Scoring system for prediction of ovarian endometriosis based on transvaginal color and pulsed Doppler sonography

Transcription

1 FERTILITY AND STERILITY Copyright" 994 The American Fertility Society Vol. 6, No. I, July 994 Printed on acid-free paper in U. S. A. Scoring system for prediction of ovarian endometriosis based on transvaginal color and pulsed Doppler sonography Asim Kurjak, M.D., Ph.D.* Sanja Kupesic, M.D., Ph.D. Department of Obstetrics and Gynecology, University of Zagreb, Zagreb, Croatia Objective: To develop a new noninvasive scoring system using clinical signs and symptoms, CA-5 levels, sonographic findings, and transvaginal color and pulsed Doppler parameters for preoperative recognition of ovarian endometriosis. Design: A 5-year prospective study in patients undergoing laparotomy and laparoscopy. Setting: Department of Obstetrics and Gynecology, University of Zagreb, Sveti Duh Hospital, Zagreb, Croatia. Patients: Six hundred fifty-six benign and malignant adnexal masses, among which 03 were surgically proved to be ovarian endometriosis. Interventions: All patients undergoing laparotomy and laparoscopy were examined by transvaginal ultrasonography with color Doppler imaging. Serum levels of CA-5 were measured the day before surgery. Main Outcome Measure: The total score was applied in all patients with adnexal masses. Results: The scoring system proved to be very useful in distinguishing ovarian endometriosis from other benign and malignant ovarian lesions, with a sensitivity of 99.0% and a specificity of 99.64%, compared with morphological scoring system's sensitivity of 83.9% and specificity of 97.%. Conclusion: The new noninvasive scoring system improves significantly the ability to discriminate between endometriosis and other benign and malignant ovarian entities. Fertil Steril 994;6:8-8. Key Words: Ovarian endometriosis, transvaginal color Doppler, scoring system Although endometriosis is a common benign gynecological condition, there still is much to learn about its etiology and pathogenesis. The ovaries and posterior leaf of the broad ligaments are the most frequent locations and the left side is more frequently affected than the right side (). The condition has aroused much interest and controversy in recent years with regard to its accurate diagnosis, infertility association, and proper treatment. Even Received October, 994; revised and accepted March 0, 994. * Reprint requests: Asim Kurjak, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Zagreb, Sveti Duh Hospital, 4000 Zagreb, Croatia (FAX: ). with the recent and ongoing achievements in operative endoscopy, clinicians still are faced with a problem of correct diagnosis, both in the sense of missing this pathology and of treating a lutein cyst for an endometrioma (, 3). Therefore, any diagnostic technique that could differentiate accurately and reliably between hemorrhagic lutein cyst, cystadenoma, dermoid cyst, ovarian malignancy, and endometrioma would be a useful additional tool for better management of this enigmatic disease. Recent introduction of transvaginal color and pulsed Doppler showed great potential for in vivo characterization of adnexal masses, particularly in differentiation between benign and malignant conditions (4). During the last 5 years, our group has been particularly interested in the possibility of accurate rec- Vol. 6, No., July 994 Kurjak and Kupesic Scoring system for ovarian endometriosis 8 ;

2 Table Scoring System for Endometriosis Based on Transvaginal Color and Pulsed Doppler Sonography Reproductive age Chronic pain (premenstrual or menstrual) Infertility B mode Position (medially, retrouterine) Bilaterality Serial sonography positive Thick walls Homogeneous echogenicity Clear demarcation from the ovary Transvaginal color Doppler Vascularization Pericystic/hilar location Regularly separated vessels Existence of notching RI < 0.40 (menstrual phase) RI = 0.4 to 0.60 (late follicular/ corpus luteum phase) CA-5 (>35 IU/ML) No. of patients ognition of ovarian endometriosis using an original scoring system produced for this purpose. MATERIALS AND METHODS The study was performed between July, 988 and July, 993. The study group consisted of 544 women with clinically suspected adnexal masses who were undergoing laparotomy and patients who