Differential diagnosis of peri- and postmenopausal ovarian cysts

Maturitas 31 (1999) 123 – 132

Differential diagnosis of peri- and postmenopausal ovarian cysts Toralf Reimer *, Bernd Gerber, Heiner Mu¨ller, Udo Jeschke, Annette Krause, Klaus Friese Department of Obstetrics and Gynecology, Uni6ersity of Rostock, D-18055 Rostock, Germany Received 15 May 1998; received in revised form 8 October 1998; accepted 13 October 1998

Abstract Objecti6es: To test the value of preoperative and intracystic parameters in the differential diagnosis of ovarian cysts. Methods: Criteria for admisson of 58 patients were age \47 years, complete history, detection of CA 125 serum level, and ultrasound findings. Tumor markers (CA 125, cancer-associated serum antigen (CASA), CA 72-4), hormones (estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH)), epidermal growth factor (EGF) receptor and c-erbB-2 amplification rate were detected in cyst fluid. Results: Of the 58 subjects, 9 (15.4%) had functional cysts, 37 (63.8%) had benign tumors and 12 (20.8%) had malignant tumors. No functional ovarian cyst presented as echoic or multilocular cyst sonographically. The serum CA 125 values demonstrated significant differences between the non-malignant and malignant patient groups (PB0.0005). The majority (63.8%, n= 37) of ovarian cysts were obtained at laparotomy, whereas only 36.2% (n= 21) were laparoscopically operated. The cyst fluid levels of FSH (PB 0.005) and LH (PB0.05) were significantly lower in the functional group than in the benign or malignant group. Malignant cysts were significantly different from non-malignant cysts regarding low E2 (PB 0.01), high FSH (PB0.05) and CASA (PB 0.02) values. There were no significant correlations between EGF receptor (P =0.14) and c-erbB-2 (P = 0.06) gene amplification rates and malignant histology. Conclusions: Simple ovarian cysts combined with normal serum CA 125 levels are candidates for conservative follow-up or laparoscopy. The serum CA 125 is a powerful marker for prediction of histology in postmenopausal ovarian cyst. Laparoscopic surgery may be considered in patients with multilocular sonographic findings and normal CA 125 serum level. Combining serum CA 125 levels with cyst fluid parameters (E2, FSH, CASA) improves the sensitivity and specificity in predicting malignancy. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cyst fluid analysis; Ovarian cyst; Postmenopause

Abbre6iations: CASA, cancer-associated serum antigen; E2, estradiol; EIA, enzyme immunoassay; FSH, follicle-stimulating hormone; LH, luteinizing hormone. * Corresponding author. Tel.: + 49-381-494-8101; fax: + 49-381-494-8102; e-mail: [email protected]. 0378-5122/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 8 ) 0 0 1 0 2 - 9

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1. Introduction It is well known that, if hereditary ovarian cancer families are excluded, the incidence of ovarian cancer is significantly higher in postmenopausal women than in premenopausal women. Although most cystic ovarian tumors are benign, the primary goal of the diagnostic evaluation is the exclusion of malignancy. Considering age as one of the most important risk factors for the development of ovarian cancer, any palpable or sonographically abnormal ovary in postmenopausal women should be considered suspect [1]. Non-palpable ovarian cysts are commonly detected by ultrasound in asymptomatic postmenopausal women, but the risk of malignancy appears to be low. Kroon et al. recommend ultrasound follow-up of stationary lesions and that surgery be confined to symptomatic cases or to those in which there is a family history of ovarian, breast, or colon cancer [2]. A complete history, physical examination and sonographic imaging are essential in evaluating a suspected ovarian mass. In postmenopausal women, serum CA 125 determinations improve sensitivity and specificity [3]. Doppler sonographic evaluation of resistance and pulsatility indices in the vessels of ovarian masses together with CA 125 further increased the prediction of malignancy, but additional work is needed before the validity of these factors is proved [4]. Biochemical and molecular biological characterization of ovarian cyst fluid to distinguish between functional and neoplastic cysts has been attempted, but analyses of fluid content with respect to histology in postmenopausal age are limited. The aim of the present study was to compare the diagnostic accuracy of clinical presentation, ultrasound and serum CA 125 in peri- and postmenopausal women undergoing laparotomy or laparoscopy for a clinical diagnosis of an ovarian cyst. Furthermore, we wanted to provide a contribution to the discussion about ovarian cysts that are suitable for a conservative procedure or for laparoscopic surgery. The second goal of our investigation was to define significant parameters

for non-malignant or malignant histology in ovarian cyst fluid by a detailed statistical analysis.

