Intratumoral Blood Flow Analysis in Ovarian Cancer:

Transcription

1 Intratumoral Blood Flow Analysis in Ovarian Cancer: What Does It Mean? Kohkichi Hata, MD, PhD, Toshiyuki Hata, MD, PhD The objective of this study is to evaluate the significance of intratumoral blood flow in ovarian cancer. Forty-seven patients with histologically proved ovarian cancer underwent transvaginal gray scale sonography, and color and Doppler sonography before surgery. Intratumoral blood flow velocity waveforms obtained from architecture within the tumor were recorded, and resistive index and peak systolic velocity were calculated. Neither resistive index values nor peak systolic velocity values differed significantly among the histological diagnoses, regardless of stage (including metastatic tumor) or morphologic classification of tumor. These results suggest that intratumoral blood flow analysis in ovarian cancer cannot provide information on individual tumor characteristics. KEY WORDS: Blood flow, intratumoral; Tumors, blood flow; Cancer, ovary; Ovary cancer; Doppler sonography. C onsiderable experimental evidence indi cates that tumor growth is dependent on angiogenesis.l The process of angiogenesis begins when a microscopic colony of tumor cells expands to a size at which simple diffusion of nutri ~ ents (and wastes) is insufficient.2 If angiogenesis is regarded as a neoplastic marker for a tumor and could be detected, an earlier diagnosis of cancer ABBREVIATIONS RI. Resistive index; PSV, Peak systolic velocity; UC, Unilocular cyst; MC, Mutilocular cyst; USC, Unilocular solid cyst; MST, Multilocular solid tumor; ST, solid tumor Received Febnmry 16, 1996, from the Department of Obstetrics and Gynecology, Shimane Medical University, lzumo, Japan. Revised manuscript accepted for publication May 4, Address correspondence and reprint requests to Kohkichi Hata, MD, PhD, Department of Obstetrics and Gynecology, Shimane Medical University, lzumo 693, Japan. would be made possible. Preliminary data suggest that it may be possible to detect the vascular changes associated with angiogenesis in early ovarian cancers using transvaginal color Doppler sonography. A possible explanation for this is that the new vessels associated with carcinoma have limited vascular tone owing to the absence of the tunica media, and as a result they form low impedance shunts-that is, they have low Rl or PI values. On the basis of this work investigators hoped it would be possible to characterize benign and malignant lesions on the basis of their vascularity.j. ~ However, as more experience was gained, the indisputable overlap between the range of Rl or PI in benign and malignant tumors became evident.5. f> Therefore, a negative color scan for a tumor does not necessarily mean that the tumor has no histologic evidence of angiogenesis. Moreover, a flow velocity waveform with a low pulsatility is not a definitive pathognomonic sign of a neoplastic tumor. In malignant tumors of the liver, kidney, pancreas, or adrenal gland, high-velocity Doppler shift signals have been reported to be a more common finding than signals with low systolic-diastolic variation by the American Institute of Ultrasound in Medicine J Ultrasound Med 15: , /96/ $3.50

2 572 TUMORAL BLOOD FLOW IN OVARIAN CANCER These findings agree with our recent report that pulsatilty analysis cannot discriminate among adnexal masses and a higher PSV could be a clue to differentiate malignant from benign adnexal tumors.lil However, it is still questionable whether PSV should be recommended for differentiation between benign and malignant ovarian tumors. The clinical usefulness of PSV as a discriminant between benign and malignant tumors must be addressed in a prospective study. In this study, with transvaginal color and pu]sed Doppler ultrasonography, we assessed intratumoral blood flow status of ovarian cancers with a highly heterogeneous group of tumors having a variety of clinical manifestations and tried to determine the significance of intratumoral blood flow analysis in ovarian cancer. MATERIALS AND METHODS Forty-seven patients with histologically proved ovarian cancer were included in this study. The age range of the patients was from 