Diagnosis of ovarian masses often proves difficult because many of the pathological conditions that affect the ovary have similar clinical and radiological manifestations.1 Current diagnostic workup used for the characterization of ovarian masses is based on gynecologic examination, transvaginal sonography (TVS) combined with color Doppler technique, and assay of specific tumor markers such as CA-125.2 For staging purposes, a careful medical history and physical examination, as well as a variety of imaging laboratory modalities, have been proposed to determine the size, shape, location, and consistency of malignant ovarian masses. The most commonly used staging modalities are TVS, serum CA-125, contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI).3,4 A wide range of accuracy (50%–90%) for CT in staging ovarian cancer has been reported.5 In a systematic review, Medeiros et al6 qualify MRI as a useful preoperative test for pelvic masses diagnosis, although further investigation is required, and data need to be confirmed. Another imaging technique that has been proposed during the last few years for evaluating cancer patients is positron emission tomography with 2-(18F)fluoro-D-glucose positron emission tomography (PET), which in contrast to CT and MRI is based on functional rather than morphological criteria.7 Castellucci et al8 studied the diagnostic accuracy of PET/CT in characterizing ovarian masses and showed that TVS had sensitivity, specificity, negative predictive value, positive predictive value (PPV), and accuracy of 90%, 61%, 78%, 80%, and 80%, respectively, compared with PET/CT values of 87%, 10%, 81%, 100%, and 92%, respectively.
Transvaginal sonography is a much more sensitive way of detecting ovarian abnormalities but lacks specificity in distinguishing between benign and malignant lesions,9 which may result in unnecessary surgery on patients with benign lesions or, conversely, inappropriate surgery in cases at malignant masses.3
Ovarian carcinoma is the leading cause of death by gynecologic malignancy, mainly due to the inability to screen for the disease especially in early stages. Because of the ovaries’ location, few early symptoms are indicative of the disease. Consequently, in more than 90% of the cases, diagnosis is delayed and occurs only in advanced stages, when the tumor causes mass effect or when it has already metastasized. Survival after diagnosis at stages I and II is remarkably better (90% and 75%, respectively, after therapy).10 Finding an effective screening tool or early detection for ovarian cancer continues to be elusive.11 No screening method or early detection tool for ovarian cancer has yet proved to be effective, a combination of TVS and the level of tumor marker CA125 included. To be precise, this combination is characterized by a specificity of 98.7% and a PPV of 10% in the current literature.12 The hypothesis was that recent technological advances in 3-dimensional power Doppler angiography (3-DPDA) may have clinical utility in the early identification of abnormal ovarian morphology and vascularity. The 3-DPDA system may improve all existing information on malignant ovarian tumors and speed up the entire patient management process.13 The purpose of this study was to assess the reliability of 3-DPDA in
- (a) differentiating malignant from benign ovarian masses,
- (b) staging ovarian cancer, and
- (c) determining the correlation with histological findings.
MATERIALS AND METHODS
A group of 318 women were referred for preoperative evaluation of a unilateral ovarian mass to the 1st Department of Obstetrics and Gynecology of the University of Athens, in Alexandra Hospital, from November 2006 to December 2010. The age of the women whose cases were examined was 47.4 ± 13.8 years with a range of 18 to 72 years. Sonography was performed by a Voluson 730 with a mechanized transvaginal 5- to 7.5-MHz probe. Once the region of interest had been identified, the volume box was superimposed, and the 3-dimensional (3-D) ultrasound volume was generated by the automatic rotation of the mechanical transducer through 360 degrees. Three perpendicular planes were displayed simultaneously, thus enabling better understanding of the morphology of the ovarian lesions. The 3-D technique analyzed 8 morphological criteria: wall structure (smooth or papillomatous >3 mm), shadowing, septa (thin [≤3 mm] or thick [>3 mm]), solid components, echogenicity (low or mixed/high), peritoneal fluid, surface of the capsule, and the relations with surrounding structures. The 3-D angiography analyzed vessel’s architecture, branching pattern, and tumor blood flow evaluated by resistance index (RI).
