Abstract
Purpose
The aim of the study was to quantitatively analyze the perfusion characteristics of choroidal metastasis using contrast-enhanced ultrasound (CEUS) and compare its perfusion characteristics with these of choroidal hemangioma and choroidal melanoma.
Methods
The patients who were clinically diagnosed with choroidal metastasis were classified as the study group, and the patients who were diagnosed with choroidal hemangioma and choroidal melanoma during the same period were classified as the comparison group. All patients underwent CEUS examination, and Sonoliver was used to obtain the data on quantitative parameters of the tumor and the adjacent normal orbital tissues, including maximum of intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (mTT). Wilcoxon signed rank test was performed to compare the quantitative parameters of choroidal metastasis and normal orbital tissues. Kruskal-Wallis test was adopted to compare the quantitative parameters of the 3 types of tumors, and Bonferroni was used to correct the results of the multiple comparisons. Receiver operating characteristic (ROC) curve analysis was used to identify valuable parameters.
Results
Twenty-six patients (26 eyes) with choroidal metastasis, 55 patients (55 eyes) with choroidal hemangioma, and 49 patients (49 eyes) with choroidal melanoma were enrolled in this study. The IMAX of choroidal metastasis was significantly higher than that of normal orbital tissues, while RT, TTP, and mTT were significantly shorter than these of normal orbital tissues (all p values were <0.001). The IMAX of choroidal metastasis was lower than that of choroidal hemangioma, and RT, TTP, and mTT were shorter than these of choroidal hemangioma and choroidal melanoma (p = 0.002, p = 0.004, p = 0.007). ROC curve analysis showed that areas under the ROC curves (AUCs) of RT and mTT (AUC = 0.851, 95% CI 0.783–0.918 and 0.849, 95% CI 0.783–0.915) were larger.
Conclusion
Quantitative analysis with CEUS can reflect the perfusion characteristics of choroidal metastasis and can exhibit the difference between its perfusion characteristics and these of choroidal hemangioma and choroidal melanoma. RT and mTT may serve as useful parameters for differentiating choroidal metastasis from choroidal hemangioma and choroidal melanoma.
Keywords: Choroidal metastasis, Contrast-enhanced ultrasound, Quantitative analysis
Introduction
Choroidal metastasis, a common intraocular malignancy in adults, is a metastatic lesion originating from malignant tumors in other parts of the body (mostly lung cancer in males and breast cancer in females) [1]. In recent years, the number of choroidal metastasis diagnosed has been increased due to prolonged survival time of patients with malignant tumors and increased detection rate of early choroidal metastasis owing to advanced examination techniques [2]. Patients with choroidal metastasis mostly visit the eye clinic due to impaired vision, visual distortion, and visual field defects, and about 34% of choroidal metastasis was first diagnosed in ophthalmology department [1, 3]. It is relatively easy to diagnose patients with a history of a known primary malignant tumor, but it could be relatively challenging if the initial manifestations of patients are ocular conditions [4]. Early and accurate diagnosis is conducive to early detection of primary malignant tumors, which is of great significance for further treatment of primary malignant tumors, prolonging the survival time of patients, and appropriate treatment of choroidal metastasis so as to save the vision of patients and improve the quality of life. The clinical application of contrast-enhanced ultrasound (CEUS) and contrast agents enables the noninvasive dynamic observation of microvessels and tissue perfusion characteristics of tumors, and constitutes an effective method for the diagnosis and differential diagnosis of tumors [5]. In addition, its application in the diagnosis of ocular diseases has also been reported [6, 7]. In this study, 26 cases of choroidal metastasis were analyzed with CEUS and were compared with choroidal melanoma and choroidal hemangioma, so as to better understand the perfusion characteristics of choroidal metastasis.
