Fotopoulou C, Ghaem-Maghami S, Van Calster B, Timmerman D, Bourne T. A multicenter prospective external validation of the diagnostic performance of IOTA simple descriptors and rules to characterize ovarian masses. Gynecol Oncol 2013;130: Sayasneh A, Wynants L, Preisler J, Kaijser J, Johnson S, Stalder C, Husicka R, Abdallah Y, Raslan F, Drought A, Smith AA, Ghaem-Maghami S, Epstein E, Van Calster B, Timmerman D, Bourne T. Multicentre external validation of IOTA prediction models and RMI by operators with varied training. Br J Cancer 2013; 108: SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Figure S1 (a) A two-step strategy illustrating the use of HE4 or ROMA as a second-stage test after experienced examiners have suggested a benign diagnosis. (b) A two-step strategy illustrating the use of HE4 or ROMA as a second-stage test after experienced examiners have suggested a malignant diagnosis.

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