GYNECOLOGIC ONCOLOGY 68, 256 262 (1998) ARTICLE NO. GO984947 A Multivariate Logistic Regressio Aalysis i Predictig Maligacy for Patiets with Ovaria Tumors Kohkichi Hata, M.D., Ph.D.,*,1 Sumiori Akiba, M.D., Ph.D., Toshiyuki Hata, M.D., Ph.D.,* ad Kohji Miyazaki, M.D., Ph.D.* *Departmet of Obstetrics ad Gyecology, Shimae Medical Uiversity, Izumo 693, Japa; ad Departmet of Public Health, Faculty of Medicie, Kagoshima Uiversity, Kagoshima 890, Japa Received August 25, 1997 Objective. Our objective was to improve the preoperative diagosis of ovaria maligacy usig a multivariate logistic regressio aalysis o the basis of demographic, serologic, gray-scale morphological, ad Doppler variables. Methods. Oe hudred sevety-oe patiets with ovaria tumors (120 beig, 51 maligat icludig 9 tumors of low maligat potetial) were studied with trasvagial B-mode, color, ad pulsed Doppler ultrasoography before surgery. Based o the gray-scale ultrasoud imagig, each tumor was classified as a uilocular cyst, multilocular cyst, uilocular cyst with solid parts, multilocular cyst with solid parts, or solid tumor. Itratumoral blood flow velocity waveforms were recorded o all tumors except uilocular cyst ad were evaluated for resistace idex (RI) ad peak systolic velocity (PSV). Serum CA 125 levels were also measured. Results. Twety tumors were uilocular cysts ad were all beig. Sevety tumors icludig all uilocular cysts which showed o flows were all beig. The remaiig 101 tumors (50 beig, 51 maligat icludig 9 tumors of low maligat potetial) preseted itratumoral blood flows. Uivariate ad multivariate logistic regressio aalyses were coducted to idetify variables predictive of ovaria maligacy i these 101 tumors. The variables icluded age, mestrual state, serum CA 125 levels, B-mode classificatio, RI, ad PSV. I uivariate aalysis, meopause, the positivity of CA 125 (>35 U/ml), ad PSV larger tha or equal to 10.4 cm/s were foud to be sigificatly associated with maligat tumors. The PSV value of 10.4 cm/s was the media i beig tumors. Multivariate aalysis showed that serum CA 125 levels (>35 U/ml) (P 0.002) ad PSV (>10.4 cm/s) (P < 0.001) were to be idepedet predictors of maligacy. Coclusio. These results suggest that itratumoral PSV is the strogest meas of differetiatig beig from maligat ovaria tumors with suspicious gray-scale ultrasoographic fidigs. 1998 Academic Press 1 To whom correspodece ad reprit requests should be addressed. Fax: 81-853-21-7443 (from April 1, 1998, 81-853-20-2264). E-mail: hata31@shimae-med.ac.jp. INTRODUCTION Ovaria lesios are of particular importace i gyecological practice owig to their maligat potetial ad the limited ability to differetiate prior to surgery betwee beig ad maligacy [1]. Modalities that have bee reported to be useful i preoperative predictio of ovaria maligacy iclude computed tomography, magetic resoace imagig [2, 3], grayscale ultrasoography [1, 4], ad serum tumor marker levels [5]. The most recet ad excitig evet is color ad pulsed Doppler spectrum aalysis [6 13]. The itroductio of trasvagial color Doppler imagig has facilitated the research i ovaria maligacy. The iitial experiece suggested that idices (resistace idex [RI] ad pulsatility idex [PI]) of blood flow impedace withi the tumor could be used to improve the predictive value of pelvic ultrasoography [6, 7]. However, the reports poited out that the overlap of the RI ad PI has eroded the validity of trasvagial color Doppler study [8, 9]. The low impedace waveforms, i.e., low RI ad PI, with low peak systolic velocity (PSV) ca ow be detected from a sigificat umber of ormal ovaries [10, 11] ad beig ovaria tumors [10, 11]. It is cosidered that low impedace flow is ot a specific fidig for ovaria cacer ad vessels withi ormal ad/or beig tissues origiated from preexistig host vasculature ofte show