Materials and Methods
From January 2015 to December 2017, 26 patients (26 eyes) who were diagnosed as choroidal metastasis and underwent CEUS examination in Beijing Tongren Eye Center of Beijing Tongren Hospital, Capital Medical University, were consecutively recruited. All patients underwent a comprehensive clinical diagnosis, including fundus photography, fundus angiography, and MRI, and all patients had a history of primary malignant tumor. For patients with tumors in both eyes, only the eye with the tumor of greater height was included. Forty-nine patients (49 eyes) with choroidal melanoma confirmed by histopathology and 55 patients (55 eyes) with choroidal hemangioma confirmed by clinical comprehensive diagnosis during the same time period were included for the study of differential diagnosis. Exclusion criteria were patients who were recently treated for primary tumor; patients who were recently treated for ocular tumor; and patients in whom the quantitative analysis could not be performed as the patients were not able to rotate their eyes during the CEUS. Signed informed consent documentation was obtained from all patients before the examination.
The MyLab90 color Doppler ultrasonic diagnosis set (Esaote, Genova, Italy) was used. A frequency of 6–18 MHz was equipped for conventional ultrasonography and color Doppler flow imaging and 3–9 MHz for CEUS. The application for small organs was chosen. The power was adjusted at about 20% in conventional ultrasonography, and the mechanical index was kept below 0.4. Conventional ultrasonography was performed to observe the location, size, shape, and internal echogenicity as well as blood supply in lesions, so as to identify the best section for CEUS. Low mechanical index, real-time contrast imaging was used for CEUS, and SonoVue (sulfur hexafluoride microbubbles; Bracco, Milan, Italy) was chosen as the contrast agent and was prepared in accordance with the instructions. One-milliliter intravenous bolus injection of SonoVue was given, followed by a 5 mL saline flush. Once the injection starts, the recording will start and last for 5 min. The results were exported in DICOM format.
DICOM data were analyzed offline with Sonoliver (Tomtec, Unterschleißheim, Germany). Three regions of interest (ROI) were outlined: (1) ROI for border, both tumor and normal tissue; (2) ROI for analysis, entire tumor; and (3) ROI for reference, normal orbital tissue adjacent to tumor and with the same size as tumor. The time-intensity curve was generated automatically (Fig. 1), and 4 quantitative parameters were extracted, including maximum of intensity (IMAX, the intensity of reference region was defined as 100% so as to evaluate the enhancement of signal intensity in tumor compared with the reference region), rise time (RT, the time for the intensity to increase from 10% to 100% of the peak intensity), time to peak (TTP, the time from the first appearance of contrast agent in ROI to reaching the peak intensity), and mean transit time (mTT, the time for the intensity to decrease from peak intensity to 50% of the peak intensity).
Fig. 1.
CEUS image (Esaote MyLab90) and the time-intensity curve of a 59-year-old female patient with choroidal metastasis. a CEUS image of choroidal metastasis: the region within the blue line is the ROI for the border region, the region within the green line is the ROI for analysis, and the region within the yellow line is the ROI for reference. b Time-intensity curve of choroidal metastasis was generated automatically by Sonoliver. Contrast agent dynamics in the reference region (yellow lines) and analysis region (green lines) are shown. Thin lines are original dynamic perfusion curves, and thick lines are perfusion curves after a best-fitting analysis. CEUS, contrast-enhanced ultrasound; ROI, region of interest.
All analyses were performed using SAS statistical software version 9.4 (SAS Inc., Cary, NC, USA). A 2-tailed p value <0.05 was considered statistically significant. Mean, standard deviation, median, and interquartile ranges were given as descriptive statistics. Normality distribution was tested with the Shapiro-Wilk test. The differences of basic features were analyzed with Kruskal-Wallis test and χ2 test. A Spearman correlation analysis was used to determine the correlation between the size and quantitative parameters of 3 tumors. The differences of the quantitative parameters between metastasis and normal eye tissue were analyzed with Wilcoxon signed rank test. Kruskal-Wallis was used to analyze the quantitative parameters' difference between choroidal metastasis and the other 2 tumors. For multiple comparisons, Bonferroni correction was applied. Boxplots were used to show the data distribution of 3 groups. Choroidal metastasis cases were defined as the case group, and choroidal hemangioma and melanoma cases were merged into 1 group, the control group. Receiver operating characteristic (ROC) curve for each quantitative parameter was drawn, and the value of the area under the ROC curve (AUC) was used to identify valuable parameters.
