Imaging in gynecological disease (7): clinical and ultrasound features of Brenner tumors of the ovary

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1 Ultrasound Obstet Gynecol 2012; 40: Published online 8 November 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Imaging in gynecological disease (7): clinical and ultrasound features of Brenner tumors of the ovary I. DIERICKX*, L. VALENTIN, C. VAN HOLSBEKE, G. JACOMEN, A. A. LISSONI**, A. LICAMELI, A. TESTA, T. BOURNE and D. TIMMERMAN *Department of Obstetrics and Gynecology, Algemeen Ziekenhuis Sint-Lucas, Gent, Belgium; Department of Obstetrics and Gynecology, Skåne University Hospital Malmö, Lund University, Malmö, Sweden; Department of Obstetrics and Gynecology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Development and Regeneration, KU Leuven, and Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Pathology, Sint Maarten Ziekenhuis Campus Rooienberg, Duffel, Belgium; **Department of Obstetrics and Gynecology, San Gerardo Universita di Milano, Monza, Italy; Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Obstetrics and Gynaecology, Imperial College Hammersmith Campus, London, UK KEYWORDS: Brenner tumor; ovarian neoplasms; preoperative diagnosis; ultrasonography ABSTRACT Objectives To describe clinical and ultrasound features of Brenner tumors of the ovary. Methods In this retrospective study, the databases of the International Ovarian Tumor Analysis (IOTA) studies and one tertiary center were searched to identify patients who had undergone an ultrasound scan before surgery for an adnexal mass that proved to be a Brenner tumor. Twenty-eight patients with 29 Brenner tumors were included, most of which had been collected within the framework of the IOTA studies. An experienced ultrasound examiner reviewed available ultrasound images (available for 14 tumors), searching for a pattern specific to Brenner tumors. Results Most patients were postmenopausal and asymptomatic. Twenty-four (83%) tumors were benign, two (7%) were borderline and three (10%) were malignant. Most benign tumors (17/24, 71%) contained solid components and manifested no or minimal blood flow on Doppler examination (19/24, 79%). Information about calcifications was available for 15 benign tumors, and in 13 (87%) calcifications were present. The five borderline and invasively malignant tumors contained solid components less often than did the benign ones (3/5, 60%) and were more richly vascularized on Doppler examination. Information about calcifications was available for four borderline or invasively malignant tumors, and in three (75%) calcifications were present. Conclusion We failed to demonstrate ultrasound features specific to Brenner tumors. A prospective study is needed to determine if ultrasound features of calcifications can discriminate between Brenner tumors and other types of ovarian tumor. Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Aim Ovarian Brenner tumors are rare, and there is little information about their appearance on ultrasound examination 1,2. The aim of this study was to describe the clinical and sonographic characteristics of Brenner tumors using the International Ovarian Tumor Analysis (IOTA) terminology 3. Background Epidemiology Brenner tumors are surface epithelial stromal tumors of the ovary 4, which were first described in detail by Fritz Brenner in Between 1.1 and 2.5% of all ovarian tumors are thought to be Brenner tumors; about 99% of them are benign 4,6 11. Brenner tumors are usually unilateral 4,7, bilateral lesions being found in only 5 14% of cases 1,4,8, There is controversy as to whether bilateral lesions are more common in the malignant subtype than in the benign subtype 7,8,12,14 17, though most malignant ones are unilateral 4,7,18. In about 30% of cases there is also a second tumor in the same ovary, most often a serous or mucinous cystadenoma 4,6,9,11. Several authors have proposed that Correspondence to: Prof. D. Timmerman, Department of Obstetrics and Gynecology, University Hospitals, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium ( dirk.timmerman@uzleuven.be) Accepted: 24 February 2012 Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Brenner tumors of the ovary 707 the cystadenomas may arise from the epithelium of the Brenner tumors. Indeed, direct transition from Brenner epithelium to mucinous or serous epithelium lining adjacent cystadenomas has been documented on several occasions. Very occasionally, the coexisting tumor is struma ovarii or a teratoma 4,19. Benign Brenner tumors can be found in women of any age but are predominantly seen in women aged years old 2,6,8 12,15. In 1971, Roth and Sternberg first described a borderline Brenner tumor 18. Women with borderline or malignant Brenner tumors are usually years old 6,7,9,12, Brenner tumors have also been diagnosed in pregnant women 7. Macroscopic appearance Benign Brenner tumors are typically small solid tumors, measuring 2 8 cm in diameter 4,6,13. Calcifications can be present