the same flow as see i maligat tumor [12]. Recetly, some studies have ivolved the measuremet of PSV ad the results have bee ecouragig [12, 13]. However, a sigificat predictor of preoperative maligacy which is objectively accepted has ot bee reported i a cliical settig. If a statistical model that accurately predicts the probability of maligacy i the patiets with ovaria tumors o the basis of simple cliical ad ultrasoographic variables is available, it would be importat for patiet couselig, selectig the optimal operative approach, icisio type, ad operative procedure. I this study, we coducted logistic aalysis usig serologic, gray-scale morphological ad Doppler variables i order to idetify the factors that ca predict maligacy prior to operatio. Herei we preset the results. 0090-8258/98 $25.00 Copyright 1998 by Academic Press All rights of reproductio i ay form reserved. 256
PREDICTION OF OVARIAN MALIGNANCY 257 TABLE 1 Histological Diagosis ad Presece of Itratumoral Flow i Beig Ovaria Tumors Histological diagosis Subjects Positive MATERIALS AND METHODS Itratumoral flow Negative Serous cystadeoma 22 7 15 Mucious cystadeoma 19 15 4 Fibroma 5 4 1 Cystic teratoma 38 9 29 Struma ovarii 2 1 1 Edometrioma 31 13 18 Corpus luteal cyst 3 1 2 Oe hudred sevety-oe wome who were electively admitted to the Shimae Medical Uiversity Hospital for operative ivestigatio of kow adexal masses ad were histologically prove to be ovaria tumors were recruited ito this study. Asymptomatic wome with a positive result from a ovaria cacer screeig program were excluded. The age rage of the patiets was from 11 to 82 years (mea, 48.2 years); 71 of the patiets were postmeopausal. Wome were cosidered postmeopausal if more tha 6 moths had elapsed sice the last mestrual period. Classificatio of histologic fidigs was made accordig to the recommeded criteria of the World Health Orgaizatio. The patiets siged a coset form as approved through the Research Ethics Committee of the Shimae Medical Uiversity Hospital. Scaig Procedures Soography was performed with a commercially available scaer, Aloka SSD-680 or Aloka SSD-2000 (Aloka Co., Ltd., Tokyo, Japa), equipped with a 5.0-MHz trasvagial trasducer (imagig, color Doppler, ad pulsed Doppler frequecies were all 5.0 MHz). Patiets who had a large tumor uderwet trasabdomial scaig with a 3.5-MHz trasducer (imagig, color Doppler, ad pulsed Doppler frequecies were all 3.5 MHz). Color ad pulsed Doppler parameters, icludig preprocessig ad postprocessig values, persistece, filter, gate width, gai, ad velocity scale, were optimized for detectio of slow flow. The spatial peak temporal average itesity at the maximum amplitude ad miimum gate width i simultaeous color ad pulsed Doppler mode was less tha 80 mw/cm 2, accordig to the maufacturer s specificatios. The preparatio of the vagial probe for trasvagial soography has bee described i the previous ivestigatio [9]. All the wome uderwet soographic examiatio withi 2 days before exploratory surgery. Each tumor was iitially classified based o the criteria reported by Valeti et al. [14]: (1) a uilocular cyst (UC) (a uilocular cyst without septa ad without solid parts or papillary excresceces), (2) a multilocular cyst (MC) (a cyst with at least oe septum but o solid parts or papillary excresceces), (3) a uilocular solid cyst (USC) (a uilocular cyst cotaiig solid parts or papillary excresceces but o septa), (4) a multilocular solid tumor (MST) (a tumor with at least oe septum ad solid parts or papillary excresceces), or (5) a solid tumor (ST) (a tumor with solid compoets i 80% or more of the tumor). Trasvagial color Doppler flow imagig was carried out to idetify itratumoral blood flow o all tumors except for a uilocular cyst. O the color Doppler flow imagig, the sample poit o the lie of pulsed Doppler beam was