Results
The study included 130 cases of choroidal tumors: 26 eyes with choroidal metastasis, 55 with choroidal hemangioma, and 49 with choroidal melanoma. Results of the Shapiro-Wilk test showed that all the continuous variables were not normally distributed; they were non-Gaussian (supplementary material, available online at www.karger.com/doi/10.1159/000510777). The median age of patients was 52 (22–77) in choroidal metastasis group, 47 (25–69) in choroidal hemangioma group, and 45 (21–72) in choroidal melanoma group (p = 0.389). The median greatest height of tumors was 4.8 mm (2.2–12.5) for choroidal metastasis, 3.2 mm (1.4–7.3) for choroidal hemangioma, and 9.9 mm (3.7–14.7) for choroidal melanoma (p < 0.001). The median largest basal diameter of tumors was 14.6 mm (8.3–19.2) for choroidal metastasis, 9.1 mm (5.7–12.0) for choroidal hemangioma, and 13.7 mm (7.9, 21.6) for choroidal melanoma (p < 0.001). The characteristics of patients are presented in Table 1. The correlation analysis showed that in these 3 types of tumors, there was no significant correlation (all p values were >0.05) between the tumor size (the greatest height and the largest basal diameter) and the CEUS quantitative parameters (IMAX, RT, TTP, and mTT). The details of correlation analysis are shown in Table 2.
Table 1.
The characteristics of patients
| Variable | Metastasis (n = 26) | Hemangioma (n = 55) | Melanoma (n = 49) | Statistics | p value |
|---|---|---|---|---|---|
| Age, years (median, range) | 52 (22–77) | 47 (25–69) | 45 (21–72) | H = 1.8876 | 0.389 |
| Sex, n (%) | |||||
| Male | 7 (27) | 37 (67) | 27 (55) | ||
| Female | 19 (73) | 18 (33) | 22 (45) | χ2 = 11.603 | 0.003 |
| Tumor size, mm (median, range) | |||||
| Height | 4.8 (2.2–12.5) | 3.2 (1.4–7.3) | 9.9(3.7–14.7) | H = 77.6754 | <0.001 |
| Base | 14.6 (8.3–19.2) | 9.1 (5.7–12.0) | 13.7(7.9–21.6) | H = 69.1167 | <0.001 |
| Pathologic diagnose, n | 0 | 0 | 49 | ||
| Clinical diagnose, n | 26 | 55 | 0 | ||
| Primary tumor, n (%) | |||||
| Lung carcinoma | 12 (46) | 0 | 0 | ||
| Breast carcinoma | 8 (31) | 0 | 0 | ||
| Renal cell carcinoma | 3 (12) | 0 | 0 | ||
| Thymic carcinoma | 2 (8) | 0 | 0 | ||
| Thyroid carcinoma | 1 (4) | 0 | 0 | ||
Table 2.
Correlation analysis on tumor size and quantitative parameters
| Types of tumor | Parameters | Height |
Base |
||
|---|---|---|---|---|---|
| r | p value | r | p value | ||
| Metastasis | IMAX | −0.13 | 0.53 | −0.32 | 0.11 |
| RT | 0.00 | 1.00 | −0.05 | 0.82 | |
| TTP | −0.16 | 0.44 | −0.20 | 0.33 | |
| mTT | 0.24 | 0.24 | 0.16 | 0.45 | |
|
| |||||
| Hemangioma | IMAX | 0.16 | 0.25 | 0.14 | 0.31 |
| RT | −0.06 | 0.66 | −0.11 | 0.42 | |
| TTP | −0.14 | 0.32 | −0.14 | 0.31 | |
| mTT | −0.03 | 0.85 | −0.12 | 0.40 | |
|
| |||||
| Melanoma | IMAX | −0.01 | 0.94 | −0.07 | 0.61 |
| RT | 0.14 | 0.34 | −0.18 | 0.21 | |
| TTP | 0.02 | 0.91 | −0.15 | 0.29 | |
| mTT | 0.13 | 0.36 | −0.26 | 0.07 | |
IMAX, maximum of intensity; RT, rise time; TTP, time to peak; mTT, mean transit time.
