Color Doppler sonography with contrast in the differentiation of ovarian tumors

Ultra-sonografia com Doppler colorido e uso de contraste na diferenciação dos tumores ovarianos

ORIGINAL ARTICLE

Color Doppler sonography with contrast in the differentiation of ovarian tumors

Ultra-sonografia com Doppler colorido e uso de contraste na diferenciação dos tumores ovarianos

Eduardo Cardoso Blanco; Ayrton Roberto Pastore; Angela Maggio da Fonseca; Filomena Marino Carvalho; Jesus Paula Carvalho; José Aristodemo Pinotti

Division of Gynecologic Oncology of the Departments of Gynecology and Obstetrics, and the Department of Radiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo - São Paulo/SP, Brazil

ABSTRACT

The objective of this study was to differentiate benign ovarian tumors from malignant ones before surgery using color and pulsed Doppler sonography, and to compare results obtained before and after use of contrast medium, thereby verifying whether contrast results in an improvement in the diagnostic sensitivity.

METHODS: Sixty two women (mean age 49.9 years) with ovarian tumors were studied, 45 with benign and 17 with malignant tumors. All women underwent a transvaginal color Doppler ultrasonographic exam. A study of the arterial vascular flow was made in all tumor areas, as well as an impedance evaluation of arterial vascular flow using the resistance index.

RESULT: Localization of the vessels in the tumor revealed a greater proportion of malignant tumors with detectable internal vascular flows (64%) than benign tumors with such flows (22%). There was a considerable overlap of these findings. The use of contrast identified a greater number of vessels with confirmation in the totality of tumors, but did not improve the Doppler capacity in tumoral differentiation. Malignant tumors presented lower values of resistance index than the benign ones, whether or not contrast was used. The cutoff value for resistance index that better maximized the Doppler sensitivity and specificity was 0.55. Through this value, an increase of the sensitivity after contrast use was obtained, varying from 47% to 82%, while specificity remained statistically unchanged.

CONCLUSION: Although the injection of a microbubble agent improved the sensitivity of the method detecting vascularization of tumors, a positive finding for vascularization by this method was not clinically useful in the differentiation of benign and malignant ovarian tumors.

Descriptors: Transvaginal ultrasound. Color Doppler sonography. Adnexal mass. Ovarian neoplasms. Contrast medium.

RESUMO

O objetivo deste estudo foi diferenciar tumores ovarianos benignos e malignos antes da cirurgia através da ultra-sonografia com uso de Doppler colorido pulsátil e comparar os resultados obtidos antes e após o uso de contraste.

MÉTODO: Foram estudadas sessenta e duas mulheres (idade média de 49,9 anos) com tumores ovarianos, sendo 45 benigos e 17 malignos. Todas foram submetidas a ultra-sonografia transvaginal com Doppler colorido. A pesquisa de fluxo vascular foi realizado em todas as áreas tumorais, assim como a avaliação da impedância através do índice de resistência.

RESULTADOS: A localização dos vasos no tumor revelaram uma maior proporção de fluxo vascular interno detectável nos tumores malignos (64%) do que nos tumores benignos (22%). Houve entretanto uma considerável sobreposição destes achados. O uso de constrate foi capaz de identificar um grande número de vasos na totalidade dos tumores, mas não melhorou a capacidade do Doppler na diferenciação entre tumores benignos e malignos. Os tumores malignos apresentaram valores mais baixos de índice de resistência.IR do que os benignos, independentemente do uso de contraste. O valor de corte do índice de resistência. que maximizou a sensibilidade e a especificidade do Doppler foi de 0,55. Com este valor foi obtido um aumento na sensibilidade após o uso de contraste, variando de 47% a 82 %, enquanto a especificidade se manteve equivalente.

CONCLUSÃO: Embora a injeção de agentes produtores de microbolhas aumentem a sensibilidade do método na diferenciação da natureza do tumor, este valor não se mostrou clinicamente util na avaliação de tumores ovarianos.

Descritores: Ultra-sonografia transvaginal. Doppler sonografia. Massas anexiais. Neoplasia ovariana. Meios de contraste.

