ABSTRACT INTRODUCTION

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1 Ultrasound Obstet Gynecol 2013; 41: Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Risk of malignancy in unilocular cysts: a study of 1148 adnexal masses classified as unilocular cysts at transvaginal ultrasound and review of the literature L. VALENTIN*, L. AMEYE, D. FRANCHI, S. GUERRIERO, D. JURKOVIC**, L. SAVELLI, D. FISCHEROVA, A. LISSONI, C. VAN HOLSBEKE ***, R. FRUSCIO, S. VAN HUFFEL, A. TESTA and D. TIMMERMAN*** *Department of Obstetrics and Gynecology, Skåne University Hospital Malmö, Lund University, Malmo, Sweden; KU Leuven, Department of Electrical Engineering (ESAT) SCD-SISTA, Leuven, Belgium; IBBT Future Health Department, Leuven, Belgium; Preventive Gynecology Unit, Division of Gynecology, European Institute of Oncology, Milan, Italy; Department of Obstetrics and Gynecology, Ospedale San Giovanni di Dio, University of Cagliari, Cagliari, Sardinia, Italy; **Department of Obstetrics and Gynecology, University College Hospital, London, UK; Gynecology and Early Pregnancy Ultrasound Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Gynecological Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine and General Faculty Hospital of Charles University, Prague, Czech Republic; Clinica Ostetrica e Ginecologica, Ospedale S. Gerardo, Università di Milano Bicocca, Monza, Italy; Department of Obstetrics and Gynecology, Ziekenhuis Oost-Limburg, Genk, Belgium; ***Department of Development and Regeneration, University Hospitals KU Leuven, Leuven, Belgium; Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy KEYWORDS: ovarian neoplasms; simple ovarian cyst; ultrasonography; unilocular ovarian cyst ABSTRACT Objectives The aim of this study was to estimate the rate of malignancy in adnexal lesions described as unilocular cysts at transvaginal ultrasound examination and to investigate if there are differences in clinical and ultrasound characteristics between and malignant unilocular cysts. Methods A total of 3511 patients with an adnexal mass underwent transvaginal ultrasound examination between 1999 and Sonologists used the International Ovarian Tumor Analysis terms and definitions to describe their ultrasound findings. Only masses operated on within 120 days after the ultrasound examination were included in the analysis and the histopathological diagnosis of the mass was used as the gold standard. Results Of the 3511 masses, 1148 (33%) were classified as unilocular cysts on ultrasound. Of these, 11 (0.96% (95% CI, )) were malignant. The malignancy rate was lower in premenopausal than in postmenopausal women: 0.54% (5/931; 95% CI, ) vs 2.76% (6/217; 95% CI, ); P = More patients with malignant unilocular cysts had a personal history of breast cancer (18% vs 2%; P = 0.02) or ovarian cancer (18% vs 0.6%; P = 0.003). Hemorrhagic cyst contents on ultrasound were more common in malignant than in unilocular cysts (18% vs 2%; P = 0.03). In seven of the 11 malignancies judged to be unilocular cysts at scan, papillary projections or other solid components were seen at macroscopic inspection of the surgical specimen. Conclusions The malignancy rate in surgically removed adnexal lesions judged to be unilocular cysts at transvaginal scan is c. 1%. Postmenopausal status, personal history of breast or ovarian cancer and hemorrhagic cyst contents on ultrasound increase the risk of malignancy. To avoid misclassifying adnexal lesions as unilocular cysts at scan, it is important to scrutinize unilocular cysts for the presence of solid components. Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION The risk of a unilocular ovarian cyst being malignant is considered to be very low, irrespective of whether the cyst is described on the basis of macroscopic inspection by a pathologist 1 or on the basis of an ultrasound image of the cyst 2 5. It has been suggested that unilocular cysts < 5 cm in diameter in postmenopausal women do not require intervention other than possibly follow-up scans. For example, in the United Kingdom Collaborative Trial on Ovarian Cancer Screening (UKCTOCS), women with a unilocular cyst with anechoic contents and a volume < 60 ml Correspondence to: Prof. L. Valentin, Department of Obstetrics and Gynecology, Skåne University Hospital Malmö, Malmö, Sweden ( lil.valentin@med.lu.se) Accepted: 19 September 2012 Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Risk of malignancy in unilocular cysts 81 (corresponding to a diameter < 5cm) are dismissed as having normal findings, while those with unilocular cysts with mixed or random echogenicity/irregular walls/solid elements have a repeat scan 6. On the other hand, Yazbek et al. reported that 11% (4/35) of borderline tumors and 4% (1/24) of epithelial ovarian cancers were classified as unilocular cysts at ultrasound examination performed by an ultrasound expert in a tertiary referral center for gynecological ultrasound 7. The aim of this study was to estimate the rate of borderline and invasive malignancy in ovarian lesions described as unilocular cysts at ultrasound examination, and to investigate if there are any differences in clinical and ultrasound characteristics between and malignant unilocular cysts. METHODS This is a retrospective analysis of prospectively collected information in the International Ovarian Tumor Analysis (IOTA) database. The IOTA study is a prospective observational international multicenter study including 21 ultrasound centers in nine countries, in which patients with adnexal masses were scanned transvaginally using a standardized research protocol Ultrasound examiners were radiologists or gynecologists highly experienced in gynecological ultrasound and with a special interest in adnexal masses. The study was conducted in accordance with precepts established by the Helsinki Declaration, the research protocol was ratified by the local Ethics Committee at each center and all participants gave informed consent to participate. Recruitment took place between 1999 and The IOTA terms and definitions 11 were used to describe ultrasound findings. Both gray-scale and color/power Doppler ultrasound examination were carried out, and information on more than 40 clinical and ultrasound variables was collected. In addition, the ultrasound examiner classified each mass as or malignant using subjective evaluation of gray-scale and Doppler ultrasound findings (subjective assessment) and stated the confidence with which the classification was made (certainly, probably, uncertain, probably malignant, certainly malignant). In the case of bilateral adnexal masses, the mass with the most complex ultrasound morphology was included in the database. If both masses had similar ultrasound morphology the largest or the one most easily accessible by ultrasound was included. Only women with masses who were operated on within 120 days after the ultrasound examination were included in the analysis. The gold standard was histological diagnosis of the surgically removed adnexal mass. Staging of malignancies was done in accordance with the International Federation of Gynecology and Obstetrics (FIGO) 12,13. For the purpose of the current study, the IOTA database was searched for tumors classified as unilocular cysts at ultrasound examination. The unilocular cysts in the database comprised our study population. The IOTA definition of a unilocular cyst is a cyst with one cyst locule, no solid components and no papillary projections (papillary projection being defined as a protrusion of solid tissue into the cyst lumen with a height 3 mm) and with cyst contents of any type of echogenicity (including the mixed echogenicity typical of dermoid cysts). Unilocular cysts with protrusions of solid tissue into the cyst lumen with a height < 3 mm are classified as unilocular cysts with irregular walls. The prospectively collected clinical and ultrasound information was compared between and malignant unilocular cysts. In addition, clinical, surgical and pathological reports and the ultrasound images of patients with a malignant unilocular cyst were retrieved and scrutinized retrospectively. Statistical analyses were carried out using the SAS System 9.3 (SAS Institute Inc., Cary, NC, USA). Fisher s exact test was used to test the statistical significance of differences in binary data; the Mann Whitney U-test was used to test the statistical significance of differences in continuous data. Two-tailed P-values < 0.05 were considered statistically significant. RESULTS The IOTA database contains information on 3511 patients with at least one adnexal mass. The number of masses contributed by each center is shown in Table S1 (online) and the histology of the masses in Table S2 (online). Of the 3511 masses, 