2. Materials and methods During a 12-month period, 58 peri- or postmenopausal patients treated at the Department of Obstetrics and Gynecology of the University of Rostock with the diagnosis of ovarian cyst were included in the study. Criteria for admisson were peri- or postmenopausal age (\ 47 years), complete history, detection of CA 125 serum level, and the ability to be examined by abdominal and transvaginal sonography. Color Doppler studies were not available. Sonography was performed with a commercially available scanner, Toshiba SSA-90A (Toshiba Medical Systems GmbH, Neuss, Germany), equipped with a 5.0-MHz vaginal probe. Patients who had a large ovarian cyst underwent transabdominal scanning with a 3.75-MHz convex transducer. Each ovarian cyst was initially classified based on two-dimensional sonographic criteria such as maximum diameter, echogenicity, uni- or multilocular appearance, cyst wall structure and solid areas. Women with more than one cyst, undergoing hormone replacement therapy, or tamoxifen treatment were excluded. Demographic data of the included 58 patients are listed in Table 1. Preoperative serum CA 125 levels were determined by enzyme immunoassay (EIA; Abbott, Wiesbaden, Germany). Levels below 35 kU/l were considered normal. The cysts were categorized according to the original pathology report. Ovarian cyst aspirates were obtained intraoperatively (laparoscopy or laparotomy) and used for cytologic, biochemical and molecular biological studies. A minimum of 5 ml of cyst fluid was required for analysis of all markers and cytology. Sufficient material was aspirated from only 42 ovarian cysts (72.4%). Samples with a low cell number (B 100 cells) yielded no usable DNA for polymerase chain reaction (PCR). Concentrations of tumor markers (CA 125, cancer-associated serum anatigen (CASA), CA 72-4) and hormones (estradiol (E2), follicle-stimulating hormone

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Table 1 Demographic data of 58 peri- and postmenopausal patients Demographic data

Histology Functional (n = 9)

Age (years) Median Range

53 48–69

BMI (kg/m 2) Median Range

29.8 23–34.6

Nulligravida Previous ovarian cyst Asymptomatic presentation Surgery Laparoscopy Laparotomy

Benign (n = 37)

Malignant (n = 12)

64 48–83

58.5 49–72

26.8 16.6–34.1

23.9 19.9–35.3

22.2% 0 33.3%

10.8% 8.1% 58.3%

8.3% 0 41.7%

88.9% 11.1%

32.4% 67.6%

8.3% 91.7%

(FSH), luteinizing hormone (LH)) in cyst fluid were detected by enzyme immuno- or immunoradiometric assays as published recently [5]. A quantitative differential PCR system was used for the estimation of epidermal growth factor (EGF) receptor and c-erbB-2 gene amplification in ovarian cyst contents. The proto-oncogene copy number was determined on genomic DNA and scored semiquantitatively (i.e. no amplification, 2–4-fold, 4–8-fold, or more than 8-fold amplification). Primer pairs, PCR and detection protocols were described previously [6]. The statistical analysis of data was performed by Wilcoxon ranked sum or chi-square tests. The level of significance was set at P B 0.05. Multiple logistic regression model was used to predict histology. 3. Results Of the 58 subjects, nine (15.4%) had functional cysts, 37 (63.8%) had benign tumors and 12 (20.8%) had malignant tumors (Table 2). The median age at surgery was 61 years (range 48 – 83 years). No functional cyst was detected at age \ 70 years. The majority of cystic malignant tumors (75%) were observed between ages 51 and 65 years (Table 3). There is no relationship with age for benign neoplasms in postmenopausal women.

