Magnetic resonance imaging and serum CA-125 in evaluating patients with endometriomas prior to medical therapy

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1 FERTILITY AND STERILITY Vl. 65, N.2, February 1996 Cpyright 1996 American Sciety fr Reprductive Medicine Printed n acid-free paper in U. S. A. Magnetic resnance imaging and serum CA-125 in evaluating patients with endmetrimas prir t medical therapy Kentar Takahashi, M.D., Ph.D.*t Sari Okada, M.D. * Masak Okada, M.D. * Manabu Kita, M.D., Ph.D.* Yasushi Kaji, M.D.:!: Kazur Sugimura, M.D., Ph.D.:!: Shimane Medical University, lzum, Japan Objective: T determine whether magnetic resnance imaging (MRI) and serum levels f CA- 125 can be used t evaluate patients with endmetrimas befre initiating medical treatment. Design: Cmparative study befre and after medical treatment. Setting: Shimane Medical University Hspital, Izum, Japan. Patients: Eleven cnsecutive patients with at least ne endmetrima> 1 mm in maximal diameter that was diagnsed by laparscpy and treated with 9 J-lg/d buserelin acetate fr 6 mnths. Interventins: Magnetic resnance imaging and bld sampling was perfrmed <2 weeks befre laparscpy. Main Outcme Measures: Signal intensity f endmetrima/signal intensity f gluteus maximum muscle n T2-weighted image (T2SI:MSI); vlume f endmetrima and serum CA-125. Results: There was a psitive linear crrelatin (r =.77) between T2SI:MSI befre treatment and the extent f decrease in the vlume f endmetrima. There was a negative linear relatinship between serum CA-125 befre treatment and the mean extent f decrease in the cyst vlume (r =.67). The reductin in vlume f endmetrima and T2SI:MSI befre treatment related t the utcme f patients. Cnclusin: The T2SI:MSI n MRI and serum CA-125 may be useful fr estimating the utcme f patients with endmetrimas befre initiating medical treatment. Fertil Steril 1996;65:2-92 Key Wrds: Endmetrima, magnetic resnance imaging, signal intensity, serum CA-125, medical treatment T assess the respnse f patients with advanced endmetrisis wh are receiving medical therapy ften is necessary. Althugh laparscpy remains the best methd, it is invasive and cstly and the status f the endmetrisis cannt be evaluated repeatedly. It has been reprted that the determinatin f the serum levels f CA-125 levels may be useful in the evaluatin and treatment f patients with endmetrisis (1-6). Several reprts have shwn magnetic resnance imaging (MRI) t be useful fr diagnsing Received March 2, 1995; revised and accepted July 29, * Department f Obstetrics and Gyneclgy. Reprint requests: Kentar Takahashi, M.D., Ph.D., Department f Obstetrics and Gyneclgy, Shimane Medical University, 9-1, Enya-ch, Izum 693, Japan (FAX: ). t Department f Radilgy. endmetrisis (7-1). We previusly fund that the MRI T2 relaxatin time reflects the irn cncentratin f the endmetrima, suggesting that the MRI T2 signal intensity may be useful fr estimating the fluid characteristics in the endmetrimas (unpublished data). In the present study, we assessed the usefulness fmri and serum CA-125, bth f which are nninvasive methds fr evaluating endmetrisis, t estimate the prgnsis f patients with endmetrima befre initiating medical treatment. MATERIALS AND METHODS Bld samples 'and MRI were btained befre and after treatment frm 11 Japanese wmen with endmetrisis, aged 23 t 3 years (mean, 29 years). Endmetrisis was diagnsed by laparscpy and 2 Takahashi et al. MR imaging and serum CA-125 in endmetrimas Fertility and Sterility