11 to 79 years (mean, 54.3 years); 30 of the patients were postmenopausal All patients underwent surgery, and classification of histologic findings was made according to the recommended criteria of the World Health Organization.9 The patients signed a consent form as approved through the Research Ethics Committee of Shimane Medical University Hospital. Sonography was performed with a commercially available scanner, Aloka SSD-680 or Atoka SSD-2000 (Aloka, Tokyo, Japan). Scanning was performed transvaginally with a 5.0 MHz transducer. In the color Doppler mode, direction of flow in relation to the transducer is indicated by shades of red or blue, within the field of view. In the color and pulsed Doppler sonographic mode, the lowest possible measurable velocity is 1.54 em/ sec. Pulse repetition frequencies are 1 to 25 KHz, the maximal penetration depth is 12 ern, and the gate width is from 1 to 10 mm. Wallfilters (50 Hz) were used to eliminate lowfrequency signals occurring from vessel wah motion. The spatial peak temporal average intensity at the maximum amplitude and minimum gate width in simultaneous color and pulsed Doppler sonographic mode is less than 80 mwi cm'2, according to the manufacturer's specifications. The preparation of the vaginal probe for transvaginal sonography has been described in the previous investigation.s All the women underwent sonographic examination within 2 days before exploratory surgery. Each tumor was initially dassi- J Ultrasound Med 15: , 1996 fied based on the criteria reported by Valentin and colleaguesto: (1) UC (a unilocular cyst without septa and without solid parts or papillary excrescences), (2) MC (a cyst with at least one septum but no solid parts or papillary excrescences), (3) USC (a unilocular cyst containing solid parts or papillary excrescences but no septa), (4) MST (a tumor with at least one septum and solid parts or papillary excrescences), or (5) ST (a tumor with solid components in 80% or more of the tumor). Transvaginal color Doppler flow imaging was done to identify intratumoral blood flow on all tumors except UC. On color Doppler flow imaging, the sample point on the line of pulsed Doppler ultrasound beam was positioned at the region of interest, where the color dots were noted, and blood flow velocity waveforms with maximum amplitude and frequency shift were recorded. Angle correction was not used because in most cases the portion of vessels was not large enough. RI (the ratio of the difference between peak systolic frequency and end-diastolic frequency to peak systolic frequency) and PSV were calculated as the combined average value obtained from five consecutive reproducible waveforms. This averaged value is reliable and is also resistant to outlying points which inevitably appear in clinical data.!' Signals arising from blood flow within the tumor in each patient were recorded, and the blood velocity waveforms with the lowest RI value were used for data analysis. The Doppler examinations were done on days 5 to 7 during the menstrual cycle for premenopausal patients, to avoid the effect of ovulation and the presence of the corpus luteum.il The intraobserver coefficient of variation for the measurement of PSV and RI was 5.4% and 5.6%, respectively. Interobserver differences among three examining doctors were 11.3% and 11.6% for PSV and Rl, respectively.12 Statistical analysis used in this study was KruskalWallis one-way analysis of variance by ranks. Data analyses were done on a Power Macintosh Performa 6210 computer (Apple Computers, Cupertino, CA) using the StatView IV statistical package (Abacus Concepts, Berkeley, CA). A P value less than 0.05 was considered to be a statistically significant difference. RESULTS Typical transvaginal Doppler sonograms of ovarian cancers are shown in Figure 1. The results of histologic examination after surgery were shown in Table 1. None of the UC were malignant, and blood flows were detectable in all malignant tumors. Neither RI values nor PSV values differed signifi-