in the tumor and are sometimes very extensive 13. Benign Brenner tumors are rarely predominantly cystic, but small cysts are often seen in solid tumors. The most common cause of grossly visible cysts is the presence of an associated mucinous cystic tumor. Some benign Brenner tumors have a macroscopic appearance similar to that of malignant tumors (see below), but papillary projections are less common in benign than in malignant ones 4,16,17. If cystic structures are part of the tumor itself, it is often a borderline or malignant one 16,17,20. Borderline and malignant Brenner tumors are typically larger than their benign counterparts, measuring up to 30 cm 4,16. Borderline and invasively malignant Brenner tumors seem to have similar macroscopic appearance, being almost entirely cystic with solid papillary projections 17. The cysts contain watery or mucoid material 4,6,7,20. Malignant tumors are sometimes necrotic and hemorrhagic 4,16,17. Microscopic appearance Histological examination of benign Brenner tumors shows epithelial cell nests growing in a fibrous stroma 15.The cells have the appearance of urothelial cells with centrally located nuclei that exhibit conspicuous grooves ( coffee bean nuclei ). There is a clear demarcation between the stroma and the epithelial cells 21. In borderline Brenner tumors, microscopic examination shows a more complex architecture with branching papillae covered by urothelial-looking cells. These putative urothelial cells can have atypical features and may contain mitoses. The papillae have fibrovascular cores. There is no stromal invasion of malignant cells in borderline Brenner tumors 7,16,17. Liao et al. 22 suggested that expression of p63 protein is limited to benign and borderline tumors. Invasive Brenner tumors are characterized by the presence of invasive epithelial cells in association with a benign or borderline Brenner component and by the presence of cystic structures with occasional papillary structures and only a small amount of fibrous tissue 7,16,17,20. They are usually high-grade transitional-cell or squamous carcinomas. It is thought that malignant Brenner tumors may arise from their benign counterparts, so careful histopathological examination of Brenner tumors is important in order not to miss small foci of malignancy 16,17,19. Clinical symptoms Almost all Brenner tumors are asymptomatic and discovered by chance, for example at the time of imaging for an unrelated indication or at surgery 1,4,6,8 10. Among patients who are symptomatic, vaginal bleeding (explained by estrogenic activity) 4,6 10,12,16, pelvic pain or the presence of a palpable pelvic mass is frequently reported 12,16,17. Patients may also present with urinary retention 16,ascites 12 or Meigs syndrome 12. Prognosis The long-term prognosis of benign Brenner tumors is good. Because of the rarity of malignant Brenner tumors, there is little information on the prognosis and long-term survival of women with borderline or malignant Brenner tumors. Progression of malignant Brenner tumors is associated with metastases within the abdominal cavity 4. Metastases are also seen in the pleura, lung, kidneys, liver, urinary bladder and skeleton 4,16. In 1963, Idelson 23 concluded that the prognosis for women with malignant Brenner tumors was poor. Long-term disease-free survival is extremely rare, although well differentiated tumors appear to have a better prognosis 16. The prognosis for women with borderline Brenner tumors appears to be much more favorable. Roth et al. 17 described 14 patients with a borderline tumor: during a follow-up time of 6 months to 10 years, 13 patients remained disease free and the 14 th patientdiedofacute leukemia shortly after diagnosis. SUBJECTS AND METHODS Patients with a histological diagnosis of a Brenner tumor of the ovary who had undergone preoperative ultrasound examination before surgical removal of the mass between 1999 and 2007 were identified from the database of the IOTA studies Phases 1, 1b and 2 (n = 3511), and from the clinical databases of the Department of Obstetrics and Gynecology, Katholieke Universiteit, Leuven, from 1991 to We found 35 patients with 37 Brenner tumors (including two bilateral tumors), of which we excluded eight tumors. Two tumors were excluded because there was also another ovarian lesion (mucinous cystadenoma and serous cystadenoma, respectively), and retrospectively it was unclear if the lesion described and measured at the ultrasound examination was the Brenner tumor or the associated ovarian neoplasm. Another two tumors were excluded because the ultrasound examination of the ovary was impaired by the simultaneous presence of other tumors (mucinous intestinal borderline tumor and adenocarcinoma of the cecum). Four tumors were

