Recently, there have been several major technical advances in the sonographic diagnosis of ovarian cancer in its early stages. These include improved assessment of tumor morphology with transvaginal sonography (TVS), and detection and characterization of tumor neovascularity with transvaginal color Doppler sonography (TV-CDS) and contrast-enhanced transvaginal sonography (CE-TVS). This paper will discuss and illustrate these improvements and describe how they enhance detection of early-stage ovarian cancer. Our initial experience with parametric mapping of CE-TVS will also be mentioned.
This year in the United States approximately 24,000 women will be diagnosed with ovarian cancer, and there will be approximately 14,000 associated deaths, predominantly from epithelial ovarian cancer (EOC). Worldwide, it is estimated that 204,449 patients with ovarian cancer will be diagnosed this year with an estimated 124,860 disease-related deaths. The incidence of ovarian cancer has been steadily increasing over the past 10 years, with an overall lifetime risk of 1.8% [
Evaluation of adnexal masses can be performed with several imaging methods, including TVS, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). CT can detect large adnexal masses but has lower sensitivity for small adnexal masses, especially in thin patients in whom adnexal lesions can be misinterpreted as other pelvic structures or loops of pelvic small bowel. Furthermore, the ability of CT to characterize adnexal lesions as benign or malignant is limited by low inherent tissue contrast, with the notable exception of ovarian dermoids that can be characterized based on the presence of macroscopic fat and/or calcification. MRI offers higher spatial and contrast resolution than CT and can characterize a wider spectrum of adnexal lesions based on magnetic signal properties or enhancement behavior, but accuracy of MRI may diminish for borderline ovarian tumors and small ovarian masses. Compared to TVS, MRI is costly and has limited availability [
TVS is widely available and offers high-resolution imaging without the use of ionizing radiation. For these reasons, TVS is the initial diagnostic modality of choice for the evaluation of most patients with a pelvic mass. As previously mentioned, TVS has limited sensitivity and specificity for the definitive diagnosis of ovarian cancer because of overlapping morphologic features seen in benign and malignant lesions. Recently, however, significant technologic advances have yielded vast improvements in the sonographic depiction of early-stage ovarian cancer, and these improvements have translated into improved sonographic discrimination of benign from malignant disease in preliminary studies. Combined evaluation of sonographic morphology and CDS forms a set of basic “simple rules” for sonographic distinction of benign from malignant ovarian masses based on the data derived from a European multicenter study which included 1,223 adnexal tumors (sensitivity 93%; specificity 90%) [
“Simple rules” for sonographic diagnosis of ovarian cancer*.
Benign | Malignant |
---|---|
(1) Unilocular cyst | (1) Irregular solid tumor |
(2) Solid components <7 mm | (2) Ascites |
(3) Acoustic shadows | (3) Papillary excrescences |
(4) Smooth multilocular | (4) Irregular multiloculated/solid tumor |
<10 cm | >10 cm |
(5) No color Doppler flow | (5) Very high color content |
*Timmerman, D, US O/G 31 : 681, 2008.
Three-dimensional transvaginal sonography (3D TVS) has improved the morphologic depiction of ovarian cancers beyond the capabilities of traditional TVS. Improvements in transvaginal color Doppler sonography (TV-CDS) have enhanced sonographic assessment of large tumor vascular networks, and contrast-enhanced transvaginal sonography (CE-TVS) now allows for interrogation of tumor microvascularity [
Conventional sonographic criteria for ovarian cancer diagnosis are based on morphological classification of ovarian masses. Ovarian malignancy is unlikely in simple cysts with smooth walls, but presence of a solid mass or solid projections (papillary excrescences) into the cyst cavity significantly increases the risk of malignancy.
Hirai has described the morphologic features on TVS associated with stage I ovarian cancer in a lay-screening population in Japan [
Morphologic signs of malignancy with histopathologic correlation on TVS in various histologic types of stage 1A ovarian cancer.
Irregular solid area in a mucinous cystadenocarcinoma
Papillary excrescences in a clear cell carcinoma
Mural nodules in an endometrioid cancer
Irregular septa and echogenic solid foci within immature teratoma
2D CDS of showing flow within papillary excrescence within a papillary cystadenofibroma.
(L) TVS of bilobed cystic ovarian mass containing a papillary excrescence in one locule. (R) CDS showing flow within papillary excrescence
Photomicrographs of histology showing vessels in (L) low power, (R) high power
3D TV-CDS of papillary excrescences within a papillary serous cystadenoma.
2D TV-CDS of papillary cystadenoma showing low-impedance flow within a papillary excrescence
3D TVS (surface rendition) showing papillary excrescences
Over the last 10 years, the diagnostic accuracy for conventional 2D TVS has been improving [
The recent development of 3D-TVS improves the detection of morphologic abnormalities indicative of neoplastic ovarian masses. In particular, small papillary excrescences or focal wall (mural) irregularities can be detected which are associated with epithelial malignant growth in ovarian masses [
TV-CDS provides depiction of the macrovascularity (over 200
Combining morphologic assessment with TVS with color Doppler features has allowed accurate assessments of whether a mass is benign or malignant by following “simple rules” [
Both micro- and macroscopically, tumor neovascularity is characterized as vessels that demonstrate irregular caliber and branching. TV-CDS can only detect flow in relatively large vessels. Microvascular (i.e., capillary) tumor neovascularity can be depicted using microbubble contrast (Figures
3D TV-CDS of papillary cystadenocarcinoma showing multiplanar reconstruction (MPR) images.
