AbstractPurposeThe objective of this study was to evaluate the diagnostic value of transvaginal contrast-enhanced ultrasound (CEUS) in differentiating benign from malignant endometrial lesions and assessing the extent of myometrial invasion.
MethodsA total of 70 patients who underwent surgery for endometrial lesions at the authors’ hospital were selected. Transvaginal ultrasound examination and CEUS were performed for quantitative and qualitative analysis. Based on the CEUS results, an International Federation of Gynecology and Obstetrics (FIGO) disease grade was assigned and compared with pathological findings.
ResultsPostmenopausal vaginal bleeding is a key clinical manifestation of endometrial carcinoma. Among the patients with endometrial carcinoma, compared with normal myometrium, the lesion areas exhibited a greater rate of rise (defined as enhanced intensity divided by enhancement time) and a shorter half-clearance time (P<0.05). These findings suggest that in endometrial carcinoma, the contrast agent displays a "fast-in/fast-out/hyperenhancement" perfusion pattern. In contrast, the characteristic perfusion pattern for benign endometrial lesions is low enhancement (P<0.05). The diagnostic accuracy of CEUS in detecting myometrial invasion was 88% (22 of 25 cases).
IntroductionEndometrial cancer is the sixth most common cancer worldwide and the second most prevalent gynecologic malignancy, representing a major health challenge with increasing morbidity and mortality rates [1]. Over the last 30 years, its incidence has risen by a staggering 132% [1,2]. Alarmingly, 10% to 15% of patients present with advanced-stage disease, facing a grim prognosis with a 5-year survival rate of just 17% [3]. Thus, the timely recognition of endometrial cancer symptoms is crucial for the implementation of effective prevention and treatment strategies.
Currently, transvaginal ultrasound represents a primary diagnostic modality for endometrial cancer in clinical settings. However, its reliance on two-dimensional (2D) imaging to measure endometrial thickness renders it inadequate for precise assessment, resulting in underdiagnosis and delayed treatment. Given the vascular characteristics of the endometrium, particularly its unique blood supply pattern, these authors hypothesize that dynamic imaging of endometrial blood flow could provide superior diagnostic information to conventional 2D ultrasound (2D US), thereby facilitating early and accurate detection of endometrial cancer. Testing this hypothesis requires the identification of an imaging modality that can effectively capture dynamic endometrial blood flow. Transvenous contrast-enhanced ultrasound (CEUS) represents a promising option. CEUS retains the versatility and portability of traditional ultrasound while enabling real-time visualization and quantitative assessment of microvascular perfusion. Its effectiveness in assessing hepatic, adnexal, and renal tumors has been demonstrated [4-6]. Nonetheless, the potential of CEUS to characterize the specific blood flow patterns of endometrial cancer remains unexplored, limiting its application in disease assessment.
Consequently, the present study aims to examine the potential of CEUS in delineating the blood flow dynamics of endometrial cancer, differentiating between benign and malignant lesions based on perfusion characteristics, and evaluating the extent of myometrial invasion. By providing robust and thorough insights into blood flow dynamics, this research strives to equip clinicians with a more reliable toolkit for early detection and prompt intervention, thus improving the clinical management of endometrial cancer.
Materials and MethodsCompliance with Ethical StandardsEthical approval for this study was obtained from the Ethics Committee of Shanghai Sixth People’s Hospital (approval No. 2021-039), and all participants provided informed consent following a thorough briefing on the study protocol. The clinical trial registration number for this study is ChiCTR2100048361.
Study PopulationA cohort of 123 patients, ranging in age from 22 to 85 years with a mean age of 56.5 years, was recruited. Among them, 70 underwent surgical intervention at Shanghai Sixth People’s Hospital between July 2021 and November 2023 (Fig. 1). The inclusion criteria encompassed the presence of endometrial thickening with heterogeneous echoes on 2D US, with or without accompanying vaginal bleeding, and inconclusive findings regarding the nature of the endometrial lesion via 2D and color Doppler imaging. The exclusion criteria comprised a history of intrauterine surgery in the previous month, concomitant cardiac or pulmonary pathologies that precluded angiography, and patient refusal of surgery.
Equipment and AgentsEquipmentA Mindray R7 color Doppler ultrasonic diagnostic system (Shenzhen Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, PRC), equipped with a transvaginal probe (model: V11-3HU, frequency: 4-9 MHz), was utilized to acquire raw ultrasound data.