The median IMAX of choroidal metastasis was 216.2% (183.2, 258.3), significantly higher than that of the normal orbital reference tissue (100.0% [100.0, 100.0]; S = 175.5; p < 0.001). The median RT, TTP, and mTT of choroidal metastasis were 12.6 s (11.3, 14.8), 20.2 s (18.2, 24.0), and 29.9 s (24.7, 33.3), significantly shorter than those of normal orbital reference tissue (18.4 s [15.2, 20.2], 23.1 s [21.2, 27.4], 49.4 s [41.5, 51.8]; S = −163.5, −124, −175.5; all p values were <0.001). See Table 3.
Table 3.
Comparison of quantitative parameters of choroidal metastasis and normal orbital reference tissue (median and interquartile)
| Group | IMAX, % | RT, s | TTP, s | mTT, s |
|---|---|---|---|---|
| Metastasis | 216.2 (183.2, 258.3) | 12.6 (11.3, 14.8) | 20.2 (18.2, 24.0) | 29.9 (24.7, 33.3) |
| Normal eye tissue | 100.0 (100.0, 100.0) | 18.4 (15.2, 20.2) | 23.1 (21.2, 27.4) | 49.4 (41.5, 51.8) |
| S | 175.5 | −163.5 | −124 | −175.5 |
| p value | <0.001 | <0.001 | <0.001 | <0.001 |
IMAX, maximum of intensity; RT, rise time; TTP, time to peak; mTT, mean transit time.
The median IMAX of choroidal metastasis was 216.2% (183.2, 258.3), significantly lower than that of hemangioma (294.9% [218.7, 380.9]; Z = −3.612, p < 0.001), but not significantly different from that of choroidal melanoma (198.5% [149.8, 232.2]; Z = 1.469; p = 0.073). The median RT, TTP, and mTT of choroidal metastasis were 12.6 s (11.3, 14.8), 20.2 s (18.2, 24.0), and 29.9 s (24.7, 33.3), shorter than those of choroidal hemangioma (20.7 s [17.2, 23], 23.8 s [21.3, 27.1], and 59.3 s [51, 76.7]; Z = −6.874, −3.207, −7.117; all p values were <0.001) and also significantly shorter than those of choroidal melanoma (15.4 s [12.1, 17.7], 24.1 s [20.5, 26.7], and 34.4 s [29.0, 42.4]; Z = −2.978, −2.833, −2.666; p = 0.002, p = 0.004, p = 0.007). See Table 4. The distributions of quantitative parameters of 3 types of tumors are shown in Figures 2, 3, 4, 5. The ROC curves of the 4 parameters (IMAX, RT, TTP, and mTT) of the case group and the control group are shown in Figure 6. ROC curve analysis showed that the AUCs (AUC = 0.851, 95% CI 0.783–0.918 and 0.849, 95% CI 0.783–0.915) of RT and mTT were larger than these of the IMAX or TTP (AUC = 0.583, 95% CI 0.484–0.683 and 0.712, 95% CI 0.595–0.828). The results demonstrated that the RT and mTT could differentiate between the 2 groups compared with the IMAX and TTP.
Table 4.
