Clinical Value Study on Contrast-Enhanced Ultrasound Combined with Enhanced CT in Early Diagnosis of Primary Hepatic Carcinoma.

Objective: To explore the clinical value of contrast-enhanced ultrasound combined with enhanced CT in the early diagnosis of primary hepatic carcinoma (PHC).
Methods: 84 patients with suspected PHC in the early stage treated in our hospital from January 2020 to January 2022 were selected as the study subjects. All patients underwent contrast-enhanced ultrasound and enhanced CT examinations, and the surgery was performed for resection of lesions within 1 month. According to the results of postoperative pathology diagnosis, the benign group and the malignant group were included. The case data were viewed for the retrospective study to analyze the clinical application value by evaluating the diagnostic efficiency of contrast-enhanced ultrasound, enhanced CT, and their combination for PHC.
Results: Among 84 suspected patients, 70 patients had PHC (malignant group) and 14 patients had other hepatic lesions (benign group) after postoperative histopathological examination. There was no significant difference in age, gender, clinical symptoms, and educational level between the two groups (P > 0.05), with obvious differences in the history of chronic hepatic disease, smoking, drinking, and infection of hepatitis B virus (HBV) between the two groups (P < 0.05). The enhancement time and regression time of the two groups were significantly different (P < 0.05), with no statistical difference in the enhancement pattern of photography (P > 0.05). For patients with PHC, the imaging features of the two inspection methods at arterial phase and lag phase were statistically different (P < 0.05). Taking pathologic findings as the gold standard, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of joint diagnosis were significantly higher than those of contrast-enhanced ultrasound and enhanced CT (P < 0.05), and the area under the curve of joint diagnosis was obviously larger than that of contrast-enhanced ultrasound and enhanced CT by placing the ROC curve for examination (P < 0.05).
Conclusion: The combination of contrast-enhanced ultrasound and enhanced CT has a higher accuracy in the early diagnosis of PHC, and the diagnostic efficiency of contrast-enhanced ultrasound is higher than that of enhanced CT. In clinical practice, the physical condition and state of illness in patients should be fully considered, and the most suitable examination method should be selected to reduce their medical burden by taking into account their economic situation.

1. Introduction

According to statistics, there are about 6.35 million patients with new-onset malignant tumor worldwide each year, while about 260 thousand patients have primary hepatic carcinoma (PHC), accounting for 4.1% [1-3], and China is the main high-incidence area for hepatic carcinoma. Because of its hidden onset, short course of disease and poor prognosis, it seriously affects public health and also brings a heavy burden to society and medical treatment in China. Early diagnosis is one of the most important measures to prevent hepatic carcinoma and improve the survival rate of patients with hepatic carcinoma, so the important direction of current study is to explore simple, convenient, and fast diagnostic methods. The alpha-fetoprotein (AFP) in serum is an important serum index for the early diagnosis of PHC, but the false negative rate is higher in the early diagnosis of small hepatic carcinoma, so that the hot spot in clinical study is to look for other effective diagnostic methods [4-6]. With the progress of modern electronic technology, medical imaging continues to develop. At present, ultrasound, X-ray, CT, radionuclide, and magnetic resonance imaging constitute four major systems of imaging diagnosis in modern medicine, which have been widely used in clinical departments and make early detection of PHC possible. Among them, ultrasound and CT are used usually, but conventional ultrasound has some limitations, such as conventional CT with a longer scanning time. In addition, the advantage of contrast-enhanced ultrasound examination is that it can effectively improve the diagnosis sensitivity and specificity of PHC by real-time observation of blood perfusion in hepatic tissues, while enhanced CT is a focused examination after injection of radiography agent into suspect area on the basis of plain scan [7-9]. However, the international guidelines recommend enhanced CT as the first-line method of imaging examination for PHC at present, while contrast-enhanced ultrasound is only used as a second-line inspection means, with a controversy in diagnostic value. Therefore, this article will select some clinical cases to carry out a retrospective study to analyze the application value of contrast-enhanced ultrasound combined with enhanced CT in the early diagnosis of PHC, in order to provide new ideas and ways for early screening and diagnosis of PHC and reduce the overall medical and economic burden on society.