were undergoing laparoscopy. In the second group, management of ovarian mass and, additionally, lysis of adhesions in infertile patients were the indications for diagnostic and/or operative laparoscopy. The mean age was 46 years (range 9 to 78 years). Of these patients, 496 (75.6%) were premenopausal and 60 (4.4 %) were postmenopausal. Ovarian endometriosis was proved histologically in 03 patients. The average age of patients suffering from ovarian endometriosis was 3 years (range 9 to 45 years). At th~ beginning of the study, a new scoring system was created in an effort to improve sensitivity and specificity in diagnosis of ovarian endometriosis. The scoring system used age, clinical signs and symptoms (pelvic pain associated with menstruation and presentation of infertility), CA-5 levels, sonographic findings, and transvaginal color and pulsed Doppler parameters (Table ). A blood sample for determination of CA -5 level was drawn the day before surgery or laparoscopy. The subjects were not taking any medication when CA-5 levels were measured. The CA -5 assay used was a simultaneous sandwich solid-phase RIA system (Centocor, Inc., Malvern, PA). Samples were run in duplicate, and the average response was calculated. If the duplicates varied >0%, the sample was reassayed. Patients were sonographically examined at least twice: when they were admitted to the department and, the day before the intervention. The peritoneal implants of endometriosis were excluded from the analysis, because no role can be expected from pelvic sonography in the minimal or mild endometriosis detection. B-mode was used to evaluate location, appearance, and width of the ovarian lesion. The morphological scoring system is based on internal borders, quality of cyst, and fluid echogenicity (4). It includes position and existence of adnexal mass bilaterality. The sonographic criteria for the diagnosis of endometriosis were thick walls, regular margins, and homogeneous low echogenicity of the fluid (Fig. ). The presence of the cyst was confirmed at least twice in different cycles before surgery (the interval between the first and second ultrasound ranged from 4 to 84 days). In 47 patients (65.09%) serial ultrasound examinations were performed. For flow visualization, color Doppler was used. The pulsed Doppler signals were obtained using a -mm volume cursor. All examinations were performed in patients' lithotomy position, using the Aloka color Doppler 680 and SSD 000 (Aloka Corporation, Tokyo, Japan), 5-MHz transvaginal probe for imaging, and 6-MHz pulsed Doppler system for blood flow analysis. Pulse repetition fre- Figure Transvaginal scan demonstrating diffuse homogeneous low level echoes dispersed throughout the cystic mass. Color Doppler shows pericystic vascular location typical for endometrioma. 8 Kurjak and Kupesic Scoring system for ovarian endometriosis Fertility and Sterility

3 Figure Transvaginal image of an 'endometrioma containing low level echoes. Note the area of increased hilar vascularity representing acute phase of hemorrhage. quency ranges were from to 4 khz. The spatial peak temporal average (SPTA) intensity was approximately 80 m W /cm Wall filters (00 Hz) were used to eliminate low frequency signals occurring from noise. The color Doppler scoring system is derived from vascular location, type of vascularization, and vascular quality. The vascular location typical for endometrioma is pericystic, at the level of ovarian hilus (Fig. ). The type of vascularization represents vascular arrangement within ovarian endometrioma: regularly separated vessels or no vessels seen. The vascular quality is Doppler waveform signal assessed in terms of resistance index (RI = peak systolic - end-diastolic Doppler shift/ peak systolic Doppler shift). The threshold value for discrimination between ovarian endometriosis and other ovarian lesions was a value of 0 for the combined scoring system. The histopathological diagnosis was considered definitive in all cases. RESULTS Transvaginal sonography demonstrated 656 adnexal masses: 580 benign, 6 borderline, and 76 malignant histologically proved ovarian lesions. For each lesion, combined scores for endometriosis were calculated the day before surgery or laparoscopy (Tables and 3). Ovarian endometriomas appeared as thickwalled