3 708 Dierickx et al. excluded because the ovary was described as normal at the preoperative ultrasound examination, and the Brenner tumor was a coincidental finding at histological examination of the ovarian specimen. The mean volume of the ovary as measured by ultrasound in these four patients was 11.0 (range, ) cm 3 and the mean volume of the corresponding Brenner tumors recorded in the pathology database was 0.9 (range, ) cm 3. One of these four excluded tumors was a tumor in a patient with bilateral Brenner tumors, the contralateral tumor being included in this study. Thus, 28 patients with 29 Brenner tumors were included in the study. Twenty of the 29 tumors were examined within the framework of the IOTA Phases 1, 1b and 2 studies 3,24,25. The remaining nine tumors were examined outside the IOTA studies at the University Hospitals, Katholieke Universiteit, Leuven, between 1991 and 2004 (seven tumors before 1999 and two tumors after 1999, the latter two being examined using the standardized examination technique proposed by the IOTA group 26, the other seven tumors being examined with a similar but not identical technique). Thus, 20 tumors were examined following the IOTA research protocol using the IOTA standardized examination technique. For these tumors the ultrasound information was collected prospectively. For the remaining nine tumors the ultrasound information had to be retrieved retrospectively (see below). All patients underwent surgery within 4 months after the ultrasound examination. Ultrasound images, ultrasound reports, research protocols (when applicable) and patient records were retrieved. Ultrasound images were available for 14 Brenner tumors. Information on the patient s age, menopausal status, postmenopausal bleeding, tenderness of the mass during the ultrasound examination and CA 125 levels was noted. Serum levels of CA 125 were measured using immunoradiometric assay kits from two companies (the CA 125 II immunoradiometric assay: Centocor, Malvern, PA, USA or Abbott Axsym system, REF 3B41-22, Abbott Laboratories Diagnostic Division, Lake Forest, IL, USA). One author (C.V.H.) reviewed all available ultrasound images of the tumors, trying to identify a specific pattern typical of a Brenner tumor. In addition, she looked for ultrasound signs of calcifications (the variable calcifications was not part of the IOTA protocol and could only be assessed retrospectively from ultrasound images unless a note had been made in the ultrasound report). She also described the nine tumors that were not included in the IOTA database with the aid of the information available in ultrasound reports and patient records and by scrutinizing the ultrasound images of these tumors if available (n = 7/9). All descriptions of all tumors in this study were made using the IOTA terms and definitions 26. Briefly, ovarian lesions were classified as unilocular, unilocular solid, multilocular, multilocular solid or solid tumors. A subjective semiquantitative assessment of the amount of detectable color Doppler signal within each tumor was made using a color score. A color score of 1 indicates that no color could be detected in the lesion, a score of 2 that only minimal color could be detected, a score of 3 that a moderate amount of color was present and a score of 4 indicates that abundant color Doppler signals were detected in the tumor 26. Calcifications were defined as echodense foci, i.e. highly reflective areas that appear white on gray-scale ultrasound with loss of acoustic echo behind them. The loss of acoustic echo behind these structures was defined as acoustic shadowing 26. RESULTS The clinical characteristics of the 28 patients with a Brenner tumor are presented in Table 1. Two patients had bilateral benign Brenner tumors; in one of the patients, only one of the tumors was included in the study, while in the other, both were included in the study. Mean age was 56.5 (range, 33 94) years and 20 patients (71%) were postmenopausal. Four patients all with a benign Brenner tumor complained of postmenopausal bleeding. The ultrasound characteristics of the Brenner tumors are summarized in Table 2. Most of the tumors (83%) were benign, including the two bilateral tumors in this series. Two tumors (7%) were borderline malignant and three (10%) were invasively malignant. The median largest diameter of the tumors was 70 mm, but tumor size varied greatly, the smallest tumor having a maximum diameter of 16 mm and the largest tumor a maximum diameter of 278 mm. Most of the unilateral tumors (17/26, 65%) were located in the left ovary. Pressure with the vaginal probe on the ovarian mass Table 1 Clinical characteristics of patients with benign, borderline and malignant Brenner tumors Type of tumor Characteristic Benign (n = 23) Borderline (n = 2) Malignant (n = 3) Total (n = 28) Age (years) 56.7 (33 79) 49.0 (45 53) 59.3 (34 94) 56.5 (33 94) Postmenopausal 17 (74) 1 (50) 2 (67) 20 (71) Postmenopausal bleeding 4 (17) 0 (0) 0 (0) 4 (14) CA 125 level No data available 4 (17) 0 (0) 1 (33) 5 (18) < 35 U/mL 17 (89) 1 (50) 1 (50) 19 (83) 35 U/mL 2 (11)* 1 (50) 1 (50) 4 (17) Data are given as median (range) or n (%). Normal CA 125 level is < 35 U/mL. *CA 125 = 42 and 119 U/mL. CA 125 = 35 U/mL. CA 125 = 57 U/mL.