Considerable evidence indicates that neovascularization is responsible for the tumoral growth and invasion¹. Ultrasonography with color and pulsed Doppler provides dynamic information concerning the distribution of tumor vessels and their impedance value through the determination of resistance (RI) and pulsatility (PI) indices. Preliminary data suggests that it is possible to detect vascular changes associated with angiogenesis in early ovarian cancer through this technique². A possible explanation for these changes is that the new blood vessels present in the carcinomas have limited muscular tonus due to the absence of the medial layer and that together with numerous existing arteriovenous shunts, they would be responsible for the low impedance registered by the RI and PI indices. However, this method presents some restrictions associated with the inaccessibility to the small caliber vessels, thus demonstrating low sensitivity for the intended purpose³. The advent of echo-enhancing substances for endovenous use, according to experiences in other organs⁴, would allow better visibility of these vessels, thereby helping in the differentiation of the neoplastic process.

The objective of this study was to differentiate benign from malignant tumors prior to surgery by using color and pulsed Doppler and to compare the results before and after use of contrast so that any improvements in resulting diagnostic sensitivity and specificity could be verified.

MATERIAL AND METHODS

This study comprised 62 women with ages varying from 13 to 84 years (average 49.9 years) with histologically confirmed ovarian tumors, 45 benign and 17 malignant ones. All patients underwent surgery, and the classification of histologic findings was made according to the World Health Organization criteria. The patients signed a consent form, as approved by the Research Ethics Committee of our University.

Contrast medium

All patients received the ultrasound contrast agent Levovist^® 400 mg/mL (8 mL) intravenously via peripheral vein. Levovist^® (Schering AG, Berlin FRG) is a suspension of especially manufactured galactose containing 99.9% galactose microparticles and a very low concentration of palmitic acid. Each vial contained 4 g of microparticles, and after suspension in water for injection was administered as a bolus via an 18-gauge plastic cannula inserted into the arm vein (injection speed: 1-2 mL/second continuously). This was followed by an additional 10 mL of physiological saline solution to flush the cannula using the same injection rate. A comparison was made of the Doppler sonographic findings before and after injection of Levovist^®. Although repetitive injections of the product were permitted (up to the maximum of 6 units) none of the cases required an additional injection.

Equipment and analysis of color Doppler signals

The ultrasonographic transvaginal exam with Doppler was performed with a commercially available scanner, GE LOGIC™ 500 , version 2.0, with abdominal and transvaginal transducers of 3.5 MHz and 5.0 MHz respectively. A Doppler filter of 50 Hz was used to eliminate low-frequency signals resulting from vessel wall motion. The color Doppler gain was increased until noise appeared and then was reduced until the noise was totally suppressed (usually this was a 50% reduction). Whenever the tumors exceeded 10 cm diameter, the study was completed via transabdominal ultrasonography. In premenopausal patients, the examination was performed between the 3^rd and 10^th days of the menstrual cycle in order to avoid the effects on the ovarian vascularization provoked by ovulation and the luteal body. The settings of the scanner controls were not altered after the injection of contrast. Vascular arterial flows were studied in all tumor areas, as was the impedance of vascular flows using RI determination. The vessels were classified as internal or peripheral according to their location. When the flow was measured in more than one vessel, the vessel with the lowest RI was chosen for study.

The video output of the scanner was tape recorded starting at 5 seconds prior to injection and continuing until the intensity of the color Doppler signals was subjectively judged to return to the base-line level. The number of vessels was evaluated within 10 mm of the tumors in the peripheral and central location.

The same examiner performed all ultrasonographic examinations.

The chi-square test was used to statistically evaluate the quantitative variables. A canonical correlation was applied to the sets of variables observed in both methods (with and without contrast) aiming at evaluating their relationship. The classification power regarding malignancy of the method used, with or without contrast, was analyzed with focus on the specificity and sensitivity of measurements that were based on Youden's index and the receiver operating characteristics (ROC). A p value below 0.05 was considered to be a statistically significant difference.

RESULTS

When determining the RI by Doppler technique without the use of contrast, it was possible to reproduce arterial flow in only 45 cases, which were therefore used for the comparative analysis between the 2 examination modalities, without and with contrast (Table 1).