Basic statistical descriptions and comparisons of quantitative parameters of 3 types of tumors (median and interquartile)
| Parameters | Metastasis | Hemangioma | Melanoma | a | b |
|---|---|---|---|---|---|
| IMAX | 216.2 (183.2, 258.3) | 294.9 (218.7, 380.9)* | 198.5 (149.8, 232.2) | Z = −3.612, p < 0.001 | Z = 1.469, p = 0.073 |
| RT | 12.6 (11.3, 14.8) | 20.7 (17.2, 23)* | 15.4 (12.1, 17.7)* | Z = −6.874, p < 0.001 | Z = −2.978, p = 0.002 |
| TTP | 20.2 (18.2, 24.0) | 23.8 (21.3, 27.1)* | 24.1 (20.5, 26.7)* | Z = −3.207, p < 0.001 | Z = −2.833, p = 0.004 |
| mTT | 29.9 (24.7, 33.3) | 59.3 (51.0, 76.7)* | 34.4 (29.0, 42.4)* | Z = −7.117, p < 0.001 | Z = −2.666, p = 0.007 |
IMAX, maximum of intensity; RT, rise time; TTP, time to peak; mTT, mean transit time.
Indicates statistical significance at the level of 0.025; as multiple comparisons were performed, p value was corrected with Bonferroni method. a refers to metastasis versus hemangioma. b refers to metastasis versus melanoma.
Fig. 2.
IMAX distribution of 3 types of tumors. IMAX, maximum of intensity.
Fig. 3.
RT distribution of 3 types of tumors. RT, rise time.
Fig. 4.
TTP distribution of 3 types of tumors. TTP, time to peak.
Fig. 5.
mTT distribution of 3 types of tumors. mTT, mean transit time.
Fig. 6.
ROC curve analysis of 4 perfusion parameters. ROC, receiver operating characteristic; IMAX, maximum of intensity; RT, rise time; TTP, time to peak; mTT, mean transit time.
Discussion
Ultrasonography is an important approach for the diagnosis and follow-up of intraocular tumors. Typical choroidal metastases are characterized by diffuse thickening in the eyeball wall, homogeneous moderate to high echoes, and irregular surface on ultrasound examination [4]. Color Doppler flow imaging allows real-time observation on the characteristics of blood flow in the tumor [8]. Previous literature has reported that choroidal metastases and choroidal melanomas can be differentiated based on the velocity of blood flow in the tumor vessels and presence of central dominant vessels in the tumor [9]. Although color Doppler flow imaging could obtain the information on blood flow in the lesion, under the condition of insufficient blood supply, extremely high intraocular pressure, low blood flow velocity, or because of the limited sensitivity of the instrument for the detection of blood flow, it may only be able to exhibit low blood flow signal (if any) in the lesion, leading to inaccurate diagnosis or even misdiagnosis as nontumorous lesion [10, 11].
The sensitivity of ultrasound for the detection of blood vessel can be significantly improved by enhancing the backscatter of blood with intravenous injection of contrast agent in CEUS [12]. In this study, CEUS revealed marked contrast agent uptake in all tumors, which was helpful for differentiating the tumor from other diseases, such as subretinal hemorrhage. Ultrasound contrast agent circulates only in the blood vessel, and its behavior in the blood vessel is similar to that of red blood cells; thus, it can be used as a tracer of red blood cells [13]. Although the concentration of contrast agent in blood vessel cannot be directly measured, relevant studies have proved that the concentration of contrast agent in blood vessel is linearly related to the signal intensity in the obtained image [14]. The change in signal intensity of contrast agent can reflect the change in contrast agent concentration in blood vessel with time. Perfusion characteristics of different tissues vary. For tumors, neovascularization provides nutrition and oxygen for the growth of tumors and thus constitutes the foundation of the growth, invasion, and metastasis of tumors, and is closely related to the development, progression, and prognosis of tumors [15]. Therefore, the indirect evaluation of the perfusion characteristics of tumors on the basis of the signal intensity of contrast agent and its changes is of great value for the diagnosis and differential diagnosis of tumors [16].