2 staged accrding t the 195 revised American Fertility Sciety (AFS) classificatin (11). Of 11 patients, 3 had stage III, and had stage IV endmetrisis. All patients had at least ne endmetrima> 1 mm in maximal diameter. Fur patients had ne cyst nly, five had tw cysts, ne had three cysts, and ne had fur cysts. Evaluatin was fllwed by a 6- mnth curse f 9 jlg/d buserelin acetate (Suprecur; Hechst, Tky, Japan). Bld samples, including thse btained after treatment, were btained n the day f MRI and during the late fllicular phase. Pst-treatment samples were btained within 2 mnths f treatment. Mter the bld was allwed t clt, it was centrifuged at 3, rpm fr 15 minutes and the serum was separated. Serum was stred at -3 C. The CA- 125 assay used was a simultaneus sandwich slidphase RIA system (Centcr, Inc., Malvern, PA). Surgery was perfrmed within 2 weeks fmri and befre the next menstrual perid. Magnetic resnance imaging was perfrmed with a 1.5-T supercnducting unit (Signa; GE Medical Systems, Milwaukee, WI). In all examinatins we used a spin-ech, multisecin imaging technique that was reprted previusly (1). T1-weighted (spin-ech [SE] 6/15 ms [repetitin timelech time]), prtn-density (2,2/15 ms), T2-weighted (2,2/ ms), and fatsaturated T1-weighted (6/15 ms) axial images were btained fr all patients. Data acquisitin was perfrmed twice; the field f view was 32 X 32 cm, and the thickness f the slice was 6 mm with a 2- mm interslice gap. A 256 X 256 matrix was used fr the T1-weighted and fat-saturated T1-weighted images. A 256 X 192 matrix was used in T2-weighted imaging. Inferir and superir saturatin pulses were applied. We measured endmetrimas >1 mm in maximal diameter in each patient. A calculated T2 image was btained with the T2-weighted image and the prtn-density image. We designated a regin f interest n the T2-weighted images cvering the endmetrima as widely as pssible. A regin f interest exceeding 1 pixels was drawn in the gluteus maximus. We designated the same regin f interest in the endmetrima n the calculated images. The signal intensity n each cnventinal image was measured three times and the T2-value n each calculated image three times. The mean value was calculated. We btained the T2-value and the signal intensity n the T2-weighted image (T2SI) f each endmetrima. T nrmalize the T2S1 amng subjects, we calculated the signal intensity f the endmetrima/signal intensity f the gluteus maximus n the T2-weighted image (T2SI:MSI). Fat-saturated T1-weighed imaging was used t measure the vlume f the endmetrima. The area f endmetrima n each image was measured by using a micrcmputer with a digitizer (NEC PC- 1 mkii; NEC Inc., Tky, Japan). The vlume f the clumn was calculated by using the frmula: vlume = A X (D 1 + D2); where A, D 1, and D2 are the area, slice thickness (6 mm), and interslice gap (2 mm), respectively. The vlume f endmetrima was calculated by adding the vlume f the clumn n each image. The MR images were read prspectively by tw f the authrs (Y.K., K.S.) with knwledge f nly the name f the disease. They specifically recrded the lesin lcatin, the lesin size, and the appearance fthe lesins (i.e., hmgeneity and signal intensity f each lesin cmpared with that f adjacent adipse tissue and striated muscle). Agreement between the tw bservers was reached in cnference after the careful assessment f serial images. Bth magnetic resnance images befre and after treatment were read separately and blindly. The data were analyzed with the Wilcxn matched-pairs signed-ranks test. RESULTS The pretreatment serum levels fca-125 and the pints f revised AFS classificatin ranged frm 29 t 92 IU/mL and frm 26 t 14 pints, respectively. In accrdance with ur previus reprt, a value f 39 IU/mL was used as the upper limit f nrmal (4). The pretreatment serum CA-125 levels were abve nrmal in 7 f 11 patients with endmetrisis (63.6%; 1 in stage III and 6 in stage IV). The mean ± SD value f psttreatment serum CA-125 level (23.5 ± 25.9 IU/mL) was significantly (P <.1) lwer than that befre treatment (46.4 ± 1. lui ml). Similarly, the mean ± SD value f pst-treatment pint f the revised AFS classificatin (7.5 ± 44.9 pints) was significantly (P <.1) lwer than that befre treatment (5.3 ± 49.1 pints). There was n significant crrelatin between the serum levels f CA-125 and the pints f revised AFS