The pattern of body mass index (BMI) with respect to age and histology is presented in Fig. 1. Patients with non-malignant ovarian cysts revealed a median BMI greater than 26 kg/m2; 48.3% (n= 28) of all patients were admitted with complaints. The most frequent symptom (36.2%) was lower abdominal pain (44.4% of all functional, 32.4% of all benign, and 41.7% of all Table 2 Histologic types of ovarian cyst aspirates in peri- and postmenopausal women (n =58) Histologic type Functional cysts Corpus luteum Parovarian Hydatid Ruptured Total Neoplastic cysts Serous cystadenoma Mucinous cystadenoma Teratoma Cystadenofibroma Cystadenoma and teratoma Borderline tumor Serous cystadenocarcinoma Granulosa cell carcinoma Total

n

%

4 2 2 1 9

6.9 3.4 3.4 1.7 15.4

29 3 1 3 1 4 7 1 49

50.0 5.2 1.7 5.2 1.7 6.9 12.2 1.7 84.6

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Table 3 Age distribution according to ovarian cyst fluid histology Age (years)

48–50 51–55 56–60 61–65 66–70 \70

Histology Functional (n= 9)

Benign (n =37)

Malignant (n =12)

n

%

n

%

n

%

3 2 2 1 1 0

5.2 3.4 3.4 1.7 1.7 0

2 9 4 5 8 9

3.4 15.5 6.9 8.7 13.9 15.5

1 5 0 4 1 1

1.7 8.7 0 6.9 1.7 1.7

malignant cysts). Vaginal bleedings were observed exclusively in patients with a functional cyst (22.2%). Meteorism (8.2%) and dyspnea (2%) were rare clinical signs of benign or malignant cysts. In each case, the diagnosis was supported by pelvic examination and ultrasound. The sonographic findings are listed in Table 4. No functional ovarian cyst presented as echoic or multilocular cyst. One borderline tumor was described as a simple cyst (anechoic, unilocular, smooth-walled, \5cm). The mean serum CA 125 values of the functional, benign and malignant groups were 16, 15 and 396 kU/l, respectively. Stastistical analyses (x 2 test) demonstrated highly significant differences for serum CA 125 levels between the nonmalignant and malignant patient groups (PB 0.0005). In our study, with 35 kU/l as cut-off value, the sensitivity of the serum CA 125 assay for the differentiation of non-malignant and malignant ovarian cysts was 75%, the specificity 95.6%, the positive predictive value 81.8% and the negative predictive value 93.6%. Three ovarian cysts with borderline malignancy yielded serum CA 125 values below 35 kU/l. The majority (63.8%, n =37) of ovarian cysts were obtained at laparotomy (one functional, 25 benign and 11 malignant cysts), whereas only 36.2% (n= 21) were obtained at laparoscopy (eight functional, 12 benign, and one malignant cysts). One borderline tumor was secondary operated following laparoscopy.

Only 54.4% (n= 31) of all 58 aspirates revealed reliable cytologic results (66.6% of all functional, 37.8% of all benign and 91.7% of all malignant cysts) due to sufficient cell amount. In the present study, the sensitivity for cytologic differentiation between non-malignant and malignant disease was 50%, the specificity and positive predictive value were 100% the negative predictive value was 88.5%. Cyst fluid hormone and tumor marker distributions (n= 42) with respect to histology are shown in Figs. 2–5. Using the Wilcoxon ranked sum test, the FSH (PB 0.005) and LH (P B 0.05) levels were significantly lower in the functional than in the benign or malignant group. The analysis of E2 (P=0.48), CA 125 (P= 0.93), CA 72-4 (P= 0.34)

Fig. 1. Median body mass index (BMI) with respect to age and histology (n =58).

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Table 4 Sonographic findings of 58 ovarian cysts in peri- and postmenopausal women Criteria

Histology Functional

Simple cyst (anechoic, smooth- walled, unilocular), B5cm Simple cyst, \5cm Unilocular, some echoes, B5cm Unilocular, some echoes, \5cm Multilocular, B5cm Multilocular, \5cm No ovarian cyst described

Benign

Malignant

n

%

n

%

n

%

5 2 0 0 0 0 2

8.6 3.4 0 0 0 0 3.4

3 5 1 5 3 17 3

5.2 8.6 1.7 8.6 5.2 29.5 5.2

0 1 1 4 0 5 1

0 1.7 1.7 6.9 0 8.6 1.7

and CASA (P = 0.53) revealed no significant differences. Malignant cysts were significantly different from non-malignant cysts regarding low E2 (P B 0.01) and high FSH (PB 0.05) and CASA (PB 0.02) values. LH (P =0.12), CA 125 (P = 0.95) and CA 72-4 (P =0.13) yielded no significant results. There were no significant correlations between EGF receptor (P = 0.14) and c-erbB-2 (P = 0.06) gene amplification rates and malignant histology in ovarian cyst aspirates (Figs. 6 and 7). Low copy EGF receptor amplification was detected in 16.7% of functional cysts, in 27.6% of benign cysts and in 42.9% of malignant cysts. Low copy c-erbB-2 amplification was seen only sporadically in the three histological subgroups. An invasive carcinoma revealed a high copy (8-fold) c-erbB-2 amplification rate. Using multiple logistic regression model with serum CA 125, cyst fluid E2, FSH and CASA values as covariates, 100% of all observed nonmalignant cysts and 83.3% of the malignant cysts could be predicted exactly. The overall correct prediction of the histologic group was 95.6%.