Top: long axis showing central flow with an irregularly shaped solid adnexal mass. Bottom: same as top in short axis
Top: 3D TV-CDS showing (combined volume redition) cluster of vessels within morphologically abnormal area. Bottom: coronal
CE-TVS of a benign fibroma.
Solid mass with no internal flow with fundamental (top right of image) and harmonic (top left) images. Time intensity curve shows relatively high peak enhancement and short wash-out time
Parametric images showing little internal flow
CE-TVS of serous cystadenoma with mural nodules.
(R) Fundamental and (L) harmonic image showing mural nodule. There is quick wash-in and wash-out within the mural nodule indicating benignancy
Parametric image showing different time of arrivals within mural nodule, wall, and septum
In our previous study, all malignant tumors and 50% of benign tumors showed detectable contrast enhancement (image intensity > 10% above the baseline) after microbubble injection [
AUC greater than 787 seconds−1 was the most accurate diagnostic criterion for ovarian cancer, with 100.0% sensitivity and 96.2% specificity. Additionally, PE greater than 17.2 dB (90.0% sensitivity and 98.3% specificity) and a
While the time-intensity curve has traditionally been calculated from mean signal intensities over a region of interest, parametric mapping of time-intensity curve variables on a pixel-by-pixel basis allows for more global visualization of tumor hemodynamics. The use of this technique in ovarian cancer has been limited to selecting the pixel with greatest peak enhancement (PE) and using that pixel’s time-intensity curve for further analysis [
Our preliminary results from a subset of 29 out of the 57 subjects analyzed in our previous region of interest (ROI) study show potential for this technique to differentiate benign and malignant ovarian masses [
The preliminary results from the subanalysis of 18 benign and 11 histologically proven malignant ovarian masses showed greatest diagnostic accuracy for maps of PE (sensitivity 100%, specificity 67%) and wiAUC (sensitivity 73%, specificity 94%), while maps of
CE-TVS can significantly improve the diagnostic ability of transvaginal sonography alone to identify early microvascular changes that are known to be associated with early-stage ovarian cancer [
Previous studies have addressed the use of CE-TVS for benign and malignant tumors by showing greater enhancement of malignant tumors on Doppler imaging. According to the initial work reported by Kupesic and Kurjak, the use of a contrast agent with 3D power Doppler sonography showed very high diagnostic efficiency (95.6%) that was superior to that of nonenhanced 3D power Doppler sonography (86.7%) [
Our preliminary clinical studies explored differences in enhancement parameters in benign versus malignant ovarian masses using a new method of CE-TVS termed pulse inversion nonlinear imaging [
As a general statement, contrast enhancement patterns significantly differ between benign and malignant ovarian masses. The addition of a vascular sonographic contrast agent allows a more complete delineation of the vascular anatomy through enhancement of the signal strength from small vessels (capillaries) and provides an entirely new opportunity to time the transit of an injected bolus. CE-TVS has higher sensitivity and specificity to differentiate between benign and malignant lesions than conventional TVS and for detecting occult stage I disease.
CE-TVS can detect tumor neovascularity (Figures
CE-TVS of borderline mucinous (intestinal) cystadenocarcinoma.
(R) Fundamental image showing mural nodule and mobile echogenic material (L), same using harmonic imaging. There is quick wash-in and long washout within the mural nodule
Parametric image different time of arrival for mural module versus wall
CE-TVS of stage I papillary serous cystadenocarcinoma.
(R) TVS shows normal sized ovary with small cystic area. (L) CDS shows marked vascularity within ovary. Time-intensity curve shows high peak intensity and long washout
Parametric image showing diffuse vascularity
Box graph of contrast-enhanced parameters. While there is no difference in time of peak (
Sensitivities and specificities of maximum enhancement, wash-in, wash-out and area under curve (AUC). Maximum enhancement, wash-out and AUC had greatest accuracy.
Receiver operator characteristerics for (a) wash-in, (b) maximum enhancement, (c) wash-out, and (d) area under curve.
Receiver operator characteristic of various parameters showing cutoff points for vascular index (VI), flow index (FI), and vascular flow index (VFI) (from [
Relative accuracy (sensitivity and specificity of enhancement kinetic parameters) of various techniques using predetermined cutoff points of: 2D VFI (>0.4), 3D VFI (>0.5), CE-TVS (max >17.2 dB), CE-TVS (
With improved imaging technology comes the potential for enhanced therapeutic measures. Specifically, this includes directed therapeutic measures after labeled microbubbles are used [
In conclusion, it is hoped that this paper may contribute to the development of new methods for diagnosing, enhancing therapy, and detecting tumor response for this dreaded gynecologic malignancy, possibly with the use of targeted microbubbles [
Supported in part by National Institute of Health, National Cancer Institute Grant R21 CA 125227-01.