Inclusion criteria. (1) Patients were diagnosed as suspected cases by B-ultrasound examination and early screening of AFP and underwent contrast-enhanced ultrasound and enhanced CT examination at the same time. (2) Patients were treated with surgical treatment in our hospital, with clear results for pathology diagnosis. (3) The time interval between imaging examination and surgery did not exceed 1 month. (4) The age was more than 18 years old. (5) Patients and their families were informed of the purpose and process of this study and signed informed consent. (6) The study complied with the Declaration of Helsinki (2013) [10].

Exclusion criteria. (1) Patients with previous history of hepatic space-occupying lesions for surgical resection; (2) patients with previous history of chemoradiotherapy in local lesions; (3) patients with the venous tumor thrombus or satellite nodules; (4) patients with the diffuse nodule in liver; (5) patients with the coagulopathy; and (6) patients who did not meet the indications of contrast-enhanced ultrasound and enhanced CT examination, such as iodine allergy.

2. Materials and Methods

2.2. Screening in Patients

84 patients with suspected PHC in the early stage treated in our hospital from January 2020 to January 2022 were selected as the study subjects. All patients underwent contrast-enhanced ultrasound and enhanced CT examinations, and the surgery was performed for resection of lesions within 1 month. According to the results of postoperative pathology diagnosis, the benign group and the malignant group were included. The case data were viewed for the retrospective study, with 54 male patients and 30 female patients in the two groups. The study was approved and supervised the implementation by the ethics committee of our hospital.

2.3. Imaging Examination

2.3.1. Contrast-Enhanced Ultrasound

The conventional liver ultrasound was performed after the photography to record the lesion location, quantity, size, and feature, and the patients were examined by contrast-enhanced ultrasound using a color ultrasound diagnosis instrument, with the setting frequency of 3–5 MHz. 2.4 ml of Sono Vue radiography agent dissolved in 0.9% of NaCl solution at a dose of 5 ml was injected completely by the superficial cubital vein in 3 seconds. 59 mg of sulfur hexafluoride gas was injected into 0.9% of NaCl solution at a dose of 5 ml, with a PH of 4.6–7.6 to form microbubbles with an average diameter of 2.5 μm by peripheral vein injection at a dose of 1.5–2.0 mL. The contrast-enhanced ultrasound imaging (CNTI) was used to regularly observe and store the changes in echo intensity of photography in the lesion area in the form of dynamic video. During the contrast examination of the target lesion, the morphology, size, boundary, blood flow signal, and echo of the lesion were observed by gray scale and color Doppler ultrasound, and the enhanced and extinctive methods of photography in the lesion were regularly observed in the whole process after entering the state of photography. When there was no clear target examination in lesions, the whole liver was observed by gray scale and color Doppler ultrasound, and then the manifestation of contrast-enhanced ultrasound in the left and right hepatic lobes was observed. Finally, the probe was continuously rotated to observe whether there was an abnormal area filled with radiography agent in the arterial phase, portal phase, and lag phase. When the low echo area was found, the observation of contrast-enhanced ultrasound was performed again after confirming the target site, and the patients kept breathing smoothly and stayed with the probe fixed during photography. For elderly patients with difficulties in breath holding, the examination of oxygen inhalation in photography was performed to ensure that the timing images of small lesions can be captured. After obtaining the timing images with diagnostic significance in photography, the whole liver was quickly scanned to explore the new lesions with weak echo after the withdrawal of the radiography agent. The small lesions in the insufficient area of imaging were observed in full time, and the examination was repeated 6–10 min after the end of imaging.

After the contrast-enhanced ultrasound, the videos of each period were viewed by two ultrasound physicians with good working experience to perform the screening of photography. The qualitative diagnosis was made in combination with clinical indicators using the double-blind method, and the consistent diagnostic results were given after consultation if the diagnostic results were inconsistent.

2.3.2. Enhanced CT

CT scan examination was performed with GE 16-slice spiral CT scanner in USA, and patients held high their upper arms and relaxed their abdomen when they were in supine position, with the scanning range from diaphragmatic top to iliac crest. The setting parameters were as follows: 120 kV of voltage, 240 mA of current, 3 mm of slice thick, and 512 × 512 of matrix. The enhanced scan was performed after the end of plain scan, and 100 ml of meglumine diatrizoate injection (specification: 100 ml; manufacturer: Xi'an Libang Pharmaceutical Co., Ltd.; NMPA approval No.: H61023349) was used by peripheral elbow venous injection at a flow velocity as 3 ml/s, with 25 s of delay scanning at the arterial phase, 60 s of delay scanning at the portal venous phase, and 120 s of delay scanning at the equilibrium phase. The image reconstruction of primal data was performed after the end of scanning.