ages 20–29 to 60–69 years [7]. The postmenopausal ovary can presumably only give rise to neoplastic growths. Nevertheless, Wolf et al. detected a frequency of 14.8% of simple adnexal cysts in 149 women aged 50 years or older [8]. According to this finding, we could identify functional ovarian cysts in a higher than anticipated incidence (15.4%). This incidence of unnecessary surgical intervention in cases of functional cysts in peri- and postmenopausal patients seems to be acceptable.

4. Discussion

Fig. 2. Box-plot diagram of estradiol in ovarian cyst fluid (n =58) for functional, benign and neoplastic histology. The box represents the range between the 25th and 75th percentiles with a horizontal line at the median. The bars delineate the 5th and 95th percentiles. The circle and asterisk indicate extreme values (circle, more than 1.5 box lengths from 75th percentile; asterisk, more than 3.0 box lengths from 75th percentile).

The most important predictor of malignant ovarian tumors is the age of the patient. Koonings et al. reported that the risk that an ovarian neoplasm was malignant increased 12-fold from

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Fig. 3. Box-plot diagram of gonadotropins (FSH, LH) in ovarian cyst fluid (n =58) for functional, benign and neoplastic histology.

Fig. 5. Box-plot diagram of CASA and CA 72-4 in ovarian cyst fluid (n = 58) for functional, benign and neoplastic histology.

Predicting whether an ovarian cyst is benign or malignant is very inaccurate if based on the physical examination alone. Findings such as lower abdominal pain or meteorism are present in both histological groups. In the rare case of vaginal bleeding, a functional ovarian cyst should be considered. In addition to a complete history and physical examination, transabdominal and transvaginal ultrasonic imagings are always indicated. However,

there is a known significant decrease of the diagnostic accuracy of transvaginal sonography in postmenopause compared with premenopause [9]. Ultrasonography has been used to challenge the concept that all postmenopausal women with minimally enlarged ovaries should undergo laparotomy. Several studies have concluded that small anechoic lesions are rarely malignant, even in the postmenopausal population [10].

Fig. 4. Box-plot diagram of CA 125 in ovarian cyst fluid (n = 58) for functional, benign and neoplastic histology.

Fig. 6. Box-plot diagram of epidermal growth factor receptor (EGF-R) gene amplification rate in ovarian cyst fluid (n = 58) for functional, benign and neoplastic histology.

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Fig. 7. Box-plot diagram of c-erbB-2 gene amplification rate in ovarian cyst fluid (n =58) for functional, benign and neoplastic histology.

Using a morphologic scoring system for simple ovarian cysts (anechoic, smooth-walled and unilocular), we accurately predicted a non-malignant outcome in 15/16 patients (93.7%) studied. Including small simple cyst size ( B5 cm) as an additional criterion, we excluded all malignant cysts. Analyzing the most frequent ultrasonic findings (some echoes, smooth-walled, multilocular) in peri- or postmenopausal ovarian cysts, we could not reliably predict the histology. Benign and malignant lesions are not characterized by different echo patterns. In fact, further diagnostic procedures are necessary for the majority of periand postmenopausal ovarian cysts. Transvaginal color Doppler ultrasound could be an additional diagnostic method in the assessment of ovarian cysts. A conservative strategy can be considered for small simple ovarian cysts. A wait-and-see approach for cyst size less than 3 cm is preferred by Osmers et al. because unilocular smooth-walled ovarian cysts of more than 3 cm are associated with a cancer risk of 9.6% [1]. Auslender et al. support the option of a conservative follow-up by repeated vaginal ultrasonic and serum CA 125 examinations of small (B5 cm) simple cysts in postmenopausal women [11]. Pardo et al. developed a conservative protocol for the treatment of