1148 (33%) were classified as unilocular cysts on ultrasound examination. The proportion of adnexal masses classified as unilocular cysts ranged from 12% to 67% in the different centers. Of 186 borderline tumors in the entire IOTA database, five (2.76% (95% CI, )) were classified as unilocular cysts on ultrasound, and of 764 invasive malignancies, six (0.79% (95% CI, )) were classified as unilocular cysts on ultrasound. Of the 1148 unilocular cysts in the IOTA database, 11 (0.96% (95% CI, )) were malignant vs 40% (939/2363; 95% CI, 38 42) of all other adnexal masses (P < 0.001). Five of the malignant unilocular cysts were borderline tumors and six were primary invasive malignancies, i.e. the rate of borderline malignancy was 0.44% (95% CI, ) and that of invasive malignancy was 0.52% (95% CI, ) (Table S2). The malignancy rate in unilocular cysts was lower in premenopausal women than in postmenopausal women: 0.54% (5/931; 95% CI, ) compared to 2.76% (6/217; 95% CI, ); P = In premenopausal women, four of 931 unilocular cysts were borderline malignant (0.43% (95% CI, )) and one was invasively malignant (0.11% (95% CI, )). The corresponding figures for postmenopausal women were one (0.46% (95% CI, )) and five (2.30% (95% CI, )) of 217 unilocular cysts. The malignancy rate in unilocular cysts with anechoic cyst fluid and regular walls on ultrasound was 1.22% (4/326; 95% CI, ) and that in unilocular cysts with another type of cyst fluid, with or without irregular walls on ultrasound, was 0.85% (7/822; 95%

3 82 Valentin et al. Figure 1 Solid lesion misclassified as a unilocular cyst with hemorrhagic cyst contents on ultrasound. The histological diagnosis was tubal carcinoma, Stage 3. CI, ); the malignancy rate in unilocular cysts with a largest diameter 5 cm at scan was 0.82% (4/486; 95% CI, ) and that in unilocular cysts with a largest diameter > 5 cm on ultrasound was 1.06% (7/662; 95% CI, ). Prospectively collected clinical and ultrasound information from the IOTA database for and malignant unilocular cysts is presented in Table 1. Women with malignant unilocular cysts were older and more were postmenopausal and had a personal history of breast or ovarian cancer than women with unilocular cysts. Cyst contents judged to be hemorrhagic on ultrasound were more common in malignant than in unilocular cysts (18% vs 2%; P = 0.03). Irregular internal cyst walls and fluid in the pouch of Douglas on ultrasound were twice as common in malignant as in unilocular cysts, but these differences, although substantial (both 27% vs 14%), were not statistically significant. The ultrasound examiner less often assigned a diagnosis of certainly to unilocular cysts that proved to be malignant than to those that proved to be (36% vs 83%; P < 0.001). Retrospective analysis of clinical, surgical and pathological reports and ultrasound images showed that, in seven of the 11 malignancies described as unilocular cysts at ultrasound examination, there was a discrepancy between the ultrasound examiner s description and the pathologist s description of the macroscopic appearance of the cyst (Table 2). In six cysts the ultrasound examiner had failed to detect papillary projections (n = 4) or solid components (n = 2) visible at macroscopic inspection by the pathologist. In the seventh case a lesion described by the ultrasound examiner as a unilocular cyst with hemorrhagic cyst contents proved to be a completely solid lesion (Figure 1). For one cyst described as unilocular, with hemorrhagic contents on ultrasound, the macroscopic description by the pathologist was unreliable. This cyst was removed by laparoscopy, and the specimen came out in pieces unsuitable for macroscopic inspection. In three cases, ultrasound findings agreed with the macroscopic description by the pathologist, i.e. the cyst was unilocular without papillary projections or other solid components also at macroscopic inspection. One of these cases was a Figure 2 A 6-cm unilocular cyst for which the histological diagnosis was mucinous borderline tumor, Stage 1. Macroscopic inspection of the surgical specimen revealed no solid components and no papillary projections. 