positioed at the regio of iterest, where the color dots were oted, ad blood flow velocity waveforms with maximum amplitude ad frequecy shift were recorded. Agle correctio was ot used because i most cases a large eough portio of vessels was ot visualized. RI (the ratio of the differece betwee peak systolic frequecy ad ed diastolic frequecy to peak systolic frequecy) ad PSV were calculated as the esemble average value obtaied from five cosecutive reproducible waveforms. This averaged value is reliable ad is also resistat to outlyig poits which ievitably appear i cliical data [15]. Sigals arisig from blood flow withi the tumor i each patiet were recorded ad blood velocity waveforms with the lowest RI value were used for data aalysis. The Doppler examiatios were coducted o days 5 7 durig the mestrual cycle for premeopausal patiets to avoid the effect of ovulatio ad the presece of the corpus luteum [16]. The itraobserver coefficiet of variatio for the measuremet of PSV ad RI was 5.4 ad 5.6%, respectively. Iterobserver differeces amog three examiig doctors were 11.3 ad 11.6% for PSV ad RI, respectively [12]. Tumor Marker Examiatio Blood samples were collected from all the patiets to measure serum levels of CA 125 with a radioimmuoassay kit TABLE 2 Histological Diagosis i Ovaria Cacers Histological diagosis Low maligat potetial Mucious cystadeoma 4 Graulosa cell tumor 5 Maligat Serous cystadeocarcioma 14 Mucious cystadeocarcioma 8 Edometrioid adeocarcioma 8 Clear cell carcioma 3 Maligat Breer tumor 2 Yolk sac tumor 2 Mixed mesodermal tumor 1 Metastatic tumor 4 N
258 HATA ET AL. FIG. 1. Represetative images of trasvagial Doppler sograms i ovaria tumors. (A) Mucious cystadeoma. (B) Mucious cystadeocarcioma, Stage Ia. (C) Edometrioid adeocarcioma, Stage IIIc. (Cetocor, Tokyo, Japa). A CA 125 level greater tha or equal to 35 U/mL was cosidered abormal. Statistical Aalysis A 2 test was used as appropriate for the evaluatio of sigificat differeces betwee edpoits. Uivariate ad multivariate logistic aalyses were coducted. Maximum likelihood parameter estimates of odds ratios were obtaied usig a statistical package, EPICURE [17]. We calculated Wald-type cofidece itervals. All P values preseted were two-sided. RESULTS There were 120 wome with beig ovaria tumors, 9 with tumors of low maligat potetial, 38 with primary ovaria cacers, ad 4 with metastatic ovaria cacers. The mea age of the patiets with beig tumors was 46.0 years (SD, 14.8) compared to 54.5 years (SD, 16.6) for those with maligat tumors. The histological classificatio is show i Tables 1 ad 2. Of the 38 primary maligat cases, 11 were stage I, 6 were stage II, 15 were stage III, ad 6 were stage IV. The 9 tumors of low maligat potetial were all stage I. Neoplasms cosidered as tumors of low maligat potetial were icluded i the maligat group. Twety tumors were uilocular cysts ad were all beig. Sevety tumors icludig all uilocular cysts which showed o flows were all beig. The remaiig 101 tumors (50 beig, 51 maligat) preseted itratumoral blood flows. Represetative images of trasvagial Doppler ultrasoograms are show i Fig. 1 I maligat tumors, o sigificat differece was foud amog the RI ad PSV values for each stage icludig metastatic cacer (Table 3). We examied the possibility of makig preoperative diagosis of maligacies usig serologic, gray-scale morphologic, ad Doppler variables. Sevety tumors without itratumoral blood flow were excluded from our aalysis. Figure 2 shows the scattered plot of PSV ad RI for the 50 beig ad 51 maligat tumors with itratumoral blood flow. PSV distributio i beig tumors overlapped with the lower half rage of PSV i maligat tumors. Table 4 shows the result of uivariate ad multivariate logistic aalysis. I uivariate aalysis, meopause, the positivity of CA 125 ( 35 U/ml), ad PSV larger tha or equal to 10.4 cm/sec were foud to be sigificatly associated with maligat tumors. The PSV value of 10.4 cm/s was the media i beig tumors. I multivariate aalysis, serum CA 125 levels ( 35 U/ml) (P 0.002) ad PSV ( 10.4 cm/s) (P 0.001) were foud to be idepedet predictor of maligacy. Table 5 shows the results of B-mode classificatio i the tumors with itratumoral blood flow. There was o sigificat differece betwee the proportio of MC or USC i beig