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echo-free findings in the pelvis, diagnosed by sonography in 182 postmenopausal women, in order to avoid unnecessary surgical intervention. Two cases of malignancy were diagnosed, no false-negative results were observed [12]. Although the results of different studies of conservative management in patients with simple ovarian cysts look promising, a final recommendation is difficult because of the small sample size. The serum CA 125 assay was developed and evaluated for its usefulness in monitoring the treatment of ovarian cancer, detecting a relapse of the disease and distinguishing benign from malignant conditions. Many authors agree that a CA 125 level is most helpful in the evaluation of postmenopausal women, because serum CA 125 levels are also elevated in a variety of benign conditions in women of reproductive age [10]. In the study reported by Vasilev et al.[13], 80% of women older than 50 years of age with pelvic masses and CA 125 levels greater than 35 kU/l had malignancies, compared with only 15% of patients less than 50 years of age. To reduce the false-positive rate in patients with benign disease, Chen et al. suggest a defining positive serum CA 125 value of greater than 65 kU/l [14]. In our report, serum CA 125 with a cut-off of 35 kU/l had a sensitivity of 75%, a specificity of 95.6%, a positive predictive value of 81.8% and a negative predictive value of 93.6%. Levels of sensitivity and specificity are comparable to data (75.2% sensitivity, 91.1% specificity) studied in 62 postmenopausal patients by Botsis et al.[4]. Most ovarian cysts discovered in peri- or postmenopausal women will required surgical evaluation. If surgical removal is indicated, when is a laparoscopic approach justified? The widespread application of minimal access surgery has raised the concern that some ovarian neoplasms are being mismanaged. Curtin [3] comes to the conclusion that by utilizing the information provided by the physical examination and ultrasound, combined with serum CA 125 determination in the postmenopausal patient, the clinician can accurately select patients who are candidates for a laparoscopic procedure. The incidence of malignant lesions at operative laparoscopy is around 2% [15]. Shalev et al. prefer

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laparoscopic management in postmenopausal women with a non-complex adnexal mass and a normal CA 125 serum level [16]. According to these criteria, our study would yielded a laparoscopic rate of 27.6% in 58 cases, but 51.7% of patients with non-malignant histology would undergo laparotomy. Although there are contraindications for laparoscopic procedures caused by ovarian cyst size or patient risk factors, only a normal serum CA 125 value is a preoperative help to decrease the laparotomy rate in benign conditions. Using the laparoscopic approach, careful intraoperative assessment of gross features and the use of frozen section may help achieve a high accuracy rate in the evaluation of ovarian cysts. The findings in borderline tumors are interesting. Even if in postmenopausal women the concomitant use of sonography and serum CA 125 assay did not permit the recognition of all malignancies, only a borderline tumor was missed. Nevertheless, some borderline tumors were detected with sonographic findings of simple cysts (n = 1), normal serum CA 125 values (n = 3) and negative cytologic results (n =4) in our study. On the other hand, all invasive carcinomas had complex sonographic findings and elevated serum CA 125 levels. However, our small number of this tumor type precludes any meaningful interpretation of these results. There are various reports about ovarian cyst fluid analyses for distinguishing between benign and malignant histology. But no study investigated specifically peri- and postmenopausal age group. The low sensitivity (26%) and negative predictive value (76%) of cytologic cyst fluid examination preclude its use for the distinction between benign and malignant tumors. The rate of positive results is significantly higher in invasive than in borderline tumors [17]. Our data in periand postmenopausal age group (sensitivity of 50%, negative predictive value of 88.5%) are consistent with these conclusions. The use of estradiol as a cyst marker is of special interest, since the ovary is a steroid-producing and a steroid-responsive organ. Estradiol cyst fluid levels higher than 3700 pmol/l may support the diagnosis of a functional cyst in pre-