17-cm mature teratoma with a microcarcinoma of struma type with ground glass echogenicity of the cyst contents on ultrasound, one was a 13-cm mucinous borderline tumor with cyst fluid of low level echogenicity on ultrasound and one was a 6-cm mucinous borderline tumor with anechoic cyst contents at scan (Figure 2). DISCUSSION We found the risk of malignancy in surgically removed adnexal lesions judged to be unilocular cysts at transvaginal scan to be 0.96%; it was 0.54% in premenopausal women and 2.76% in postmenopausal women and the difference in malignancy rate between preand postmenopausal women was statistically significant. Hemorrhagic cyst contents on ultrasound increased the risk of malignancy, as did a personal history of ovarian or breast cancer. However, seven of the 11 malignant cysts described as unilocular on ultrasound proved to contain papillary projections or other solid components at macroscopic inspection of the corresponding surgical specimen by the pathologist. The strength of our study is that it is large and multicenter and that data were prospectively collected following a standardized research protocol and using standardized terminology to describe the masses. This increases the likelihood that our results are generalizable. A limitation of our study is that it includes only women who were operated on. The true malignancy rate in cysts judged to be unilocular on ultrasound is likely to be much lower than that in our study, because many unilocular cysts are left in situ 4,5, In studies in which (mostly asymptomatic) women with adnexal cysts judged to be unilocular on ultrasound were recommended for followup with ultrasound examination or were indeed followed with ultrasound examination for up to 13 years, four of 4361 (0.09%) unilocular cysts in 3797 (0.11%) patients (most postmenopausal) were found to be malignant

4 Risk of malignancy in unilocular cysts 83 Table 1 Prospectively collected clinical and ultrasound information for and malignant unilocular cysts (n = 1148) Variable Benign (n = 1137) Malignant (n = 11) P Clinical characteristics Age (years) 36 (15 90) 60 (26 82) Postmenopausal 211 (19) 6 (55) Nulliparous 611 (54) 6 (55) 1 Hysterectomy 43 (4) 1 (9) 0.35 Current hormonal treatment 172 (15) 1 (9) 1 Personal history of ovarian cancer 7 (< 1) 2 (18) Personal history of breast cancer 23 (2) 2 (18) 0.02 Family history of ovarian cancer 20 (2) 0 (0) 1 Family history of breast cancer 77 (7) 0 (0) 1 CA 125 (U/mL)* 19 (2 3500) 20 (7 147) 0.50 Ultrasound characteristics Bilateral 165 (15) 1 (9) 1 Largest diameter (mm) 56 (8 760) 57 (25 171) 0.49 Mean diameter (mm) 48 (8 340) 48 (23 156) 0.49 Volume (cm 3 ) 54 ( ) 58 (7 1940) 0.48 Echogenicity of cyst contents Anechoic 322 (28) 4 (36) 0.52 Homogeneous low level 154 (14) 1 (9) Ground glass 412 (36) 4 (36) Hemorrhagic 28 (2) 2 (18) 0.03 Mixed 221 (19) 0 (0) Irregular walls 161 (14) 3 (27) 0.20 Fluid in pouch of Douglas 162 (14) 3 (27) 0.20 Fluid in pouch of Douglas (mm) 14 (1 61) 18 (10 38) 0.46 Ascites 9 (< 1) 0 (0) 1 Acoustic shadows 169 (15) 0 (0) 0.38 Color Doppler blood flow No flow 603 (53) 5 (45) 0.76 Minimal flow 384 (34) 6 (55) Moderate flow 138 (12) 0 (0) 0.38** Strong flow 12 (1) 0 (0) Venous blood flow only 81 (7) 2 (18) 0.19 Spectral Doppler results Pulsatility index 1.00 ( ) 1.68 ( ) 0.41 Resistance index 0.61 ( ) 0.72 ( ) 0.39 Peak systolic velocity (cm/s) ( ) ( ) 0.60 Time averaged maximum velocity (cm/s) 6.00 ( ) 5.85 ( ) 0.93 Diagnosis on basis of subjective assessment Certainly 938 (83) 4 (36) < Probably 188 (17) 6 (55) Uncertain 9 (< 1) 1 (9) Probably malignant 1 (< 1) 0 (0) Certainly malignant 1 (< 1) 0 (0) Data are given as n (%) or median (range). *CA 125 was measured in 742 (65%) patients with a mass and in 11 (100%) patients with a malignant mass. Pulsatility index, resistance index, peak systolic velocity and time-averaged maximum velocity were measured in cases with detectable color Doppler signals and detectable arterial blood flow, i.e. in 453 (39%) patients with a mass and in four (36%) patients with a malignant mass. Anechoic vs others. Hemorrhagic vs others. No flow vs others. **No or minimal flow vs moderate or strong flow. Certainly vs others. at eventual operation 5,14 20,23. The clinical course in patients who did not undergo surgery suggests that their unilocular cysts were all (Table 3). The rate of histologically confirmed malignancy in adnexal cysts judged to be unilocular at transvaginal scan has been described in nine studies (Table 4) 2,3, However, the definition of unilocular cyst in the nine studies is