cystic structures containing marked internal echoes in 86 (83.4 %) patients, multiocular cysts in 7 Vol. 6, No., July 994 (6.8%) patients, whereas solid-cystic appearance was present in 0 (9.7%) patients. The median diameter of the endometrioma was 55.3 mm (range 8 to 60 mm). Although at times the internal pattern represented a predominantly solid appearance, some acoustic enhancement always was demonstrated. In such cases, ballotement through the abdominal wall caused movements of the echoes, confirming the liquid mass. Most of ovarian endometriomas (87.04%) were positioned medially or retrouterine. A well-demarcated separation between the endometrioma and the normal adjacent ovarian stroma was noticed in 85.4 % of cases. Bilateral changes were detected ultrasonically and proved surgically in 43.7% of cases. Endometrioma was confused morphologically for an acute hemorrhagic cyst in seven patients, which is not surprising because of the similar blood content (Table 4). In seven patients with hemorrhagic cysts, sonography indicated endometriomas. Acute onset of the symptoms in these patients was suggestive for the hemorrhage, whereas a history of chronic pain was associated with endometriosis. In a follow-up, endometriomas remained constant both in size and internal echo pattern, whereas all the hemorrhagic cysts resolved or decreased in size during the one or two ensuing cycles. Seven more false-negative cases were observed: the sonographic reports indicated five cystic teratomas and two ovarian cystadenomas. The five false-negative cases by morphological scoring alone were caused by cystic teratomas in patients with partly solid appearance of endometriosis. In three, surrounding scarification process was obvious. These structures were confused for high amplitude reflectors with acoustic shadowing typical for dermoid cysts. Two patients with ovoid, huge multilocular endometriomas were interpreted incorrectly as mucinous cystadenomas. Sonographic evaluation, whether alone or in combination with tumor markers, did not determine the nature of the lesion before Doppler assessment. In one patient with ovarian cystadenocarcinoma, the septations, papillary projections, and solid areas were absent. Pelvic sonography demonstrated a small unilocular cyst of 8 mm with a smooth cystic wall, containing homogeneous fluid of low echogenicity. Eight more false-positive cases were observed: the, morphological scoring system indicated endometriomas in six patients with homogeneous dermoid cysts and two cystadenomas. When we performed CA-5 analysis in 4 false Kurjak and Kupesic Scoring system for ovarian endometriosis 83

4 Z_E r Table The Accuracy of Combined Scoring System in the Assessment of Benign Adnexal Masses Histopathology Morphological score Resistance index* No. with CA-5 >35 IU/mLt Total score Benign tumors Functional cysts Follicular (n = 04) Corpus luteum (n = 08) Dermoid cysts (n = 54) Cystadenoma (n = 7) Fibroma (n = 8) Theca-granulosa cell tumor (n = 3) Brenner's tumor (n = 4) Endometriosis (n = 03) Pelvic inflammatory disease (n = 4) to 6 to 9 6 to 0 4 to 6 5 to 7 4 to 7 5 to 8 7 to 0 5 to ± ± ± ± ± ± ± ± ± 0. o (0.0) (.85) 9 (5.0) 8 (5.0) (5.0) (5.0) (5.0) 65 (63.) 3 (0.48) 8 to 3 to to 9 to 8 0 to 0 to to 3 0 to 5 to 8 * Values are means ± SD. t Values in parentheses are percentages. negatives by morphological score, we found an increased CA-5 value in nine (64.8%) patients. Color and pulsed Doppler showed vascularization typical for endometrioma in 3 patients: regularly separated vessels at the level of ovarian hilus with an RI between 0.40 and Existence of notching was noticed in 0 of 4 false negatives. When we analyzed serum CA-5 levels in 6 false positives, we found normal results in 4 (87.5%) patients. Color and pulsed Doppler analysis showed typical luteal blood flow in six hemorrhagic cysts. Five dermoides showed no areas of vascularity, whereas two cystadenomas had an RI > The morphological score indicated endometrioma in a patient with endometrioid cystadenocarcinoma (stage Ia). Color Doppler demonstrated massive diastolic flow and an RI of 0.38, suggestive of ovarian malignancy. Sensitivity of vaginal sonographic characterization of endometriomata was 83.9%. Specificity and positive predictive values of this scoring system were 97. % and 