After injection of the contrast during the color Doppler exam, enhancement of vascular signals presented by the adnexal masses was found at a mean time of 25 seconds ±14 (SD), this effect remaining for a variable period of time of 185 seconds ±45 (SD). All patients presented an increase of Doppler sign intensity, with the appearance of new vessels in 77% of the tumors (Figs. 1, 2).

Regarding the RI, the measures of central tendency (mean) and of variability (standard deviation) observed in the benign and malignant tumor groups are presented in table 2.

Statistically significant differences (p < 0.001) were observed between the average values for both RI1 and RI2 in the benign vs. malignant comparisons. The average values of RI1 and RI2 were not significantly different in either the benign or the malignant tumor group comparisons (Table 2).

Regarding vessel location in tumors, a higher proportion of malignant tumors had internal vascular flows within a solid component or septation (64%) than did benign tumors with internal flows (22%). A significantly greater number (c2 = 10.06, p = 0.0065) of benign compared to malignant tumors had peripheral flow without evidence of internal flow (Table 1). The use of contrast allowed the identification of a greater number of centrally located vessels in both groups of tumors, with this increase being more evident in benign tumors, in contrast with the results obtained without the use of contrast (Fig. 2).

Whether or not contrast was used, the malignant tumors had smaller RI values than the benign ones did (Table 2).

The cutoff RI value that better maximized the Doppler sensitivity and specificity was 0.55, as demonstrated by the use of receiver operating characteristics (ROC) methodology.

It was noted that the Youden's index for all cutoff RI values was higher when the contrast was used. The comparison of sensitivity values for both methods, when considering the 0.55 cutoff value, showed a significant difference at the 8% level (the chi-square test was applied with the Yates' correction factor), thereby confirming the superior Doppler results when using contrast, based on the Rl determination (Table 3).

When the internal flow was used as an indicator of malignancy, the sensitivity and specificity for internal flow versus either peripheral or no flow through color Doppler were 65% and 78%, respectively. After use of the contrast, the sensitivity and specificity were 88% and 47% respectively (Table 4).

As it can be seen, the sensitivity and specificity values of the color Doppler are low, independent of the use or not of the contrast for the classification of the tumors. There is no evidence that the increase of sensitivity observed with the use of contrast is significant (c²=1.47, p = 0.2252, with Yates' correction).

DISCUSSION

The analysis of the epidemiological aspects of ovarian cancer has generated a great deal of interest, especially regarding the detection and characterization of the ovarian masses through radiological imaging. Since 1958, when for the first time Donald identified a voluminous pelvic-abdominal ovarian cyst ultrasonographically, this technique has been systematically used in differentiating between benign and malignant tumors⁵.

Although the transvaginal route is presently considered to produce results that are sensitive for the detection of malignancy, the diagnostic confidence is not sufficient to obviate invasive procedures like laparoscopy and laparotomy. Thus, notwithstanding the efforts for improving the diagnostic accuracy, many studies have demonstrated that morphological evaluation of transvaginal ultrasound has found 80% to 90% sensitivity and from 65% to 95% specificity^6-8.

Color and pulsed Doppler have been widely investigated and proposed as possible means to augment ultrasonography in differentiating adnexal masses. Unfortunately, there is much controversy in the literature regarding the actual utility of the Doppler techniques for this application.

The presence and localization of the blood flow demonstrated through ultrasonography with color Doppler were initially used in an attempt to characterize ovarian masses^9-12. Fleischer et al.¹⁰ found statistically significant differences in the location of blood vessels in benign lesions, where they tend to be peripheral, compared to malignant lesions where they tend to be central. Our data also showed a significantly higher percentage of malignant compared with benign tumors with internal flow. Similarly, the presence of a peripheral location of vessels or their absence is better related to benignity (PNV=85%). It is interesting to point out that 88% of the tumors in our study in which no blood flow was observed were benign (n = 15). Previous studies using Doppler technology also reported the rarity of identifying flows in predominantly benign ovarian masses^12-15.