classificatin either befre r after treatment. Similarly, there was n significant crrelatin between the ttal vlume f endmetrima and the serum CA-125 level either befre r after treatment and between the ttal vlume f endmetrima and the pint f revised AFS classificatin either befre r after treatment. There was n significant crrelatin between the vlume f endmetrima and each value f T2-weighted imaging btained either befre r after treatment. Pretreatment, the maximal cyst vlume was ml whereas the minimal cyst vlume was 1. ml. Vl. 65, N.2, February 1996 Takahashi et al. MR imaging and serum CA-125 in endmetrimas 29

3 3 ;J' 5 '-" c '.5 Q) = Q) Q) ::2 2 - :> 1 1 I'V Pretreatment Psttreatment Figure 1 Changes in vlume f endmetrimas befre and after treatment. The ttal vlume f the endmetrima in each patient ranged frm 7.9 t ml. The vlume f the endmetrima significantly (P <.1) decreased after treatment (Fig. 1). The extent f decrease ranged widely, frm 1.6% t 99.%. Cncerning the extent f decrease in vlume f endmetrima, there was n significant crrelatin between the T2-value and T2SI fr the endmetrima btained by MRI befre treatment and the extent f decrease in vlume f endmetrima. Hwever, the T2SI:MSI befre treatment related t the extent f decrease in vlume f endmetrima. Thirteen f 14 endmetrimas with T2SI:MSI >5. befre treatment had the reductin >5% in size f endmetrima. Only ne f seven endmetrimas with T2SI:MSI <5. befre treatment had a decrease f >5% f cyst vlume. There was a psitive linear crrelatin (n = 11, r =.77, P <.5) between the T2SI:MSI befre treatment and the extent f decrease in vlume f the largest endmetrima (Fig. 2). Similarly, there was a negative linear relatinship between the serum levels fca-125 befre treatment and the mean extent f decrease in vlume f endmetrima (n = 11, r =.672, P <.5; Fig. 3)... 1 E ".. = t..., : y= ,,.2=.62 r.l Value r TlSIIMSI Figure 2 Crrelatin between T2SI:MSI befre treatment and the extent f decrease in the largest vlume f endmetrimas. Fur patients had clinical recurrence with pelvic pain and tw patients cnceived spntaneusly within 6 mnths after discntinuatin f treatment. The remaining five are being fllwed still and the prgnsis is gd at 6 mnths after discntinuatin f treatment. The serum CA-125 level and the revised AFS befre treatment did nt relate t final utcme in patients with endmetrima after treatment. Hwever, the reductin in size f endmetrima and value ft2si:msi befre treatment exceedingly related t final utcme. Three f fur patients with recurrence sign had lw value f mean extent f decrease in vlume f the endmetrima «5%) and six f seven patients with gd prgnsis had a mean extent f decrease f >5% f cyst vlume. All seven patients with gd prgnsis had T2SI:MSI >5. in the largest endmetrima befre treatment. On the cntrary, three f fur patients with recurrence had T2SI:MSI <5.. Therefre, the sensitivity, specificity, psitive predictive value, and negative predictive value fr effective therapy f endmetri- 1 9 ';; i ,... " y = ,,.2 = Serum CA 125 (lulml) Figure 3 Crrelatin between serum levels f CA 125 befre treatment and the extent f decrease in vlume f endmetrimas. 29 Takahashi et al. MR imaging and serum CA 125 in endmetrimas Fertility and Sterility

4 mas using 5. f T2SI:MSI were 1%, 75%, %, and 1%, respectively. DISCUSSION An endmetrima is frmed by repeated hemrrhage and is thus a retentin cyst. The cyst fluid can cntain a varying amunt f hemglbin. The fluid cntent als can change as the cyst prgresses. The cncentratin f irn can increase expnentially and the viscsity f the fluid can rise. The present study fcused n the cntent f the endmetrima in that a change in its cntent might crrelate with the age fthe endmetrima. In ur previus study (unpublished data), the irn cncentratin and the three values f T2-weighted imaging (T2-value, T2SI, and T2SI:MSI) were crrelated negatively. In particular, the crrelatin