Sonographic criteria used for diagnosing ovarian malignancy were based on the scoring system described by Kurjak et al.14 The presence of papillary projections greater than 3 mm, visualization of solid parts, high or mixed echogenicity of the tumor contents, irregular surface of the capsule, disturbed relationship with surrounding structures, complex vessel architecture, and RI value lower than 0.42 received a score of 2, whereas in cases with thick septa greater than 3, we added 1 point for shadowing and peritoneal fluid.
Malignant tumors were staged surgically according to the criteria established by the International Federation of Gynecology and Obstetrics. The study protocol was approved by the hospital’s ethical committee, and all patients consented to participate in the study.
The diagnostic accuracy of 3-D technique and 3-D angiography was estimated by receiver operating characteristic curve, and the χ 2 test was used for statistical analysis. P < 0.001 was considered to be significantly different (Fig. 1).
Data from ultrasound findings, surgical procedures, and pathological findings helped evaluate the potential malignancy of the tumor. The 3-DPDA allowed detailed analysis of the tumor’s vascular architecture. Irregular and randomly dispersed vessels with complex branching patterns that did not follow the geometry of the normal preexisting vasculature (having even smaller branches and diameters) were associated with ovarian malignancy.
Histopathology identified 225 benign and 93 malignant ovarian neoplasms. The 3-DPDA revealed 215 benign ovarian masses with cutoff score lower than 6 masses and 103 malignant ovarian masses with cutoff score greater than or equal to 6. A cutoff value of 6 was used for the discrimination of benign and malignant masses, based on a specific scoring system concerning 3-D ultrasonographic criteria.
An increased score (≥6) was associated with higher risk of ovarian malignancy. The distribution of final histopathology with 3-DPDA classification is shown in Table 1. The 3-DPDA diagnosed 6 malignant masses as benign: 3 adenocarcinomas, 2 mucinous borderline (in this study, borderline tumors were counted as malignant tumors), 1 endometrioid adenocarcinoma—false negative, and 16 benign ovarian masses as malignant: 3 mucinous cystadenomas, 3 benign teratomas, 5 endometriomas, 2 fibromas, 1 serous papillary cystadenoma, 2 corpus luteum cysts—false positive. The combined morphologic and 3-DPDA examination reached sensitivity and specificity of 93.5% and 92.9%, respectively, whereas PPV was 84.5% and negative predictive value was 97.2%.
Benign masses with histopathologic-type benign Brenner, mucinous cystadenoma (12/15), teratoma (31/34), endometrioma (50/55), fibroma (5/7) (Fig. 2), serous cystadenoma, simple cyst, corpus luteum cyst (26/28), and serous papillary cystadenoma (7/8) have shown total score of less than 6. On the contrary, malignant masses with histopathologic-type serous papillary adenocarcinoma, adenocarcinoma (16/19), malignant teratoma, mucinous cystadenocarcinoma (Fig. 3), mucinous borderline (4/6), mucinous adenocarcinoma, clear-cell carcinoma, dysgerminoma, endometrioid adenocarcinoma (15/16), papillary adenocarcinoma, malignant Brenner, leiomyosarcoma, mixed müllerian tumor, serous borderline tumor, serous papillary borderline, serous papillary cystadenocarcinoma, and serous cystadenocarcinoma have shown total score of greater than or equal to 6.
Among women younger than 50 years (167 women, 52.5%), the most common benign mass was endometrioma (35.9%), and the most common malignant neoplasm was adenocarcinoma (15.2%). Among women older than 50 years, the most common benign ovarian mass was serous cystadenoma (36.3%), and the most common malignant tumor was serous papillary adenocarcinoma (23.9%). Three-dimensional analysis with high score of 6 or greater was associated with malignant histopathologic types in older women (54.7 ± 10.5 years).
The sonographic appearance of a malignant ovarian mass by 3-DPDA was characterized by papillary protrusions, septa, abnormal surface, abnormal echogenicity, and vascularity in the center or at the periphery with abnormal branching pattern, scattered vessels, and vascular shunts.
The present study also revealed that there is no correlation between cutoff value of 6 or greater and the grade and stage of ovarian cancer, but there is a borderline relation between the high score and the stage, the grade, and the probability of metastatic disease (Table 2).