3 J Ultrasound Med 15: , 1996 HATA AND HATA 573 A B Figure ta, Typical transvaginal Doppler sonograms in ovarian cancers. Stage Ia, Mucinous cystadenocarcinoma. B, Stage Illc, Malignant Brenner tumor. cantly among serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma, clear cell carcinoma, and malignant Brenner tumor (Table 1). The Rl and PSV values did not differ significantly among low malignant potential, common epithelial, sex cord-stromal, germ cell, and metastatic tumors, respectively (Table 1). No significant difference was found among the RI and PSV values for each stage (including metastatic ovarian cancer), (Table 2). Likewise, significant differences were not noted among the RI and PSV values for any of the ultrasonographic classification types (Table 3). DISCUSSION With color and pulsed Doppler sonograph}" we can detect tumor blood flow in vivo. Intra tumoral blood flow analysis presents hemodynamic conditions of the tumor numerically. This estimate is considered to be objective, and its reproducibility has been validated.s In this study, we tried to investigate whether intratumoral blood flow analysis, RJ, and PSV in ovarian cancer correlate with individual tumor characteristics (e.g., staging, histolog}" and morphology of tumor). If we can find a correlation between Doppler blood flow analysis and individual tumor characteristics, we can plan the operative method Table 1: Histologic Diagnosis and Results of Doppler Blood Flow Analysis with 47 Ovarian Cancers Histologic Diagnosis RI PSV (cm/s) Median Range N Median Low malignant potential tumors Mucinous csytadenoma Common epithelial tumors Serous cystadenocarcinoma Mucinous cystadenocarcinoma Endometrioid adenocarcinoma Clear cell carcinoma Malignant Brenner tumor Q Q Q <> <> Sex cord-stromal tumors Granulosa cell tumor Range Germ cell tumors Embryonal carcinoma D Metastatic tumors D

4 574 TUMORAL BLOOD FLOW IN OVARIAN CANCER J Ultrasound Med 15: , 1996 Table 2: Staging, Including Metastatic Tumor, and Results of Doppler Blood Flow Analysis with 47 Ovarian Cancers Stage N Median I n III IV Metastatic tumor Rl PSV (cm / s) Range Median Range M and chemotherapy preoperatively and suggest a prognosis for the patient. However, neither RI values nor PSV values differed significantly for stag ing, histology, and morphology of the tumor. We could not find new positive results. Kurjak and associatesn reported that transvaginal color and pulsed Doppler sonography could be used in detection of areas of angiogenesis. It is believed that analysis of blood flow characteristics as well as site of angiogenesis and the amount and arrangement of this microvascular network may help in distinguishing malignant from benign tumors.lj Wu and coworkersl4 found that the Rl values of epithelium-derived neoplasms showed a significant progressive decrease from benign tumors toward borderline malignancy, early-stage ovarian carcinoma, and finally, advanced-stage ovarian malignancies. They regarded the RI values as a parameter indicating the angiogenetic intensity of neoplasm rather than as a definite indicator of malignancy, although this intensity of angiogenesis may, in general, reflect the malignant potentiaj.14 Hollingsworth and colleagues's stated that analysis of angiogenesis in advanced-stage ovarian cancer might be a useful prognostic factor, which influenced overall survival and disease-free survival in their immunohistochemical study. They also noted that the degree of angiogenesis differed for each type of advanced-stage ovarian cancer.js Wu and coworkers14 did not mention the prognosis for patients, even in advanced-stage patients. Valentin and coworkerslll reported that PSV tended to be higher in stage I or IT than in stage Ill or IV ovarian cancers. They commented that theoretically the blood circulation would be expected to differ between early- and late-stage ovarian cancers, and growth rate (and thus the need for neovascularization) might differ, as might the presence and extent of necrotic and neovascularized areas.ao However, no significant difference was found among the RI and PSV values for any stage, not even metastatic ovarian cancer, in this investigation. Little is known of the significance of angiogenesis on ovarian cancer. Intratumoral blood flow analysis represents the summation of hemodynamic conditions within the tumor and might in part reflect the intensity