between the cncentratin f irn and the T2SI:MSI was clse (r =.74, P <.1). A crrespnding decrease in T2SI:MSI was bserved as the cncentratin f irn, and the viscsity f the cyst fluid increased. Cncerning the relatinship between irn cncentratin and magnetic resnance relaxatin time, previus reprts have shwn that the cncentratin f methemglbin and free Fe 3 + ins in an intracranial hematma are related t the T2-value whereas the hematcrit is related t the Tl-value (12, 13); the Tl-value and the cncentratin f irn in the endmetrima were crrelated negatively (14). In the present study, we investigated the clinical applicatins f MRI by measuring the values f T2-weighted imaging (T2-value, T2SI, and T2SI:MSI) as nninvasive markers and fund that T2SI:MSI was related t the extent f decrease in vlume f the endmetrima. As the value f T2SI:MSI increased-r as the cncentratin f irn in the cyst fluid decreased-the extent f decrease in vlume f the endmetrima tended t increase, as the T2S1 value and the irn cncentratin in cyst fluid shw a strng negative crrelatin (unpublished data). Thus, medical treatment may be mre effective fr treating patients with lw cncentratin f irn rather than high cncentratin f irn in endmetrimas. We als fund that the reductin in size f endmetrima and T2SI:MSI befre treatment exceedingly related t final utcme. Althugh the magnetic resnance criteria fr assessment f medical therapy in patients with endmetrimas must be evaluated further in a prspective study including a large series f patients, T2SI:MSI >5. befre treatment may be able t expect a decrease f >5% f cyst vlume and gd prgnsis after medical treatment. Cncerning the serum levels f CA-125 as an anther nninvasive marker, the mean extent f decrease in vlume f the endmetrimas tended t decrease after treatment as the serum CA-125 levels increased befre treatment. The serum levels f CA- 125 were greater than nrmal in 7 f 11 patients with endmetrisis because the subjects studied had disease in stages III and IV. This finding supprts the view that endmetrisis shuld be cnsidered as a cause f an increase in serum levels f CA-125. Althugh it is difficult t interpret this finding, we refer t inflammatin thery f Barbieri (15), which states that the inflammatin assciated with endmetrisis may increase the rate at which CA-125 is shed frm the cell membranes f endmetritic lesins, leading t an increase in CA-125 in the bdy fluids (i.e., the leaky capillary endmetrium). We cannt explain the relatinship between the serum level f CA-125 and the value n MRI. Hwever, as an "ld" endmetrima shwed a minimal decrease in vlume, the inflammatin in case f advanced endmetrisis with ld endmetrimas wuld increase, thus leading t an elevated serum level f CA-125. In cnclusin, T2SI:MSI n MRI and serum CA- 125 levels befre treatment reflected the extent f decrease in the vlume f the endmetrima, which is useful infrmatin fr medical therapy. Althugh the final cnclusin must be evaluated in a prspective study that includes a large series f patients with endmetrisis, this new applicatin f a cmbinatin f MRI and serum levels f CA-125 may be useful in the develping the prgnsis f endmetrisis befre initiating medical treatment. REFERENCES 1. Barbieri RL, Nilff JM, Bast RC Jr, Schaetzl E, Kistner RW, Knapp RC. Elevated serum cncentratins f CA-125 in patients with advanced endmetrisis. Fertil Steril 196; 45: Pittaway DE, Fayez JA. The use f CA-125 in the diagnsis and management f endmetrisis. Fertil Steril 196; 46: Takahashi K, Yshin K, Nagata H, Kusakari M, Kita M. CA-125 is an effective marker fr patients with external endmetrisis and n danazl: case reprts. Fertil Steril 19; 5: Takahashi K, Kijima S, Yshin K, Shibukawa T, Kita M. Serum CA 125 as a marker fr patients with external endmetrisis. Int J Fertil 199;34: Takahashi K, Yshin K, Kusakari M, Kath S, Shibukawa T, Kita M. 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