Ovarian cancer shows no early or specific symptoms in most patients and that is why the diagnosis of malignancy is often achieved late in the disease process or even during surgery. This is mainly due to the low accuracy of transvaginal ultrasound (which is currently the first-choice imaging method for the characterization of ovarian lesion) distinguishing benign versus malignant lesions.2,15 This low accuracy at presurgical differential diagnosis can lead to suboptimal surgical approaches:
- (a) benign lesions erroneously characterized as “probably malignant” could undergo unnecessary and invasive laparotomy, and
- (b) on the other hand, a malignant lesion erroneously characterized as “probably benign” may be surgically approached without the necessary caution, which may worsen the prognosis through possible rupture of the tumoral capsule and consequent peritoneal dissemination of the disease.
Currently, the tumor markers CA-125 and human epididymis protein 4 (HE4) as well as the risk of ovarian malignancy index are used as tools for differentiating between low- and high-risk patients with ovarian cancer.16 The risk of ovarian malignancy index Jacob’s model based on ultrasound findings, menopausal status, and serum CA-125 level is a good method in discrimination between the benign and malignant adnexal masses and demonstrated a sensitivity of 85.4% and a specificity of 96.9%.17 Moore et al18 reported that HE4 and CA-125 with the risk of ovarian malignancy algorithm had a high sensitivity (93.8%) for the prediction of ovarian cancer in women with a pelvic mass. Another multimarker test, the Ova1 index, incorporates imaging, menopausal status, CA-125, and 4 other proteomic biomarkers. Use of Ova1 provides 85% to 96% sensitivity at 28% to 40% specificity, depending on menopausal status.19
In the last decade, several methods have been designed to differentiate benign from malignant ovarian masses. The technique of 3-DPDA was offered as a specific mode of evaluating ovarian masses and altering screening for early detection of the disease before the appearance of any symptoms.20 Several studies have reported the use of 3-DPDA. Although some have shown that 3-D improves the PPV of ultrasound screening, not all agree, as summarized in the proceedings at the American Institute of Ultrasound in Medicine Consensus Conference.21 Some authors agree that although 3-DPDA in the diagnosis of adnexal masses appeared more reproducible than 2DUS, the difference was not statistically significant, and 3-DPDA might be useful in a selected subset of adnexal masses.22,23
Our results indicate that 3-DPDA provides a reduction of the false-positive findings through detailed investigation of the ovarian lesion morphology. The 3-D technique is also capable of supplying useful information in tumors with solid content. However, this supplementary information is of limited value because there are no generally accepted cutoff values for RI and pulsatility index or blood flow velocity.24 Differences in operator variance and system sensitivity contribute to an already confusing analysis at variable overlap in blood flow parameters between benign and malignant ovarian tumors and are another element of the current debate regarding attempts to achieve accurate differentiation of ovarian tumors on the basis of their vascular characteristics.
In advanced cases of ovarian malignancy, one can determine the extent of tumor infiltration through the capsule and estimation of the tumor spread by careful observation of the relationship with other pelvic structures.
Recent studies have dealt with the contribution of the histogram technique in ovarian carcinoma and estimating the vascularity and perfusion between malignant and benign ovaries. In these studies, it is reported that 3-DPDA vascular indices (vascular index, flow index, vascular flow index) could be helpful in reducing the false-positive rate in cystic-solid and solid vascularized adnexal masses. The use of different cutoff values for 3-DPDA indices for discriminating between benign and malignant adnexal masses is also recommended.20,23,25
To our knowledge, this study includes the largest number of patients in worldwide literature and is based on a specific and simple scoring system, which can be worked by an experienced and confident sonographer. We included a table with the reported studies 3-DPDA in detection of ovarian malignancy (Table 3). In our study, 3-DPDA diagnosed 6 malignant masses as benign (false negative) and 16 benign as malignant (false positive). In the current study, there was a statistical significance between high score (≥6) and the stage of the disease (P = 0.027), the probability of metastasis (P = 0.012), and the grade of the tumor (borderline correlation) (P = 0.078).
This element allows us to consider that 3-D ultrasonographic analysis has a high diagnostic accuracy in discriminating benign versus malignant ovarian masses.
In conclusion, 3-DPDA with the precise and detailed characterization of an ovarian mass might determine treatment options and speed up the entire management process.
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Keywords:Copyright © 2013 by IGCS and ESGO
Three-dimensional power Doppler angiography; Ovarian cancer; Benign vs malignant; Histopathology