4 Brenner tumors of the ovary 709 Table 2 Sonographic characteristics of benign, borderline and malignant Brenner tumors Type of tumor Characteristic Benign (n = 24) Borderline (n = 2) Malignant (n = 3) Total (n = 29) Side Left 15 (71) 0 (0) 2 (67) 17 (65) Right 6 (29) 2 (100) 1 (33) 9 (35) Bilateral 2 Largest diameter of tumor (mm) 69 (20 278) 90 (60 120) 66 (16 143) 70 (20 278) Tender mass during ultrasound scan 2 (8) 0 (0) 0 (0) 2 (7) Type of mass at scan Unilocular 5 (21) 1 (50) 0 (0) 6 (21) Multilocular 2 (8) 0 (0) 1 (33) 3 (10) Unilocular solid 1 (4) 0 (0) 0 (0) 1 (3) Multilocular solid 4 (17) 1 (50) 1 (33) 6 (21) Solid 12 (50) 0 (0) 1 (33) 13 (45) Echogenicity of cyst fluid No data available No cystic fluid Anechoic 4 (27) 1 (50) 0 (0) 5 (26) Low level 6 (40) 1 (50) 1 (50) 8 (42) Ground glass 1 (7) 0 (0) 1 (50) 2 (11) Hemorrhagic 0 (0) 0 (0) 0 (0) 0 (0) Mixed 4 (27) 0 (0) 0 (0) 4 (21) Color score No flow 7 (29) 0 (0) 0 (0) 7 (24) Minimal flow 12 (50) 1 (50) 1 (33) 14 (48) Moderate flow 5 (21) 1 (50) 1 (33) 7 (24) High flow 0 (0) 0 (0) 1 (33) 1 (4) Calcifications No data available Yes 13 (87) 1 (50) 2 (100) 16 (84) No 2 (13) 1 (50) 0 (0) 3 (16) Acoustic shadowing 14 (58) 1 (50) 1 (33) 16 (55) Fluid in pouch of Douglas 2 (8) 0 (0) 1 (33) 3 (10) Ascites 1 (4) 0 (0) 0 (0) 1 (3) Papillations 1 (4) 1 (50) 0 (0) 2 (7) Irregular internal wall 3 (13) 1 (50) 2 (67) 6 (21) Subjective assessment by original ultrasound examiner Benign Malignant Not possible Data are given as median (range) or n (%). during the ultrasound examination caused pain in only two women (7%). Most benign Brenner tumors (71%) contained solid components, 12 tumors (50%) being purely solid, four multilocular solid (17%) and one unilocular solid (4%). If cystic fluid was present, the echogenicity of the cyst content was most often anechoic or of low echogenicity. Slightly more than half of the benign tumors cast acoustic shadows. Papillary projections were found in one (4%) benign Brenner tumor and irregular internal walls in three (13%). Ascites and fluid in the pouch of Douglas were rare. Most of the benign Brenner tumors (79%) manifested no or minimal flow on color Doppler ultrasound. Information about calcifications was available for 15 benign Brenner tumors, and in 13 of these (87%) calcifications were present. Ultrasound images of benign Brenner tumors are shown in Figures 1 4. The five borderline and invasively malignant Brenner tumors tended to contain solid components less often than did the benign ones (3/5 (60%)) and to have higher color scores (3/5 (60%) manifesting moderate or high flow), papillations were present in one of the two borderline tumors and irregular internal cyst walls were noted in three (60%) of the five malignancies. Information about calcifications was available for four borderline or invasively malignant tumors, and in three of these (75%) calcifications were present. An ultrasound image of an invasively malignant Brenner tumor is shown in Figure 5. The original ultrasound examiner correctly classified the ovarian tumor as benign or malignant using subjective assessment in 72% (21/29) of the tumors (in two tumors the ultrasound examiner was uncertain about benignity/malignancy). DISCUSSION We have described the ultrasonographic features of Brenner tumors of the ovary, but we failed to identify