8.0%. The negative predictive value of transvaginal sonography was 97.5% (Table 4). Indeed, our results in distinguishing ovarian endometriomata by the morphological scoring system alone showed that it is not possible to characterize ovarian lesions with acceptable accuracy. In 3 of 4 patients with a false-negative diagnosis by B-mode, color Doppler was decisive in definitive diagnosis when used in combined assessment for ovarian endometriosis. Endometrioma supplying vessels were identified in 9 (88.3%) patients. The most prominent vascular area in these cystic structures was at the level of ovarian hilus. The resistance index values measured from this location were usually greater than Blood flow indexes varied between low (RI = 0.36 to 0.40) in 5.83%, intermediate in 4.75% (RI = 0.4 to 0.50), and high (RI = 0.5 to 0.60) in the remaining 40.77%. The total absence of blood flow was noticed in.65% of patients. In patients with inflamma- Table 3 The Accuracy of Combined Scoring System in the Assessment of Borderline and Malignant Adnexal Masses Morphological Resistance No. with CA-5 Total Histopathology score index* >35 IU/mLt score Borderline tumors (n = 6) 4 to ± (50.0) 3 to 8 Malignant tumors Cystadenocarcinoma (n = 38) to ± (89.47) 0 to 7 Endometrioic adenocarcinoma (n = 9) 6 to ± (00.0) 6 to 9 Germ cell tumor (n = 4) 3 to ± 0.07 (50.0) 9 to 3 Anaplastic ovarian carcinoma (n = ), (00.0) 8, 9 Metastases to ovary (n = 7) to ± 0. 5 (88.3) 8 to * Values are means ± SD. t Values in parentheses are percentages. 84 Kurjak and Kupesic Scoring system for ovarian endometriosis Fertility and Sterility

5 Table 4 Results True positive (n = 73) False negative (n = 4) False positive (n = 6) True negative (n = 553) The Accuracy of Morphological Scoring System Morphological score 73 Endometriomas 7 Hemorrhagic cysts 5 Dermoid cysts Cystadenomas 7 Endometriomas 6 Endometriomas Endometriomas Endometrioma Histopathology 73 Endometriomas 7 Endometriomas 5 Endometriomas Endometriomas 7 Hemorrhagic cysts 6 Dermoid cysts Cystadenomas Ovarian carcinoma tory changes surrounding the endometrioma, color Doppler showed intermediate RI values (0.4 to 0.50). Moderate elevation of serum CA-5 has been observed in 63. % of patients suffering from endometriosis. The sensitivity and specificity of preoperative CA-5 levels, using a cut-off of >35 IU/mL, were 63.0% and 83.8%, whereas positive and negative predictive values were 36.93% and 93.57% (Tables and 3). In 04 patients the combined scoring system suspected an endometrioma (Table 5). The false-positive results were caused by a vascularized homogeneous cystic teratoma and hemorrhagic cyst. Elevated serum CA-5 levels (40 IU/mL for cystic teratoma and 4 IU/mL for hemorrhagic cyst) were obtained. In both of these cases, color Doppler demonstrated an intermediate RI in visualized tumor vessels: in the first case, within the small bulge on the lateral cystic wall (RI = 0.48) and, in the second case, at the edge of inner wall of the ovarian cyst (RI = 0.45). Both ovarian tumors had a total score value of. One false-negative result was observed when the combined noninvasive scoring system for endometriosis indicated a corpus luteum cyst. The serum CA-5 level in this case was 8 IU/mL, whereas color Doppler had not revealed any area of neovascularization. Sensitivity of the combined scoring system was 99.04%. Specificity and positive predictive values were 99.64% and 98.0%, respectively. The negative predictive value of the new scoring system was 99.8%. Of 03 patients, 45 were diagnosed correctly as having bilateral endometrioma. No malignancy was observed in the group of patients suggestive of ovarian endometriosis by combined score. DISCUSSION Since its first description by Sampson (5), endometriosis has remained a puzzling disease of unknown histogenesis and etiology. Indeed, the nature of the disease and the mechanisms of the associated infertility and/or pain still are not understood. Recently, Wheeler (6) indicated that endometriosis might be present in as many as 0% of the female population of reproductive age, based on surgical findings in women undergoing surgery in which endometriosis was not a likely diagnosis. Pauerstein (7) reviewed the literature on the prevalence of endometriosis and clearly demonstrated that the reason for the diagnostic intervention influences the detected prevalence. Many years ago Scott and Te Linde (8) presented the sites of endometriosis detected in a series of 56 cases. They showed the ovaries to be the most common site followed by pelvic peritoneum. In an infertility population of 8 women, Jenkins et al. () similarly noted the ovary to be a major site (54.9%) followed by the posterior broad ligament (35.