not always clear. Moreover, the definitions are not uniform, the size of cysts is highly variable and characteristics of the study populations differ. Of the 1687 surgically removed lesions classified as unilocular cysts on ultrasound, 1.6% were malignant (Table 4). However, the malignancy rate in the study of Osmers et al. 30 is much higher (10.4%) than that in any other published study. Possibly their study population was a selected high-risk group, or possibly some incidental unilocular cysts were associated with seropapillary peritoneal cancer (which may be a common phenomenon 5 ). If we exclude the study of Osmers et al. 30 and consider only the results of the remaining eight published studies, the malignancy rate in surgically removed unilocular cysts is 0.84% (13/1553), which is similar to the 0.96% rate in our study. We present a point estimate of the rate of malignancy in unilocular cysts, but we did not study the malignant

5 84 Valentin et al. Table 2 Detailed information on the 11 unilocular cysts that proved to be malignant Age (years) Personal history of ovary cancer Personal history of breast cancer CA 125 (U/mL) Diagnosis on basis of subjective assessment Largest diameter (mm) Echogenicity of cyst fluid Fluid in POD (mm) Bilateral Irregular cyst walls Agreement with macroscopy Final diagnosis 42 No No 7 Certainly 50 No No 14 Probably 69 No Yes 26 Certainly 60 No No 10 Probably 41 Yes No 78 Certainly 26 No No 13 Probably 43 No No 147 Probably 82 No Yes 20 Probably 58 Anechoic 0 No No Yes Borderline, mucinous (pseudostratification and atypia), Stage Low-level 0 No No Yes Borderline, mucinous, Stage Ground glass 18 No No Yes Mature teratoma with 48 Anechoic 0 No No No (papillations 53 Ground glass 0 No No No (papillations 140 Anechoic 0 No No No (papillations 45 Anechoic 38 No No No (papillations 75 Ground glass 0 No No No (solid part 62 No No 68 Uncertain 57 Ground glass 10 Yes Yes No (solid part 71 No No 84 Certainly 65 Yes No 13 Probably microcarcinoma of struma type Borderline (focus of atypical cells), serous, Stage 1 Borderline, serous, Stage 1 Borderline, serous, Stage 1 Seropapillary peritoneal cancer, Stage 3 Infiltration of neuroendocrine carcinoma in a cystic teratoma (previous breast cancer of neuroendocrine type) Carcinoma, endometrioid, Stage 3 37 Hemorrhagic 0 No Yes No (solid tumor) Carcinoma, tubal, Stage 3 25 Hemorrhagic 0 No Yes Non-optimal specimen Recurrent mucinous invasive cancer in the ovary, Stage 1 POD, pouch of Douglas.

6 Risk of malignancy in unilocular cysts 85 Table 3 Malignancy rates in adnexal lesions judged to be unilocular cysts at transvaginal scan and managed by follow-up: literature review Study Years of recruitment MP status Echogenicity of cyst fluid Wall regularity Size Women with unilocular cysts (n) Time in follow-up Women operated on (n) Malignancy in surgical specimen (n/n) Malignancy rate per woman in study population (% (n/n)) Aubert et al PostMP Anechoic?? mm months (mean, 31.5 months) Auslender et al PostMP Hypoechogenic Smooth mm months (mean, 31 months) Conway et al PostMP Anechoic Smooth mm 116 (20 lost to follow-up) Valentin and Akrawi 17 (median, 3 years) PostMP Any Smooth 3 80 mm* years Castillo et al PostMP Anechoic? (no papillae) ml; 50 mm in 84% Nardo et al PostMP?? < 50 mm (18 50 mm) Sarkar and Wolf PostMP Anechoic Smooth, no papillae Modessit et al > 50 years (mixed) ml (mean, 16.3 ml) Any? No papillae < 100 mm (mean, 27 mm) Alcazar et al PreMP?? < 60 mm (15 60 mm) 149 (153 cysts) 0 0 (0/36) 9 0/9 0 (0/60) 5 years (?) 18 0/18 0 (0/96) 12 0/12 0 (0/121) 87 months 45 1 / (1/149) years / (2/226) 314 (378 cysts) 2763 (3259 cysts) 3 weeks 13 years 9 1**/ (1/314) 4 days 14 years (mean, 6 years) months (median, 42 months) 133 0/133 0 (0/2763) 0 0/32 Total of nine studies 3797 women (4361 cysts) (4/3797 women) (0.09, 4/4361 cysts) *Refers to all adnexal lesions included in the study; this study includes also cysts other than unilocular ones. The study includes an additional 39 cysts with more complicated but ultrasound morphology. Not all 12 cysts operated on were unilocular. Squamous cancer in a papillation overlooked at scan in a dermoid cyst. Indication for surgery was cyst growth. **At surgery this cyst was no longer unilocular; a papillary projection had developed. 95% CI, % CI, ?, unequivocal information not available; MP, menopausal.