As a result of this and other works, it can be concluded that a significant number of tumors, either of benign or malignant nature, do not present blood vessels at ultrasonographic evaluation with Doppler technology. The improper concept of "lack of blood flow" in benign tumors presented by some authors^8,16-18 could be resulting from technical limitations associated with Doppler ultrasound rather than from phenomena actually related to angiogenesis. Thus, care must be taken when considering whether the absence of vascularization is to be used as a criterion of assessment, since information revealed through Doppler ultrasonography is highly dependent on variations in technology and could easily change as technology improves.

Currently, the use of some new technological resources has been fundamental for the increase in the detection of blood vessels, and consequently for the diagnostic accuracy of Doppler use in the differentiation of pelvic masses. The first resources that were of technological origin did not always have satisfactory results with the use of amplitude Doppler (Angio®, Power®, Energy®, Power-Angio, etc.). Subsequently, based on experiences with other organs^19-26, results have been obtained by applying echo-enhancer agents via intravenous administration. In this connection, the use of LevovistÒ permitted the identification of new blood vessels in tumors that had undetectable vascular flow initially and in other tumors that already had revealed vascular flow of peripheral distribution. In 12 cases of the latter, the new localization (central) was chosen for diagnostic purposes. Although more vessels were detected, the use of contrast did not improve the method's capacity for predicting malignancy. Whether or not contrast is used, color Doppler showed a limited utility in the differentiation of ovarian tumors.

When determining RI, significantly lower values were registered in malignant tumors as compared with the benign ones, independent of the use or not of contrast (Table 2). Considerable overlap of RI values was observed between the 2 groups of tumors, thus confirming the findings in other publications^27-33. The lower RI values found in both groups of tumors after use of contrast would result from the detection of vascular signs of low amplitude and obviously lower resistance that were not detected by the conventional Doppler technique.

In contrast with the first studies performed with pulsed Doppler in ovarian tumors^16,34, where high sensitivity (96%) and specificity (95%) in the identification of malignant tumors were obtained with RI <0.40 values, later works questioned the veracity of these findings. Thus, authors such as TEKAY & JOUPILLA¹⁴ obtained, for a RI cutoff value of 0.50, 46% sensitivity and false positive rates of 11% in the detection of malignancy. The results of SCHNEIDER et al.³⁵, for RI <0.40 values were remarkably similar. Subsequent studies have also showed low rates of detection for ovarian cancer when using different cutoff values^36-39. The false positive rates in these investigations varied from 2% to 48%.

In the population covered by this study, the discriminatory power range of RI in the differentiation of tumors was between the 0.50 and 0.60 values, from which 0.55 was the one that best maximized the sensitivity and specificity simultaneously. For this cutoff value, the pulsed Doppler without and with contrast showed specificity rates statistically similar to 93% and 89%, respectively.

A variety of benign lesions might lead to an erroneous diagnosis, including teratomas³⁴, endometriomas⁴⁰, and thecomas⁴¹. In these studies, the presence of these types of tumors was confirmed following initial detection using pulsed Doppler.

A significant increase in sensitivity (from 47% to 82%) was observed after administration of the contrast agent, leading to a significant difference at the level of 8% (chi-square test with Yates' correcting factor). The primary clinical usefulness of this technique is associated with reliability of the method for predicting benignity (PNV for malignity = 93%). However, the problem still persists regarding the identification of malignity.

CONCLUSION

The use of echo-enhancing agents such as Levovist^® considerably improved the performance of the Doppler ultrasonographic technique through the increase of the vascular signal, thereby permitting better identification of the blood vessels and analysis of the impedance standard of the blood flow originating from them. Although our data show that statistical statements can be made about benign and malignant tumors following the use of contrast agents, they are of little clinical use, especially in the context of evaluating an individual patient, because of the low sensitivity that is still present.

ACKNOWLEDGMENTS

This study was supported by the generous grants from the FAPESP ("Fundação de Amparo à Pesquisa do Estado de São Paulo").

We thank Miss Mina R. Steinberg, Miss Claudia Vieira, and Miss Beatriz Stojanoff for their secretarial assistance.

Received for publication on July 03, 2002

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Publication Dates

• Publication in this collection
  04 Dec 2003
• Date of issue
  2003

History

• Received
  03 July 2002