%), the anterior or posterior pouch of Douglas (each 34%), and the uterosacral ligaments (8%). Over the last 0 years, there has been a large increase in the number of infertile patients found to have endometriosis. It is uncertain whether this represents an actual increase or is simply a reflection of the more frequent use of laparoscopy in the investigation of the infertile couple. Controversy, however, exists about the relationship between small amounts of asymptomatic endometriosis and infertility. It does appear that there is a relationship because endometriosis has been reported in up to 60% of women undergoing laparoscopy for infertility (9). This compares with an incidence of.5% to 5% in fertile controls. The Table 5 Assessment of Noninvasive Scoring System for Endometriosis Noninvasive scoring system True positive (n = 0) 0 Endometriomas False negative (n = ) Hemorrhagic cyst False positive (n = ) Endometrioma Endometrioma True negative (n = 55) Histopathology 0 Endometriomas Endometrioma Hemorrhagic cyst Dermoid cyst Vol. 6, No., July 994 Kurjak and Kupesic Scoring system for ovarian endometriosis 85

6 term "chocolate cyst" is used frequently to describe the endometrial cyst of the ovary, but it is misleading' as a similar content can be found in hemorrhagic functional cysts and ev~n in some neoplastic tumors. The outside characteristics of the ovarian endometrioma are well known but they do not always suffice for reliable diagnosis. There were several papers on diagnosis of endometriosis by transabdominal sonography (0-4). Typically, ovarian endometriomas have been described as cystic masses that are entirely or predominantly anechoic (, ). In other reports (0, 3), they have been characterized more commonly as a complex mass. In the recent transvaginal study by Kupfer et al. (3), 8% of 3 surgically proved endometriomas showed a presence of a homogeneous hyperechoic "carpet" of low level echoes. To the best of our knowledge, this is the first report on combined transvaginal color and pulsed Doppler assessment and CA -5 levels in patients with ovarian endometriosis. At laparoscopy or laparotomy, most of the typical endometriotic lesions frequently are surrounded by a substantial amount of blood vessels. According to the transplantation theory of Sampson (5), viable endometrial cells that reach the peritoneal cavity by retrograde menstruation could implant and form the endometriotic lesions. Further progression of the lesions depends on different factors: the hormonal, immunologic, and vascular environment. Oosterlynck et al. (5) investigated the presence of angiogenetic factors in peritoneal fluid of women with endometriosis. They found that increased angiogenic activity could be important for further outgrowth and progression of these ectopic endometrial implants. It seems that the extant of fibrosis and presence of focal hemorrhage correlate with hormonal responsiveness of these implants. The collagen layer (6) may alter the vascularity and the diffusion of the nutrients and oxygen into the endometrioma. It is possible that toxic factors within the lesion or increased pressure caused by accumuation of chocolate fluid alter the vascularity and result in impaired response to cyclic endogenous hormones. Color Doppler ultrasound has good potential in evaluating blood flow patterns in patients with ovarian endometriosis. Low impedance/high diastolic flow (RI = 0.36 to 0.40) is present when there is a hemorrhage during the menstrual phase of the cycle (Fig. 3). Existence of a notch in such cases indicates persistence of an initial resistance from the muscular lining of pre-existing arterioles and is 86 Kurjak and Kupesic Figure 3 The same patient. Pulsed Doppler shows low resistance of blood flow (resistance index, 0.375) during the menstrual phase of the cycle. Repeated scan in early luteal phase demonstrated an intermediate