7 86 Valentin et al. Table 4 Malignancy rates in surgically removed adnexal lesions judged to be unilocular cysts at transvaginal scan: literature review Malignancy rate (n/n (%)) PreMP PostMP All Years of Echogenicity Wall Study recruitment MP status of cyst fluid regularity Size n Bord Inv All Bord Inv All Bord Inv All Kroon and Andolf PostMP Anechoic? < 50 mm 43 0/43 0/43 0/43 0/43 0/43 0/43 Bailey et al PostMP or?? < 100 mm 45 0/45 0/45 0/45 > 50 years Granberg et al Mixed??? 45 0/45 0/45 0/45 Valentin et al Mixed?? ml 41 0/41 0/41 0/41 Shalev et al PostMP Anechoic Smooth > 10 mm 43 0/43 0/43 0/43 0/43 0/43 0/43 Gramellini et al Mixed Any IOTA*? 35 1/35 (2.6) 0 1/35 (2.6) Ekerhovd et al Mixed Anechoic? mm 660 3/413 (0.73) Osmers et al PreMP Any? > 30 mm 641 3/641 (0.47) Osmers et al PostMP Any Smooth > 30 mm 134 1/134 (0.75) 2/641 (0.31) 5/641 (0.78) 4/247 (1.6) 3/660 (0.45) 3/641 (0.47) 13/134 (9.7) 14/134 (10.4) 1/134 (0.75) 4/660 (0.61) 2/641 (0.31) 13/134 (9.7) 7/660 (1.1) 5/641 (0.78) 14/134 (10.4) Total of nine studies 3/641 (0.47) 2/641 (0.31) 8/1054 (0.76) 1/220 (0.45) 13/220 (5.9) 18/467 (3.9) 8/1687 (0.47) 19/1687 (1.1) 27/1687 (1.6) Current study Mixed Any IOTA* mm /931 (0.43) 1/931 (0.11) 5/931 (0.54) 1/217 (0.46) 5/217 (2.3) 6/217 (2.8) 5/1148 (0.44) 6 /1148 (0.52) 11/1148 (0.96) Total of ten studies /1572 (0.32) 3/1572 (0.19) 13/1985 (0.65) 2/437 (0.46) 18/437 (4.1) 24/684 (3.5) 13/2835 (0.46) 25/2835 (0.88) 38/2835 (1.34 ) *Cysts with protrusions of solid tissue < 3 mm in height are classified as unilocular (with wall irregularity). 95% CI, %.?, unequivocal information not available; Bord, borderline tumor; Inv, invasive malignancy; IOTA, International Ovarian Tumor Analysis; MP, menopausal.

8 Risk of malignancy in unilocular cysts 87 Table 5 Proportion of borderline and invasive adnexal malignancies classified as unilocular cysts on ultrasound: literature review Proportion of unilocular cysts in malignant adnexal masses (n/n (%)) Study Borderline Invasive Any adnexal malignancy Exacoustos et al. 31 3/33 0/82 3/115 Fruscella et al. 32 4/113 No invasive 4/113 Valentin et al. 3 0/1 0/27 0/28 Gramellini et al. 29 0/5 0/15 0/20 Valentin 33 0/5 0/19 0/24 Hata et al. 35 0/9 0/42 0/51 Jokubkiene et al. 34 0/6 0/21 0/27 Granberg et al. 2 No information No information 0/39 Total of eight studies 7/172 (4.1) 0/206 7/417 (1.7) Current study 5/186 (2.7) 6/764 (0.8) 11/950 (1.2) Total of nine studies 12/358 (3.4) 6/970 (0.6) 18/1367 (1.3) potential of unilocular cysts. Others have tried to do so in follow-up studies 5,14 20,23. Such studies are fraught with difficulties. Because unilocular cysts appear and disappear, even in postmenopausal women 5,21,22, it is difficult to ascertain whether an ovarian malignancy in a woman with previous diagnosis of a unilocular cyst developed from that particular cyst or whether it developed de novo while the previous cyst resolved. Lifelong follow-up would be needed to settle the matter. In any case, the risk of developing ovarian cancer does not seem to be higher in women with ovarian unilocular cysts < 10 ml (i.e. a diameter < mm) than in women with no cystic lesions in their ovaries 22. Yazbek et al. found that 11% (4/35) of borderline tumors and 4% (1/24) of epithelial ovarian cancers were described as unilocular cysts on ultrasound 7.Theserates are much higher than those in our study and those reported elsewhere in the literature (Table 5) 2,3,29, Differences in study populations, as well as failure of the ultrasound examiner to detect papillary projections or solid components might explain the discrepancies. In agreement with our results, both Ekerhovd et al. 28 and Osmers et al. 25,30 found the risk of malignancy in unilocular cysts to be higher in postmenopausal than in premenopausal patients. They also stated that the risk of malignancy increased with cyst size (statistical significance not reported) 25,28,30, while in our study the size of and malignant unilocular cysts did not differ (Table 1). Osmers et al. found that the risk of malignancy was unrelated to the echogenicity of cyst fluid (anechoic vs echoic) 25,30. Our results suggest that the finding of hemorrhagic cyst contents on ultrasound is associated with an increased likelihood of malignancy. The reason is probably that solid tumor and hemorrhagic cyst contents may be confused, as happened in one case in our study, and it may be difficult