Contrast agentThe SonoVue contrast agent (Bracco Group, Milan, Italy), which primarily consists of sulfur hexafluoride gas microbubbles encased in a phospholipid monolayer, was a key component of the imaging protocol. Before administration, SonoVue was diluted with 5 mL of 0.9% normal saline and then agitated to produce a homogeneous milky white solution, in strict accordance with the manufacturer’s instructions.
Ultrasound ScanThe investigation began with transvaginal ultrasound to assess the endometrial echo pattern and to measure the thickness of the endometrium. Next, color Doppler blood flow mode was used to identify the region in the median sagittal section of the uterus with the strongest blood flow signals, which was designated as the region of interest (ROI). After pinpointing this location, a bolus of contrast agent (2.0 mL) was injected through the cubital vein, at which point a timer was started on the imaging system. During the examination, both the probe and the patient remained completely still. Dynamic angiographic images of the ROI were then sequentially captured over 3 minutes to ensure comprehensive collection of data for later analysis.
CEUS AnalysisQuantitative analysisAutomated examination and analysis of images were performed using the ultrasound equipment’s built-in auto-contrast quantification software. Time-intensity curves (TICs) were subsequently generated. Manual delineation of two ROIs followed: Region of Interest 1 (ROI1) covered the enhanced area of the endometrial lesion, while Region of Interest 2 (ROI2) included a segment of normal myometrium. This procedure yielded two TICs for each patient. The calculated parameters included basic intensity (BI), peak intensity (PI), and enhanced intensity (EI), where EI represents the difference between PI and BI. Other parameters included arrival time (AT), time to peak (TTP), and enhancement time (ET), calculated as the difference between TTP and AT. Additionally, the half-clearance time and the rate of rise (defined as EI divided by ET) were determined.
Qualitative analysisThe comparative assessment of TICs in relation to endometrial lesions and normal myometrium enabled the identification of qualitative contrast perfusion parameters. These parameters include contrast agent wash-in time (categorized as fast-in, iso-in, or slow-in), contrast agent wash-out time (fast-out, iso-out, or slow-out), and enhancement intensity (hyperenhancement, isoenhancement, hypoenhancement, or no enhancement).
Determination of myometrial invasion depthThe assessment of myometrial invasion was facilitated by a clear demarcation between the lesion and the normal myometrium during the early stages and upon resolution of contrast agent perfusion. Notably, myometrium that had been infiltrated by endometrial cancer prior to perfusion demonstrated a relatively distinct boundary with normal myometrium. The extent of myometrial invasion was measured from the point of deepest penetration within the myometrium to the myometrial-endometrial interface. These measurements were categorized as either less than 50% myometrial invasion, corresponding to International Federation of Gynecology and Obstetrics (FIGO) stage Ia, or greater than 50% invasion, corresponding to FIGO stage Ib.
Both qualitative and quantitative analyses were performed by two attending ultrasound physicians, who reached a consensus on the final results after discussing and resolving any discrepancies in their findings.
Pathological AnalysisHistological diagnosis and staging of all specimens were conducted by two pathologists in accordance with the 2009 FIGO staging criteria.
Data AnalysisThe recorded data were statistically analyzed using SPSS for Windows version 28.0 (IBM Corp., Armonk, NY, USA). Differences between groups were assessed with the t-test, and disparities between lesions were evaluated using the chi-square test. A two-sided P-value of less than 0.05 was considered to indicate statistical significance.
ResultsPatient and Tumor CharacteristicsNo significant difference in mean age was observed between the patients with endometrial carcinoma and those with benign endometrial lesions. However, a significant difference in endometrial thickness was noted (P<0.05), with the carcinoma group exhibiting greater thickening (Table 1). Of the 30 patients diagnosed with endometrial carcinoma, 26 were postmenopausal and four were premenopausal. Abnormal vaginal bleeding was noted in 28 of these patients. In contrast, of the 35 patients with benign endometrial lesions, 14 were postmenopausal and 21 were premenopausal; 11 of these patients experienced abnormal vaginal bleeding. The difference in the frequency of abnormal vaginal bleeding between the groups was statistically significant (P<0.05), underscoring the clinical relevance of postmenopausal vaginal bleeding as an indicator of endometrial carcinoma. Histopathological analysis revealed that among the patients with endometrial carcinoma, 27 had endometrial adenocarcinoma, one had endometrial serous carcinoma, and two had endometrial carcinosarcoma. Stratification by FIGO staging identified 19 cases as stage Ia, six as stage Ib, and five as stage II. Additionally, patient characteristics were compared between high- and low-grade endometrial carcinoma subgroups (Supplementary Table 1) following FIGO grading guidelines. The benign endometrial lesion group consisted of 25 cases of endometrial polyps, two of endometrial hyperplasia, seven of submucosal uterine fibroids, and one of atypical polypoid adenomyofibroma.