RI value (>0.45). suggestive for benign tumors (7). Therefore, to distinguish this condition from ovarian malignancy, a careful study of ovarian endometrioma vascularity during the late follicular phase or early luteal phase is recommended. Serial color and pulsed Doppler evaluation is useful in doubtful cases. Five of six patients with low vascular resistance «0.40) in early postmenstrual phase showed intermediate RI values (>0.46) in late follicular or early luteal phase. It is postulated that the effect of medical treatment is highly dependent on the arrival of metabolically active products via a blood supplying network. Based on our experience, varying vascularity between lesions may determine the efficacy of therapy. Medical treatment of ovarian endometriomas with fibrotic plaques is never successful (8). Intraperitoneal injection of GnRH analogs could be used successfully in patients with optimal vascular pattern. The scarification process surrounding the implants modifies the vascularization, which is possible to detect by transvaginal color Doppler. Clearly, an avascular lesion must be removed surgically. Even though a combination of transvaginal ultrasonography and color Doppler flow imaging may identify ovarian endometriosis with great reliability, measurement of CA-5 levels seems to enhance sensitivity of the new scoring system. CA5 is a cell surface antigen expressed on certain cells derived from embryonic coelomic epithelium, the measurement of which aids in the diagnosis and clinical follow-up of patients with ovarian carcinoma (9). Scoring system for ovarian endometriosis Fertility and Sterility

7 Elevation of CA-5 levels has been noted in patients with other benign conditions of the pelvis, such as endometriosis, myoma, adenomyosis, acute pelvic inflammatory disease, and ovarian cysts (0). The mechanism by which the elevated serum concentration of CA-5 occurs in women with endometriosis has not been clarified yet. McBean and Brumstead () showed that the endometrium of women with advanced endometriosis represents a potential source of elevated serum levels of CA -5. Disruptions of normal barriers between tissue and the intravascular space could explain increased amounts of this antigen. A majority of studies measuring CA-5 values in patients with endometriosis have demonstrated elevation of serum CA-5 levels during menses (). Elevation specifically during menses may result from retrograde flow and increased peritoneal inflammation which is more pronounced than in women without disease. O'Shaughnessy et al. (0) demonstrated that screening tests based on the relationship of multiple CA-5 levels throughout the menstrual cycle are more sensitive for detection of endometriosis than tests based on a single CA-5 level. In our study, measurements of CA-5 in patients with ovarian endometriosis showed values between 6 and 65 IV jml. In 65 patients (63. %), levels> 35 IV jml were obtained. In patients with severe endometriosis, serum CA-5 levels were measured during both the menstrual and late follicular phase of the menstrual cycle. Menses levels were significantly higher (P < 0.05) than follicular levels. Five patients had levels> 65 IV jml during the menses. When the same group was examined in the late follicular phase, none of the patients had levels> 65 IV jml. Other benign ovarian lesions presented serum CA-5 levels> 35 IVjmL in 9 patients (9.64%). In our series of 70 patients with ovarian malignancy, serum CA-5 levels were elevated in 6 patients (88.57%). Recently, there were several multicentric studies on the successful use of transvaginal color and pulsed Doppler in the early detection of ovarian ma- ignancy (4, 3, 4). The most common cause of false-positive results has been found in the ovarian endometriomata group. It seems that our new scoring system for reliable detection of endometriomas potentially can reduce the number of false positives in screening programs for ovarian malignancy. Transvaginal color Doppler is a promising noninvasive method to highlight women who might have endometriosis. It is hoped that combined scoring systems that use both transvaginal ultrasound color flow Doppler as an imaging technique and the CA-5 level can stand in place of laparoscopy in obvious cases. Study of the vascularity seems to be the