5 710 Dierickx et al. Figure 2 Ultrasound image of a solid benign Brenner tumor (color score 2) containing an anechoic cystic component of 2 2-cm (calipers 1 and 2) and calcifications (calipers 3 and 4) in a 59-year-old asymptomatic woman. Note acoustic shadowing (====>). Figure 1 Ultrasound images of: (a) a 5-cm purely solid benign Brenner tumor (color score 2) in a 60-year-old woman with postmenopausal bleeding and (b) a 3-cm purely solid benign Brenner tumor (color score 3) in a 40-year-old asymptomatic woman. ultrasound features specific for such tumors. Many benign Brenner tumors appeared to be completely solid on ultrasound examination, but some were cystic with or without solid components. Most were poorly vascularized on color Doppler examination. Our study included too few borderline and invasively malignant Brenner tumors for a conclusion to be reached on possible ultrasound features typical of these. Ultrasound findings compatible with calcifications did seem to be common in Brenner tumors. However, information on the presence/absence of calcifications was collected retrospectively, and information was available for only 19 of the 29 tumors. Therefore, our information on calcifications may be biased and must be interpreted with caution. The strength of our study is that, to the best of our knowledge, it is the largest study describing ultrasound characteristics of benign Brenner tumors. Green et al. 1 and Athey and Siegel 2 described the gray-scale ultrasound findings in nine and four benign Brenner tumors, respectively. In addition, we found two publications, one describing gray-scale ultrasound findings in one benign Figure 3 Ultrasound image of a 6-cm multilocular solid Brenner tumor (color score 2) in a 79-year-old-woman with postmenopausal bleeding. There is a septum ( ) in the anechoic cystic component of this benign tumor. The internal cyst walls are regular and there are no papillary projections. Brenner tumor 27 and the other describing both gray-scale and Doppler ultrasound findings in a benign Brenner tumor in pregnancy 28. A limitation of our study is that it was retrospective. For the 20 tumors included in the IOTA study ultrasound information was collected prospectively, but for nine tumors the ultrasound information was collected retrospectively from ultrasound reports, patient records and ultrasound images. Moreover, our results regarding ultrasound signs of calcifications may not be reliable, because information on calcifications was retrieved retrospectively for all tumors. Another limitation is the small number of borderline and malignant Brenner tumors included.