Five patients initially suspected of having lesions occupying the uterine cavity, as indicated by 2D US, displayed no intrauterine perfusion of contrast agent on CEUS. They were subsequently diagnosed with intrauterine hemorrhage, a finding that was corroborated by hysteroscopy (Fig. 2). At the 3-month follow-up, all five patients exhibited a normal appearance of the intima. Due to the lack of contrast agent perfusion in the uterus, quantitative analysis could not be conducted for these patients, resulting in their exclusion from the study.
Comparison of CEUS Results between Endometrial Carcinoma and Benign Endometrial LesionsQuantitative analysisIn the cohort with endometrial carcinoma, the lesion area demonstrated a significantly higher rate of rise (EI/ET) and a shorter half-clearance time compared to the normal myometrium (P<0.05). However, no significant differences were observed in other parameters between the lesion area and the normal tissue. TIC analysis was also performed for patients with high- and low-grade endometrial cancer, as detailed in Supplementary Tables 2 and 3. Unlike the carcinoma group, within the benign endometrial lesion group, the CEUS TIC parameters displayed no significant differences between lesion area and normal myometrium (P>0.05) (Tables 2, 3).
Qualitative analysisThe qualitative assessment of CEUS TIC parameters revealed distinct contrast agent perfusion patterns between benign and malignant endometrial lesions, with significant differences observed between the groups (P<0.05) (Table 4). Endometrial carcinoma displayed a characteristic "fast-in/fast-out/hyperenhancement" perfusion pattern, whereas benign endometrial lesions generally showed low enhancement (P<0.05). Moreover, most of the benign endometrial lesions (30 of 35) exhibited characteristic angiographic features, such as the "island sign," which indicates a clear demarcation between the benign lesion and normal endometrial tissue (Fig. 3).
Diagnostic performance of CEUSA comparative analysis of the diagnostic performance of CEUS for benign and malignant endometrial lesions, using pathological results as the gold standard, is shown in Table 5. CEUS correctly identified 26 cases of endometrial carcinoma and 32 benign lesions. The results also included four instances of underdiagnosis and three of overdiagnosis, yielding an overall diagnostic accuracy of 89.2%. All four underdiagnosed lesions were stage IA endometrial carcinomas; pathology reports indicated no myometrial invasion in three cases and less than 50% invasion in one case. The three overdiagnoses involved patients with endometrial polyps, including one with glandular complex dysplasia.
CEUS diagnosis of myometrial invasion in patients with endometrial carcinomaAmong the 30 patients with endometrial carcinoma, 25 were diagnosed with pathological stage I disease, while five were diagnosed with stage II. CEUS detected all of the lesions, with a diagnostic accuracy rate of 88% (22/25) for identifying myometrial invasion (Table 6). Notably, CEUS accurately diagnosed 16 of the 19 patients with stage Ia endometrial carcinoma, while three cases were overdiagnosed (Fig. 4). Furthermore, CEUS correctly classified all six patients with stage Ib endometrial carcinoma.
DiscussionEndometrial cancer is a leading malignant neoplasm impacting the female reproductive system, commonly seen in perimenopausal and postmenopausal women. In the last 20 years, its incidence has markedly increased, especially among younger women. Consequently, endometrial cancer has risen to become the second most common gynecologic malignancy, second only to cervical cancer. In certain developed cities, it is the most prevalent of these conditions [7,8].
While postmenopausal vaginal bleeding and endometrial thickening are key clinical indicators for the diagnosis of endometrial cancer, these alone are not sufficient. Additional imaging techniques are essential to improve diagnostic precision. CEUS has emerged as a pivotal tool for distinguishing between benign and malignant endometrial lesions. CEUS enables the assessment of parenchymal organ perfusion by using angiographic microbubbles that mimic the behavior of erythrocytes upon intravascular administration. The movement of these microbubbles into and out of tissues provides insights regarding the status of microcirculatory perfusion [9]. Thus, CEUS offers an advantage over conventional 2D US by facilitating the detailed examination of microcirculatory perfusion patterns, which helps distinguish between benign and malignant conditions.