The qualitative diagnosis was made by two ultrasound physicians with good working experience combined with clinical indicators using the double-blind method, and the consistent diagnostic results were given after consultation if the diagnostic results were inconsistent.

2.4. Surgical Treatment

All patients met the surgical indications and completed the corresponding preoperative examination. According to the specific conditions of each patient, the lesions were removed by surgery, and a histopathological examination was performed after surgery.

2.5. Observation Indices

The pathological results were the gold standard to compare and analyze the manifestation of contrast-enhanced ultrasound and signs and symptoms of enhanced CT in the two groups, and the data were integrated to evaluate the diagnostic efficacy of contrast-enhanced ultrasound, enhanced CT, and their combination in early PHC.

2.6. Statistical Treatment

In this study, the experimental data were processed by SPSS22.0 to calculate the differences between the two groups, and GraphPad Prism 7 (GraphPad Software, San Diego, USA) was used to draw pictures of the data. The study data including enumeration data and measurement data were tested by x2 and t-test, indicated by (n (%)) and ( ± s), which were in line with normal distribution. When P < 0.05, the differences in data between the two groups were considered to be statistically significant.

3. Results

3.1. Condition of Histopathology and Statistics of Routine Data

Among 84 suspected patients, 70 patients had PHC (included in malignant group) and 14 patients had other hepatic lesions (included in benign group) after postoperative histopathological examination. There was no significant difference in routine data such as age, gender, clinical symptoms, and educational level between the two groups (P > 0.05), with significant differences in history of chronic hepatic disease, smoking, drinking, and infection of HBV between the two groups (P < 0.05) as shown in detail in Table 1.

Table 1

Routine data of patients.

Observation indices	Malignant group (n = 70)	Benign group (n = 14)	X 2/t	P
Age (years)	57.19 ± 8.29	57.00 ± 8.54	0.078	0.938
Gender			1.493	0.222
Male	43 (61.43)	11 (78.57)
Female	27 (38.57)	3 (21.43)
Clinical symptoms
Nausea and vomiting	51 (72.86)	10 (71.43)	0.012	0.913
Fatigue and anorexia	33 (47.14)	7 (50.00)	0.038	0.845
Abdominal distension	37 (52.86)	8 (57.14)	0.086	0.769
Hepatic pain	57 (81.43)	11 (78.57)	0.062	0.804
Continuable low fever	18 (25.71)	4 (28.57)	0.049	0.824
History of chronic hepatic disease	37 (52.86)	3 (21.43)	4.620	0.032
Educational level			0.010	0.919
Below high school	26 (37.14)	5 (35.71)
High school and above	44 (62.86)	9 (64.29)
Smoking (average ≥1 piece/d, lasting for 1 year)	34 (48.57)	2 (14.29)	5.600	0.018
Drinking (≥60 tael/month)	41 (58.57)	3 (21.43)	6.453	0.011
Infection of HBV (positive HbsAg)	55 (78.57)	6 (42.86)	7.454	0.006

3.2. Contrast-Enhanced Ultrasound Diagnosis

The enhancement time and regression time of the two groups were significantly different (P < 0.05), with no statistical difference in enhancement pattern of photography (P > 0.05) as shown in detail in Table 2.

Table 2

Performance of contrast-enhanced ultrasound.

Groups	Enhancement time (s)	Regression time (s)	Enhancement pattern of photography
			Fast in fast out	Fast in same out
Malignant group (n = 70)	17.57 ± 3.07	83.17 ± 10.23	32 (45.71)	38 (54.29)
Benign group (n = 14)	7.64 ± 3.04	230.71 ± 11.48	6 (42.86)	8 (57.14)
t/X2	11.065	48.279	1.090
P	<0.001	<0.001	0.296

3.3. Comparison of Imaging Features in Patients with PHC

According to the statistics results in Figure 1, the imaging features of the two inspection methods at arterial phase and lag phase were statistically different (P < 0.05) as shown in the specific images in Figure 2.