PREDICTION OF OVARIAN MALIGNANCY 259 FIG. 1 Cotiued
260 HATA ET AL. TABLE 3 Stagig ad Results of Doppler Blood Flow Aalysis i Ovaria Cacers Icludig Metastatic Tumors Resistace idex Peak systolic velocity (cm/s) Stage Mea SD Media Mea SD Media I 20 0.464 0.085 0.442 28.3 18.9 24.5 II 6 0.53 0.079 0.545 36.4 14 31.3 III 15 0.566 0.133 0.542 34.8 15.7 30.2 IV 6 0.477 0.133 0.496 26.8 6.7 26.9 Metastatic tumor 4 0.477 0.056 0.487 29.4 14.4 25.9 ovaria tumors (15/50, 30%) ad the proportio i stage I ovaria cacer (7/20, 35%) (P 0.68). The proportio i stages II IV (3/27, 11.1%) was sigificatly lower tha that i stage I (P 0.048) (Table 5). The proportio of positive serum CA 125 levels i beig ovaria tumor (12/50, 24%) did ot sigificatly differ from the proportio i stage I (7/20, 35%) (P 0.36). The proportio i stages II IV (23/27, 85.2%) was sigificatly higher tha that i stage I (P 0.0003) (Table 6). DISCUSSION Doppler blood flow aalysis has bee applied to differetiate beig from maligat ovaria tumors. It has maily bee a sigle idex such as the RI, PI, or PSV that has bee used as a idicator of the risk of maligacy by calculatig the diagostic idices. It would be uwise to coclude that the patiet has a high probability of maligacy simply o the basis of low RI or PI, or high PSV [6, 7, 12, 13]. I practice, most physicias use a combiatio of pelvic examiatio, tumor marker assessmet [5], ad gray-scale ultrasoud characteristics [1, 4] to make a preoperative diagosis of ovaria cacer. The other characteristics described above eed to be take ito cosideratio ad by doig so the risk of maligacy for the combiatio of several variables may ot be very high FIG. 2. The scattered plot of peak systolic velocity ad resistace idex (ope circle, beig tumor; closed circle, maligat tumor). compared to that based oly o a sigle idex derived from blood flow waveforms. Therefore, we have used multivariate logistic regressio aalysis o the basis of demographic, serologic, gray-scale morphological, ad Doppler variables to predict the probability of maligacy i this study. We did ot iclude tumor volume measured by gray-scale ultrasoography. The reasos are as follows. All UCs were beig irrespective of tumor volume, ad all maligat tumors had itratumoral architecture (e.g., MC, UST, MST, or ST) regardless of tumor volume i our study. Tumor volume was less meaigful because its compoets seemed to correlate better with maligat potetial. Moreover, asymptomatic wome with a positive result from a ovaria cacer screeig program were excluded from the subjects. I ovaria cacer screeig, tumor volume is the importat edpoit equal to itraovaria appearace to detect early ovaria cacer [18]. The process of agiogeesis i tumors begis whe a coloy of cells expads to a size where the simple diffusio of utriets (ad waste) is isufficiet [19]. A growig tumor, where cells are stimulatig the productio of ew capillary sprouts, appears aalogous to a orga i the embryo. The aalogy is ot valid, however, because tumors cotiue to alter their itrisic vasculature i a way that ormal orgas do ot. The abormal processes are iduced by agiogeic factors oe of which has bee isolated from tumor cells [20]. The relatioship betwee tumor agiogeesis ad Doppler fidigs i ovaria cacer has bee speculative. Reyolds et al. [21] first testified this hypothesis. Thymidie phosphorylase (TP) is a ezyme which catalyzes