Prior investigations have revealed marked disparities in CEUS parameters between endometrial cancer and benign lesions [10-13]. However, among TIC parameters, this study identified significant differences between endometrial cancer and normal myometrium only in the rate of rise and the half-clearance time. A high rate of rise indicates a swift increase in contrast volume, while a shortened half-clearance time suggests a faster dissipation of contrast agent. Although the other parameters (AT, TTP, ET, BI, PI, and EI) showed no significant differences, they remain useful for qualitatively assessing the kinetics of the contrast agent in lesion and myometrial areas within a given patient. Endometrial cancer exhibited a distinct perfusion pattern described as "fast-in/fast-out/hyperenhanced," whereas benign endometrial lesions did not display typical contrast agent wash-in or wash-out patterns and only exhibited low enhancement. The CEUS features of endometrial carcinoma are closely linked to its pathophysiology. Endometrial carcinoma is characterized by the formation of neovasculature involving many tortuous blood vessels. The enhancement characteristics of endometrial carcinoma are primarily determined by the density of blood vessels within the tumor, vascular distortion, and the presence of arteriovenous fistula [14]. The high blood supply to the tumor and the large inner diameter of tumor vessels can produce a "fast-in" pattern. The high density and severe torsion of blood vessels in the tumor contribute to the continuous perfusion of the contrast agent, while numerous arteriovenous fistulas shorten the duration of contrast enhancement, causing the agent to disappear more quickly [15]. Consequently, contrast agent perfusion in endometrial carcinoma occurs earlier, more rapidly, and with greater intensity than in normal myometrium. Benign endometrial lesions lack typical angiographic perfusion and wash-out patterns, which may stem from the smaller caliber of the vessels supplying the lesions. Additionally, due to the absence of tortuous small vessels or arteriovenous fistulas in benign lesions, angiography generally does not show persistent high-intensity enhancement or rapid wash-out, an important distinction from endometrial carcinoma. Another diagnostic feature of benign lesions, termed the "island sign," is characterized by greater enhancement following CEUS compared to the surrounding normal endometrial tissue, thus resembling a small island. This finding, not present in angiographic images of endometrial carcinoma, indicates a clear boundary between a benign lesion and the normal endometrial region.
In this study, a quantitative analysis between endometrial cancer and benign lesion cohorts could not be conducted due to interindividual differences in age, heart rate, and body mass index, all of which impact the concentration of contrast microbubbles and the perfusion rate. Consequently, direct quantitative comparisons risked inaccuracies. Instead, this study incorporated a comparative analysis of the endometrial lesion and normal myometrial tissue within the same patient, ensuring a more objective and robust evaluation.
Hysteroscopic vaginal endometrial curettage remains the gold standard for diagnosing endometrial cancer, as it enables precise localization and complete removal of intrauterine lesions. However, determining the depth of myometrial invasion through hysteroscopic curettage can be challenging [16]. Contrast-enhanced magnetic resonance imaging has become the preferred modality for assessing the depth of myometrial invasion, cervical stromal infiltration, and pelvic lymph node metastasis, with reported accuracy rates of 83% to 92% [17]. In this retrospective analysis, the performance of CEUS and FIGO staging was evaluated in 25 patients with early-stage endometrial cancer. The overall accuracy was 88%. Three cases of stage Ia lesions were overdiagnosed due to intrauterine disease or hemorrhage-induced myometrial compression, which interfered with the accurate assessment of myometrial invasion depth. In contrast, all stage Ib endometrial cancers were correctly identified. Accordingly, CEUS represents a valuable tool for conducting preoperative FIGO staging and developing tailored clinical management strategies.
The limitations of this study include its modest sample size and single-center design. Future studies with larger cohorts are essential to validate and generalize the utility of CEUS in the imaging of endometrial cancer.
Transvaginal CEUS has emerged as a practical and effective imaging technique for differentiating benign and malignant endometrial lesions, providing valuable assistance in clinical diagnostics. Additionally, it is useful for assessing the depth of myometrial invasion in patients with early-stage endometrial carcinoma, thereby guiding personalized surgical interventions. Thus, CEUS holds promise as a key resource in determining appropriate clinical surgical plans, highlighting its role in the management of endometrial lesions.
NotesAuthor Contributions Conceptualization: Xu Y, Ying T. Data acquisition: Guo F, Yan Y, Huang C, Wang X, Wu X. Data analysis or interpretation: Guo F, Yan Y, Huang C. Drafting of the manuscript: Guo F, Yan Y, Huang C, Wang X, Wu X. Critical revision of the manuscript: Xu Y, Ying T. Approval of the final version of the manuscript: all authors. AcknowledgementsThe study was supported by the academic project of Shanghai Sixth People’s Hospital (No. ynhg202010).
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