Figure 1

Comparison of imaging features in 70 patients with PHC (%). Notes: the imaging features of contrast-enhanced ultrasound were as follows: arterial phase (66 cases with high enhancement and 4 cases with equal enhancement), portal phase (10 cases with equal enhancement and 60 cases with low enhancement), and lag phase (3 cases with equal enhancement and 67 cases with low enhancement). The imaging features of enhanced CT were as follows: arterial phase (55 cases with high enhancement and 15 cases with equal enhancement), portal phase (17 cases with equal enhancement and 53 cases with low enhancement), and lag phase (10 cases with equal enhancement and 60 cases with low enhancement). represents a significant difference in imaging features between the two inspection methods at arterial phase (X2 = 7.368, P < 0.001). represents a significant difference in imaging features between the two inspection methods at lag phase (X2 = 4.155, P=0.042).

Figure 2

Imaging data of patients with PHC. (a) Shows a male PHC patient' picture of contrast-enhanced ultrasound at arterial phase, whose name was Chen Li and age was 69 years old. (b) Shows a male PHC patient' picture of contrast-enhanced ultrasound at arterial phase, whose name was Chen Gengui and age was 60 years old. (c) Shows a male PHC patient' picture of contrast-enhanced ultrasound at lag phase, whose name was Shen Dahong and age was 71 years old. (d) Shows a PHC patient' picture of contrast-enhanced ultrasound at lag phase, whose name was Chen Hongxiu and age was 63 years old.

3.4. Diagnostic Efficacy

Taking pathological findings as the gold standard, the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of joint diagnosis were significantly higher than those of contrast-enhanced ultrasound and enhanced CT (P < 0.05), and the area under the curve of joint diagnosis was obviously larger than that of contrast-enhanced ultrasound and enhanced CT by placing the ROC curve for examination (P < 0.05) as shown in detail in Tables 3–5 and Figure 3.

Table 3

Comparison of same pathological findings.

Pathological findings	Joint diagnosis		Contrast-enhanced ultrasound		Enhanced CT		Summing
	+	−	+	−	+	−
+	65	5	60	10	57	13	70
−	1	13	3	11	4	10	14
Summing	66	18	63	21	61	23

Table 4

Diagnostic efficacy.

Diagnostic methods	Accuracy	Sensitivity	Specificity	Positive predictive value	Negative predictive value
Joint diagnosis	92.86	92.86	92.86	98.48	72.22
Contrast-enhanced ultrasound	84.52∗	85.71∗	78.57∗	95.24∗	52.38∗
Enhanced CT	79.76∗	81.43∗	71.43∗	93.44∗	43.48∗

Note: represented that P was less than 0.05 compared with joint diagnosis.

Table 5

Area under the curve.

Inspection variables	Area	Standard errora	Asymptotic sig.b	Asymptotic 95% confidence interval
Joint diagnosis	0.929	0.044	<0.001	0.000–1.000
Contrast-enhanced ultrasound	0.821	0.068	<0.001	0.687–0.955
Enhanced CT	0.764	0.076	0.002	0.616–0.912

Notes: areferred to the nonparametric hypothesis; bmeant null hypothesis, namely, real area as 0.5; and sig. is the P value.

Figure 3

ROC curve.

4. Discussion

PHC is a malignant tumor with high mortality in clinic, and China is a high incidence area of PHC according to epidemiological information. Therefore, the form of prevention and diagnosis and treatment on PHC in China is very serious, which has gradually become a public health problem, threatening the health and quality of life of residents. A large number of previous studies have shown that disease progression of hepatic carcinoma develops faster than other malignant tumors, which is related to the dual blood supply of the hepatic artery and portal vein to the liver [11, 12]. In addition, surgery is the main radical treatment for PHC at present, and some patients have been diagnosed in the middle and late stages due to the lack of obvious symptoms in the early clinical stage and the rapid development of the disease, while surgical treatment is difficult and patients even miss the operative chance. Therefore, early diagnosis is of great significance to improve the success rate of surgery and prognosis. At present, PHC is mainly found early by imaging examination technology in clinic, and the inspection methods like ultrasound and CT are used usually for early diagnosis, with an obvious advantage, but conventional ultrasound and CT examination have certain limitations for smaller lesions [13, 14]. According to previous clinical experience, different methods of imaging examination have their own characteristics in the diagnosis of hepatic carcinoma, and the complementary advantages, integrated application and comprehensive assessment are also more emphasized for early diagnosis. Therefore, this study analyzed the application efficiency of contrast-enhanced ultrasound combined with enhanced CT in the early diagnosis of PHC to provide a reference for the early diagnosis of PHC.