The quantitative parameters obtained with CEUS in this study included intensity parameters IMAX and time parameters RT, TTP, and mTT, which were commonly used for the quantitative analysis of CEUS [17]. Although the height and basal diameter of 3 types of tumors varied, there was no correlation between the height and basal diameter and the quantitative parameters after excluding the influence of the size of the tumors on the quantitative parameters in CEUS. The intensity parameter IMAX reflects the perfusion volume of contrast agent in tumors. Choroidal metastasis has rich blood supply and abundant neovascularization; hence, compared with the adjacent normal orbital tissue, choroidal metastasis has greater perfusion volume [9, 18]. CEUS showed that IMAX of choroidal metastasis was higher. Choroidal melanoma is also a hypervascular malignant tumor, but its IMAX was not significantly different from that of choroidal metastasis. It is generally believed that benign tumors have less blood supply, but choroidal hemangioma is a unique type of vascular disease consisting of rich but enlarged thin-walled blood vessels and a small amount of connective tissue stroma. In this study, the IMAX of choroidal hemangioma was significantly higher than that of choroidal metastasis, which accurately reflected the hypervascular feature of choroidal hemangioma and the difference of perfusion volume between choroidal hemangioma and choroidal metastasis. Time parameters RT and TTP reflect the speed of contrast agent entering the tissue, while mTT reflects the clearance speed of contrast agent. Because of the high blood flow velocity in malignant tumors, the abnormal vascular anastomosis, vascular circle, and arteriovenous fistula between neovascularization and arteries and veins, choroidal metastases are characterized by faster entry and clearance of contrast agent compared with adjacent normal orbital tissues [15, 19]. Although choroidal hemangioma is also a hypervascular disease, its blood vessels are mainly composed of lumens with low blood flow velocity and such a histopathological feature can explain the longer RT, TTP, and mTT of choroidal hemangioma in comparison with choroidal metastasis [19]. Though both choroidal metastasis and choroidal melanoma are malignant tumors, CEUS showed that choroidal metastasis had shorter RT, TTP, and mTT, which may be explained by the fact that choroidal melanoma grows slower than choroidal metastasis does, and the vessels of choroidal melanoma are relatively maturer. Meanwhile, the rapid growth of choroidal metastasis requires abundant neovascularization for nutrition supply; therefore, it has more unique vascular structures such as vascular circle and arteriovenous fistula to ensure faster circulation. In recent years, anti-neovascularization drugs have been used in the treatment of choroidal metastasis and were proven to be effective to a certain extent, indirectly illustrating the feature of abundant neovascularization in choroidal metastasis [20]. In addition, previous studies have reported higher systolic blood flow velocity in choroidal metastases compared with choroidal melanomas, which may explain the faster entry and clearance of contrast agent in choroidal metastasis [21]. In this study, ROC analysis was further performed for the 4 parameters, which revealed that the AUCs of RT and mTT were larger, suggesting that RT and mTT were better parameters for distinguishing choroidal metastasis from control cases.
In conclusion, we quantitatively analyzed the perfusion characteristics of choroidal metastasis with CEUS, which revealed differences in perfusion among choroidal metastasis, choroidal hemangioma, and choroidal melanoma. RT and mTT may serve as useful parameters for differentiating choroidal metastasis from choroidal hemangioma and choroidal melanoma.
Statement of Ethics
This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethical Review Committee of Beijing Tongren Hospital, Capital Medical University.
Conflict of Interest Statement
The authors declare that they have no competing interests.
Funding Sources
This work was supported by the Science & Technology Project of Beijing Municipal Science & Technology Commission (Z151100001615052).
Author Contributions
D.L. and W.Y. performed study design and concept and wrote the manuscript; D.L., Z.W., W.C., Q.Z., Y.L., R.C., L.S., Q.L., and Y.L. involved in data acquisition; D.L. and K.C. carried out data analysis; D.L., W.Y., and W.W. revised the manuscript.
Data Availability Statement
The data will be available upon reasonable request.
Supplementary Material
Supplementary data
Funding Statement
This work was supported by the Science & Technology Project of Beijing Municipal Science & Technology Commission (Z151100001615052).
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Supplementary Materials
Supplementary data
Data Availability Statement
The data will be available upon reasonable request.