6 Brenner tumors of the ovary 711 Figure 4 Color Doppler ultrasound image of a 4-cm solid benign Brenner tumor with minimal detectable blood flow in a 50-year-old asymptomatic woman. The multiple echodense foci are indicative of extensive calcifications (=>). Their acoustic shadowing (====>) impairs visualization of the remaining part of the ovary. Figure 5 Ultrasound images of a 14-cm malignant Brenner tumor (color score 3) in an asymptomatic 94-year-old woman (CA 125, 57 IU/mL). The tumor was multilocular solid (a). The cyst wall was irregular and the cyst fluid was anechoic (b). The mean age of our patients was 56.5 years, and most patients were postmenopausal. This is consistent with the literature 1,2,6,8,9,12,15,17. Moreover, in accordance with the literature most patients were asymptomatic 4,6,12. In our series, 14% of patients had postmenopausal bleeding. In the literature, the frequency of abnormal uterine bleeding in pre- and postmenopausal women with Brenner tumors varies from 10 to 50% 2,4,6,8,9,12. It is not clear from the literature whether Brenner tumors show a predilection for the right or left ovary 7,8,12,14,15, but in our series, most unilateral Brenner tumors were located in the left ovary. Blaustein s textbook of pathology also reports that unilateral lesions are more common in the left ovary 13. In our series 2/24 (8.3%) benign Brenner tumors were bilateral. This is in accordance with the literature, which reports values for bilaterality ranging from 5 to 14% 4,8, Association with a second ovarian neoplasm is common in Brenner tumors 4,6,11,12, and two of the 37 Brenner tumors that we identified from our databases were associated with a second ovarian neoplasm in the same ovary. However, these two cases were excluded (see Methods). The ultrasound appearance of the Brenner tumors in our series agrees well with the macroscopic appearance of Brenner tumors described in the pathology literature 4,6,13 ; many were solid, but the malignant tumors were less often completely solid than their benign counterparts. The size of the benign Brenner tumors (median largest diameter 7 cm) in our series also agrees well with the size of benign Brenner tumors reported in the literature. However, the malignant tumors were smaller than what one would expect from data presented in the pathology literature, where borderline and malignant Brenner tumors are reported to be larger than 8 10 cm and up to 30 cm in diameter 4,13,16,17. According to the pathology literature 13, calcifications may occur in Brenner tumors, and calcifications have also been reported in 83% (5/6) of benign Brenner tumors on computed tomography 29.We found ultrasound features suggestive of calcifications in 13 (87%) of 15 benign Brenner tumors with information available, but as stated above this result may be biased. We found descriptions of ultrasound images of 15 benign Brenner tumors in the literature, of which 10 (67%) were described as solid and three (20%) as cystic solid. Ultrasound signs of calcifications were detected in seven (47%) of the 15 tumors 1,2,27,28. Color Doppler findings were described for only one benign Brenner tumor, in which only sparse color Doppler signals were detectable 28. We found one publication describing the ultrasound features of one borderline Brenner tumor. This tumor was described as a 14-cm multilocular solid tumor with papillations arising from its septa 30. In a recent publication 31, the ultrasound appearance of 15 malignant Brenner tumors was described. In that series, nine (60%) of the 15 tumors were solid, 13 (87%) were richly vascularized, and median size was 180 (range, ) cm 3. By and large, our results agree with those of other ultrasound studies, perhaps with the exception that fewer of our benign Brenner tumors were purely solid. In the literature, about 1% of Brenner tumors are reported to be malignant 6,11. However, in our study five patients (18%) had a borderline or malignant Brenner tumor. This is probably explained by many of the centers

7 712 Dierickx et al. contributing cases to our study being tertiary oncological referral centers with a higher than normal proportion of malignant tumors. Because of the small number of borderline (n = 2) and malignant (n = 3) tumors in our series, we cannot draw any conclusions as to whether these subtypes manifest any specific ultrasound features. However, in the literature most borderline and invasive Brenner tumors are described as being very large cystic tumors with papillary or polypoid solid masses that protrude into the cyst lumen 4,13,16,17,20. Figure 5 shows an ultrasound image of one of the malignant Brenner tumors in our study that is compatible with this description. A dermoid cyst may sometimes contain calcifications, and acoustic shadowing is a common feature of dermoid cysts 32,33. In theory, therefore, a Brenner tumor could be misdiagnosed as a dermoid cyst or vice versa. However, none of the authors in the present study experienced such confusion. Some rare types of ovarian tumor manifest typical ultrasound features that may help suggest a correct specific diagnosis before surgery. This is true of struma ovarii (the struma pearl ) 34, granulosa cell tumors ( Swiss cheese appearance ) 35 and Sertoli Leydig cell tumors 36. However, in our study, the experienced ultrasound examiner who scrutinized the available ultrasound images of 14 Brenner tumors failed to detect any specific ultrasound characteristics. It is possible that ultrasound signs of calcifications could be a clue to the diagnosis, but our results with regard to calcifications are unreliable, because the information on calcifications was collected retrospectively in most cases. Although our study seems to be the largest one describing ultrasound features of Brenner tumors of the ovary, the number of cases included (n = 29) remains small and images were available for only 14 cases. 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