In this study, 70 patients had PHC (malignant group) and 14 patients had other hepatic lesions (benign group) after postoperative histopathological examination among 84 suspected patients. There were significant differences in history of chronic hepatic disease, smoking, drinking and infection with HBV between the two groups (P < 0.05), which were consistent with the results of David et al. [15-17], and the results have shown that the chance of hepatocellular carcinoma in HBsAg-positive patients is 25–37 times higher than that in noninfected population. In addition, familial aggregation of HBV infection can significantly increase the incidence of HBV-related hepatic carcinoma. It is also reported that obesity, psychological factors, and diabetes are associated with the occurrence of PHC, with a synergistic effect [18-21]. Due to the special characteristics of hepatic carcinoma, it has a higher guiding value to clarify the risk factors that are easy to cause diseases and to develop prevention measures and early screening in the clinic, so that large-sample and multi-center studies in this direction can be carried out in subsequent studies to further explore its potential application value in early screening and prevention of PHC. Furthermore, the enhancement time and regression time of the two groups were significantly different in the contrast-enhanced ultrasound examination (P < 0.05), with no statistical difference in the enhancement pattern of photography (P > 0.05). For patients with PHC, the imaging features of the two inspection methods at arterial phase and lag phase were statistically different (P < 0.05). When PHC occurs, the atypical dual blood supply of the portal vein and hepatic artery is gradually transformed into arterial blood supply mainly, which is accompanied by a series of hemodynamic changes in the liver at the same time. Compared with soft tissue, the scattered echo intensity of blood cells is lower, showing no echo in the ultrasound image, and conventional ultrasound examination often results in poor microvascular imaging due to limited resolution. The contrast-enhanced ultrasound examination enhanced the haemal scattering in the backward direction by the radiography agent, which could present the blood flow state of the lesion more clearly. At the same time, the radiography agent in the blood was not easy to produce pseudomorphism, which could clearly show the blood perfusion characteristics of different phases in lesions, thereby improving the detection rate of PHC [22-24]. In the early diagnosis of no clear lesion, it is necessary to observe whether there is an abnormal area filled with radiography agent or a small lesion that cannot be detected in the arterial phase, portal phase, and lag phase. If there is an abnormality in the low echo area, it is necessary to inject radiography agent for contrast-enhanced ultrasound after clarifying the target area, and observe the enhancement mode of contrast-enhanced ultrasound in the target area to determine whether the abnormality is benign or malignant.

Taking pathologic findings as the gold standard, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of joint diagnosis were significantly higher than those of contrast-enhanced ultrasound and enhanced CT (P < 0.05). The area under the curve of joint diagnosis was significantly larger than that of contrast-enhanced ultrasound and enhanced CT by placing the ROC curve for examination (P < 0.05). Compared with enhanced CT, contrast-enhanced ultrasound has a higher signal-to-noise ratio of blood flow signals, which can more accurately reflect the low-velocity blood flow direction in tumor tissue. Enhanced CT cannot dynamically observe the shape of a lesion in real time, and the diagnosis results are susceptible to the interference of radiography agents in lesions, with a certain radiation and no compatibility for repeated examination in the short term. Chenxiaoli et al. [25] have reported that contrast-enhanced ultrasound is more sensitive than enhanced CT in the diagnosis of small lesions. In addition, contrast-enhanced ultrasound has the advantages of rapid diagnosis, no wound and no radiation, which is more easily accepted by patients. However, the contrast-enhanced ultrasound cannot compromise multiple lesions, and it is also affected by the operators' experience, with some limitations. In clinic, according to the actual situation of patients, the combination application of enhanced CT and contrast-enhanced ultrasound can make up for the deficiency of a single examination and realize comprehensive diagnosis and treatment.

In summary, contrast-enhanced ultrasound combined with enhanced CT has a higher accuracy in the early diagnosis of PHC, and the diagnostic efficiency of contrast-enhanced ultrasound is higher than that of enhanced CT. In clinical practice, the physical condition and state of illness of patients should be fully considered to select the most suitable examination method combined with their economic situation.