to detect irregularities and papillary projections when cyst contents appear hemorrhagic on ultrasound. Our finding of higher malignancy risk in unilocular cysts in women with a personal history of ovarian or breast cancer is also clinically likely. Still, our numbers are small and therefore our results with regard to hemorrhagic cyst contents and personal history of ovarian or breast cancer as being risk factors for malignancy in unilocular cysts, although statistically significant, need to be interpreted with caution. To determine which factors can predict malignancy in unilocular cysts, one would need a number of malignant unilocular cysts sufficiently large for multivariate logistic regression analysis to be possible. The predicting variables in such an analysis could be menopausal status, personal history of breast or ovarian cancer, family history of breast or ovarian cancer, echogenicity of cyst fluid, wall irregularity and possibly the color content of the cyst wall at color Doppler ultrasound examination. Approximately 80 malignant unilocular cysts would be needed to perform a relevant multivariate logistic regression analysis. However, because it has taken us 8 years to collect 11 cases of malignant unilocular cysts from 21 centers, we doubt that it will be possible to collect data sufficient for an appropriate multivariate analysis within a reasonable time. In our study, seven of the 11 malignant cysts judged to be unilocular on ultrasound contained papillary projections or solid components at macroscopic inspection by the pathologist. Because the risk of malignancy is higher in lesions containing septa and solid components than in unilocular cysts 1, it is important that the ultrasound examiner scrutinizes cyst walls for the presence of papillary projections and thoroughly searches for solid components in any cyst that appears to be unilocular at scan. If there are technical problems, e.g. bowel gas or other factors preventing a detailed view of the lesion, the patient should be rescanned and the uncertain nature of the mass should be noted. Based on the results of our study and our extensive review of the literature, it seems safe to leave cysts judged to be unilocular on ultrasound in situ, as long as the ultrasound examiner feels confident that the presence of papillary projections or other solid components was not overlooked. However, one should be aware that postmenopausal status increases the risk of malignancy, and that personal history of breast or ovarian cancer as well as hemorrhagic cyst contents are also likely to do

9 88 Valentin et al. so. Another point to be noted is that wall irregularity was twice as common in malignant than it was in unilocular cysts in our study. Although this difference did not reach statistical significance, we believe that the possibility of malignancy should be considered in unilocular cysts with irregular walls. After all, the difference between a papillary projection as defined by the IOTA group 11 and a wall irregularity is only a matter of size. There are insufficient published data on the longterm behavior of different types of unilocular cysts to provide an evidence-based statement on optimal followup of unilocular cysts left in situ. A large prospective observational study is needed to elucidate the natural history of different types of unilocular cysts before an evidence-based recommendation on the optimal followup regimen can be made. ACKNOWLEDGMENTS This work was supported by the Swedish Medical Research Council: grant numbers K X A, K X B, K X A and K X ; funds administered by Malmö University Hospital; two Swedish governmental grants: ALF-medel and Landstingsfinansierad Regional Forskning; and Reasearch supported by Research Council KU Leuven: GOA-MANET; IWT-TBM (IOTA); Belgian Federal Science Policy Office: IUAP P6/04 (DYSCO); Research Foundation Flanders (FWO Vlaanderen, N, N; research project grant G049312N); Research Council KUL: GOA MaNet, IBBT: Future Health Dept., Belgian Federal Science Policy Office: IUAP P7/ (DYSCO, Dynamical systems, control and optimization, ). REFERENCES 1. Granberg S, Wikland M, Jansson I. Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: criteria to be used for ultrasound evaluation. Gynecol Oncol 1989; 35: Granberg S, Norstrom A, Wikland M. Tumors in the lower pelvis as imaged by vaginal sonography. 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