two reactios: (i) the reversible phosphorylatio of thymidie ad other 2 -deoxyribosides ad (ii) deoxyribosyl trasfer betwee pyrimidies. Overexpressio of the ezyme has bee associated with the developmet of various cacers [22]. The structure of huma TP is idetical to that of plateletderived edothelial cell growth factor (PD-ECGF) which has marked agiogeic activity [23]. Reyolds et al. [21] reported that the expressio of mrna for TP (PD-ECGF) has bee show to be sigificatly elevated i ovaria tissues (corpora lutea, beig ad maligat tumors) with high blood velocity as determied by color Doppler imagig before surgery. We also have show previously that there is a positive correlatio
PREDICTION OF OVARIAN MALIGNANCY 261 TABLE 4 The Results of Uivariate ad Multivariate Logistic Aalysis i the Ovaria Tumor with Itratumoral Blood Flow Uivariate Multivariate Parameter Beig Maligat Odds ratio 95% cofidece iterval P value Odds ratio 95% cofidece iterval P value Meopause No 31 20 Referet Referet Yes 19 31 2.5 1.1 5.6 0.022 1.4 0.3 8.2 0.676 CA 125 35 U/ml 38 20 Referet Referet 35 U/ml 12 31 4.9 2.1 11.6 0.001 5.4 1.7 17.0 0.002 B-mode ultrasoography MC 5 3 Referet Referet USC, MST, ST 45 48 1.8 0.4 7.9 0.442 0.7 0.1 4.4 0.704 Resistace idex 0.544 25 33 Referet Referet 0.544 25 18 0.5 0.2 1.2 0.134 0.4 0.1 1.2 0.1 Peak systolic velocity 10.4 cm/s 25 2 Referet Referet 10.4 cm/s 25 49 24.5 5.4 111.9 0.001 18.4 3.5 96.7 0.001 Note. The odds ratio ad 95% cofidece iterval were obtaied from logistic models adjustig for age. MC, multilocular cyst; USC, uilocular solid cyst; MST, multilocular solid tumor; ST, solid tumor. betwee the cocetratio of TP (expressed as uits/mg protei) i homogeates of beig ad maligat ovaria masses ad the itratumoral PSV recorded immediately before surgery [24]. Therefore, we ca ow detect agiogeesis which could be a eoplastic marker for a tumor by trasvagial color Doppler. I this ivestigatio, multivariate logistic regressio aalysis revealed that PSV is the strogest predictor of ovaria maligacy. We arbitrarily set the cutoff value of PSV at 10.4 cm/s (the media i beig tumors). The fixed value is useful i presetig the results of statistical aalysis i a succict maer, but i cliical situatios there is ot likely to be such a sharp cutoff poit. No sigificat differece was foud amog the PSV values for each stage icludig metastatic cacer. TABLE 5 Results of B-Mode Classificatio i the Tumors with Itratumoral Blood Flow B-mode classificatio MC USC MST ST Beig ovaria tumor ( 50) 5 10 28 7 Ovaria cacer Stage I ( 20) 3 4 12 1 Stage II ( 6) 0 0 5 1 Stage III ( 15) 0 3 3 9 Stage IV ( 6) 0 0 2 4 Note. MC, multilocular cyst; USC, uilocular solid cyst; MST, multilocular solid tumor; ST, solid tumor. There was o sigificat differece betwee the proportio of MC or USC i beig ovaria tumor ad the proportio i stage I ovaria cacer. The proportio i stages II IV was sigificatly lower tha that i stage I. Moreover, the proportio of positive serum CA 125 levels showed the same results as see i morphologic classificatio. The detectio ad assessmet of ovaria lesios is a importat part of gyecologic practice. I particular, there is good evidece for the eed to detect ad treat maligat disease before the capsule has ruptured (i.e., at FIGO stage I) [25]. PSV seems to be sesitive for detectig early evet (agiogeesis) occurrig i the early stage of ovaria cacer which other diagostic modalities caot do. It is temptig to speculate that false-positive results might have arise from beig tumors with partially trasformed cells. TABLE 6 Results of CA 125 Evaluatio i the Tumors with Itratumoral Blood Blow 35 U/ml CA 125 35 U/ml Beig ovaria tumor ( 50) 38 12 Ovaria cacer Stage I ( 20) 13 7 Stage II ( 6) 1 5 Stage III ( 15) 3 12 Stage IV ( 6) 0 6
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