of angiogenesis. However, the underlying principles of the color and pulsed Doppler sonography are beyond the scope of this hypothesis. Moreover, ovarian cancer is composed of a variety of histologic types. Clinical course and prognosis differ for each histologic type.t 6 We cannot suppose that these differences reflect the Doppler blood flow analysis. A UC is rarely cancerous, whereas the presence of solid parts or papillary projections within a tumor implies a great risk of malignancy.l7.18 Valentin and coworkers o classified the sonographic appearance into five types and concluded that none of UC and MC were malignant and that the rate of malignant tumor increased from UST to MST to ST. We also considered that this sonographic classification might correlate with the intratumoral blood flow analysis; however, this hypothesis was not proved. Table 3: Gray Scale Ultrasonographic Classification and Results of Doppler Blood Flow Analysis with 47 Ovarian Cancers Gray-Scale Rl PSV (cm/s) Ultrasonographic Classification N Median Range Median Range Unilocular cyst 0 Multicular cyst Unilocular solid cyst >-36.9 Multilocular solid cyst Solid tumor

5 J Ultrasound Med 15: , 1996 HATA AND HATA 575 In conclusion, intratumoral blood flow analysis in ovarian cancer could not reveal information on tumor characteristics (e.g., staging, histology, and morphology of tumor). However, in view of the small number of patients, these observations must be considered preliminary. Further studies will focus on what Doppler blood flow analysis in ovarian cancers signifies and whether this study has clinical usefulness or not. REFERENCES 1. Folkman J: What is the evidence that the tumors are angiogenesis dependent? J Nat) Cancer Inst 82:4, Folkman J, Merler E, Agemathy C, et al: Isolation of a tumor factor responsible for angiogenesis. J Exp Med 33: 275, Kurjak A, Zalud I, Alfrievic Z: Evaluation of adnexal masses with transvaginal color ultrasound. J Ultrasound Med 10:295, Weiner Z, Thaler I, Beck D, et at: Differentiating malig nant from benign ovarian tumors with transvaginal color flow imaging. Obstet Gynecol79:159, Hata K, Hata T, Mana be A, et al: A critical evaluation of transvaginal Doppler studies, transvaginal sonography, magnetic resonance imaging, and CA 125 in detecting ovarian cancer. Obstet Gynecol80:922, Schneider VL, Schneider A, Reed KL, et al: Comparison of Doppler with two-dimensional sonography and CA 125 for prediction of malignancy of pelvic massess. Obstet Gynecol81:983, Taylor JWK, Ramos I, Carter D, et al: Correlation of Doppler US tumor signals with neovascular morpholog ic features. Radiology 166:57, Hata K, Hata T, Kitao M: Intratumoral peak systolic velocity as a new possible predictor for detection of adnexal malignancy. Am J Obstet Gynecol172:1496, Serov SF, Scully RE, Sobin LH: International histological classification of tumors. No.9, Histological typing of ovar ian tumors. Geneva, World Health Organization, Valentin L, Sladkevidus P. Marsal K: Limited contribution of Doppler veloctmetry to the differential diagnosis of extrauterine pelvic tumors. Obstet Gynecol83:425, Thompson RS, Trudinger BJ, Cook CM: Doppler ultra sound waveform indices: A/8 ratio, pulsatility index and Pourcelot ratio. Br J Obstet Gynaecol95:581, Hata K, Hata T, Senoh D, et al: Change in ovarian arterial compliance during the human menstrual cycle assessed by Doppler ultrasound. Br J Obstet Gynaecol 97:163, Kurjak A, Predanic M, Kupesic-Urek S, et al: Transvaginal color and pulsed Doppler assessment of adnexal tumor vascularity. Gynecol Oncol 50:3, Wu CC, Lee CN, Chen TM, et al: Incremental angiogenesis assessed by color Doppler ultrasound in the tumori ~ genesis of ovarian neoplasms. Cancer 73:1251, Hollingsworth HC, Kohn EC, Steinberg SM, et al: Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol147:33, Scully RE: Tumors of the Ovary and Maldeveloped Gonads. Washington, DC, Armed Forces Institute of Pathology, Granberg 5, Norstoma A, Wikland M: Tumors in the lower pelvis as imaged by vaginal sonography. Gynecol Oncol 37:224, Rottem S, Levit N, Thaler I, et al: Classification of ovarian lesions by high-frequency transvaginal sonography. J Clin Ultrasound 18:359,1990