guideline for the management of patients suffering from endometriosis. Reliable blood flow analysis of the endometriotic implant has the overwhelming advantage, after which the effective treatment can be instituted. The success of medical treatment is dependent upon delivering metabolically active products via an endometrioma blood supply. Surrounding inflammation and scarification processes change delivery ofthe medication. In avascular lesions, surgical therapy should be recommended. Transvaginal color Doppler already has proved to be a method of choice for analysis of regional blood flow in patients with adnexal masses (4) and is complementary to laparoscopy. These two most exciting developments in the field of gynecology in recent years might change the approach and can help the clinician to determine the best treatment options available to patients suffering from endometriosis. REFERENCES. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenic implications of anatomic distribution. Obstet Gynecol 986;67: Brosens IA. Classification of endometriosis revisited. Lancet 993;34: Kupfer MC, Schwimer RS, Lebovic J. Transvaginal sonographic appearance of endometriomata: spectrum of findings. J Ultrasound Med 99;: Kurjak A, Shalan H, Kupesic S, Predanic M, Zalud I, Breyer B, et al. Transvaginal color Doppler sonography in the assessment of pelvic tumor vascularity. Ultrasound Obstet GynecoI993;3: Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 9;3: Wheeler JM. Epidemiology of endometriosis-associated infertility. J Reprod Med 989;34: Pauerstein CJ. Clinical presentation and diagnosis. In: Schenken RS, editor. Contemporary concepts in clinical management. Philadelphia: Lippincott, 989: Scott RB, Te Linde RW. External endometriosis: the scourge of the private patient. Ann Surg 950;3: Houston DE, Noller RL, Melton LJ, Selvin BJ. Incidence of pelvic endometriosis in Rochester, Minnesota. Am J EpidemioI987;5: Sandler MA, Karo JJ. The spectrum of ultrasonic findings in endometriosis. Radiology 978;7:9-3.. Coleman BG, Arger PH, Mulhern CB. Endometriosis: clinical and ultrasonic correlation. Am J Radiol 979;3: Vol. 6, No., July 994 Kurjak and Kupesic Scoring system for ovarian endometriosis 87

8 r. Athey A, Diment DD. The spectrum of sonographic findings in endometriosis. J Ultrasound Med 989;8: Goldman SM, Minkin SI. Diagnosing endometriosis with ultrasound: accuracy and specificity. J Reprod Med 980;5: Friedman H, Vogelzang RL, Mendelsohn EB. Endometriosis detection by ultrasound with laparoscopic correlation. Radiology 985;57: Oosterlynck DJ, Meuleman C, Sobis H, Vandeputte M, Koninckx PRo Angiogenic activity of peritoneal fluid from women with endometriosis. Fertil Steril 993;59: Metzger DA, Szpak CA, Haney AF. Histologic features associated with hormonal responsiveness of ectopic endometrium. Fertil Steril 993;59: Fleischer AC, Cullinan JA, Williams LL, Kepple DM, Peery CV. Color Doppler sonography of benign pelvic masses: the spectrum of findings. In: Kurjak A, editor. An atlas oftransvaginal color Doppler. London: Parthenon Publishing, 994: Malinak LR, Wheeler JM. Combination medical-surgical therapy for endometriosis. In: Shaw RE, editor. Endometriosis. London Lanes: Parthenon Publishing, 990: Bast RC Jr, Klug TL, St John E. A radioimmunoassay using monoclonal antibody to monitor course of epithelial ovarian cancer. N Engl J Med 983;309: O'Shaughnessy A, Check JH, Nowroozi K, Lurie D. CA 5 levels measured in different phases ofthe menstrual cycle in screening for endometriosis. Obstet Gynecol 993;8: McBean JH, Brumstead JR. In vitro CA 5 secretion by endometrium from women with advanced endometriosis. Fertil Steril 993;59: Jager W, Meier C, Wildt L, Sauerbrei W, Lang N. CA-5 serum concentrations during the menstrual cycle. Fertil Steril988;50: Campbell S, Bourne TH, Reynolds K, Hampson J, Royston P, Whitehead MI, et al. Role of colour Doppler in an ultrasound based screening programme. In: Sharp F, Mason WP, Creasman W, editors. Ovarian cancer. Biology, diagnosis and management. London: Chapman and Hall Medical, 99: Kurjak A, Predanic M. New scoring system for prediction of ovarian malignancy based on transvaginal color Doppler sonography. J Ultrasound Med 99;: Kurjak and Kupesic Scoring system for ovarian endometriosis Fertility and Sterility