menopausal women [18]. Jeppsson et al. showed that postmenopausal patients with malignant ovarian tumors had increased concentrations of E2 in the peripheral blood [19]. Several authors reported ovarian estrogen secretion in postmenopausal women [20]. Our results revealed significant higher E2 levels in non-malignant than in malignant cysts (PB 0.01). The pituitary hormones FSH and LH are elevated approximately 15-fold and 5-fold for a number of years following menopause. These changes during the period when malignant ovarian cyst incidence markedly increases suggests a role for these hormones in the development of the disease. Unexpectedly, we found significant lower FSH (PB 0.005) and LH (PB 0.05) values in functional cysts than in neoplastic cysts, and higher FSH levels (PB 0.05) in malignant cysts than in non-malignant cysts. Previous investigations regarding correlation between gonadotropins and ovarian tumors were mainly done with blood samples. Significantly lower serum FSH levels were demonstrated in postmenopausal women with malignant ovarian tumors. No significant differences were found between the groups regarding the serum LH levels [21]. Kobayashi et al. suggest that the human ovary is a target organ for pituitary gonadotropins even after menopause, and binding sites for FSH and LH localize in the cortical stroma [20]. High serum gonadotropin levels in perimenopause suggested the existence of low ovarian gonadotropin receptors levels. However, the regulation of gonadotropin receptors is poorly understood in the human [22]. There are many reports about the role of serum tumor markers in the differentiation of benign and malignant ovarian neoplasms [23]. In contrast, analyses of ovarian cyst fluid content with respect to menopausal status have not been published. Menczer et al.[24] showed that cyst fluid levels of CA 125 could not be used to distinguish between benign and malignant ovarian cysts in 44 women (age range 16–82 years). This result was confirmed in a study with 80 patients (age range 14–85 years) by Gaetje et al.[18]. Recently, we have described statistically significant correlations of CA 125 (PB0.0005) with neoplastic histology

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[5]. In the present report we have not found significant differences between non-malignant and benign ovarian cysts in peri- and postmenopausal women. The low rate of mucinous cysts, only three mucinous cystadenomas in our investigation, might explain the missing significance of CA 72-4. CASA is detected using monoclonal antibodies that bind to an epitope on the polymorphic epithelial mucin, a glycoprotein. Initial observations indicate that CASA might play a role in the early detection of ovarian cancer [23]. Christensen et al. found that malignant ovarian tumors and endometrioma could be separated from other adnexal masses by a cyst fluid content of CASA greater than 10 kU/l (P B 0.05) [25]. Our CASA test revealed a moderate significance (P B 0.02) to discriminate between non-malignant and malignant outcome. According to these findings, the tumor marker evaluation in ovarian cyst fluid alone does not improve the detection of malignant cysts. Whether benign lesions (e.g. cystadenomas and teratomas) are precursors of malignancies is an unanswered question. Presumed intraepithelial neoplasia has been reported in otherwise benign serous cystadenomas, and in early-stage invasive epithelial cancer several authors have described the presence of transitional changes from normal epithelium to intraepithelial neoplasia to invasive cancer [3]. While these findings do not conclusively prove that epithelial ovarian cancers arise from benign cystadenomas, they suggest that at least in some cases this occurs. Selection of these cases could be possible by cyst fluid analysis. In previous work we have shown that low copy EGF-receptor gene amplification seems to be a marker for neoplastic histology in ovarian cysts [6]. The present results indicate that the median EGF-receptor gene amplification rate increase from functional to benign and from benign to malignant histology (Fig. 6). Although statistically non-significant and of limited sample size, further studies would be reasonable to investigate this gene structure abnormality in peri- and postmenopausal ovarian cysts. The levels of EGF-receptor expression have been claimed to be higher in malignant ovarian

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tumors than in benign tumors or in the normal ovary [26]. Scambia et al. [27] showed a significant relationship between EGF-receptor expression and a shorter overall survival and progression-free survival in patients with primary ovarian cancer. In addition, various studies have suggested that c-erbB-2 overexpression is a marker of poor prognosis [28] and lack of response to chemotherapy in ovarian cancer [29]. The aim of our study was to determine the value of preoperative and intracystic parameters in the differential diagnosis of ovarian cysts. Sonographically simple ovarian cysts combined with normal serum CA 125 levels are candidates for conservative follow-up or laparoscopy when no regression occurs. The CA 125 serum value should be used as powerful marker for prediction of histology in postmenopausal ovarian cyst. Laparoscopic surgery may be considered in patients with multilocular sonographic findings and normal CA 125 serum level. Unfortunately, these conclusions are not completely correct for borderline tumors. Combining serum CA 125 levels with cyst fluid parameters (E2, FSH, CASA) improves the sensitivity and specificity in predicting malignancy, particularly in postmenopausal women. The unexpected findings of intracystic gonadotropin values and EGF-receptor gene amplification rate need further investigation. We presume that there are additional risk factors for malignancy that molecular biological analysis of ovarian cyst fluid will allow us to evaluate.

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