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Assessing Hepatic Fibrosis Using 2-D Shear Wave Elastography in Patients with Liver Tumors: A Prospective Single-Center Study
Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–8, 2017 Ó 2017 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2017.07.003
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Original Contribution ASSESSING HEPATIC FIBROSIS USING 2-D SHEAR WAVE ELASTOGRAPHY IN PATIENTS WITH LIVER TUMORS: A PROSPECTIVE SINGLE-CENTER STUDY ZHONGXI HUANG,*y WEI ZHENG,*z YAO-JUN ZHANG,*y LI XU,*y JIN-BIN CHEN,*y JIAN-CONG CHEN,*y MIN-SHAN CHEN,*y and ZHONGGUO ZHOU*y * Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; y Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; and z Department of Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China (Received 21 January 2017; revised 27 June 2017; in final form 7 July 2017)
Abstract—The purpose of this study was to investigate the diagnostic performance of 2-D shear wave elastography (2-D-SWE) in evaluations of liver stiffness in patients with liver tumors before resection. A total of 121 consecutive patients with hepatocellular carcinoma (HCC) (n 5 93), intra-hepatic cholangiocarcinoma (n 5 6), mixed hepatocellular carcinoma and intra-hepatic cholangiocarcinoma (n 5 6), liver metastases (n 5 10) and benign tumors (n 5 6) were prospectively enrolled in this study from June 2015 to March 2016. Three valid 2-D-SWE measurements for each patient and median liver stiffness values were calculated. Fibrosis staging was evaluated according to the METAVIR scoring system. A receiver operating characteristic curve analysis was used to assess diagnostic performance. In this study, we found that median liver stiffness values were significantly higher in patients with primary liver tumors than in those with liver metastases and benign tumors (11.80 kPa vs. 5.85 kPa, p , 0.001). In addition, liver stiffness, assessed using 2-D-SWE, was highly correlated with pathologically confirmed liver fibrosis stage. Liver fibrosis stage and liver stiffness values were analyzed using Spearman’s correlation (0.708, p , 0.001). The median liver stiffness values were as follows: F1, 6.7 kPa; F2, 6.33 kPa; F3, 9.2 kPa; F4, 13.7 kPa. The area under the receiver operating characteristic curves of the liver stiffness values that predicted significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 83.5%, 91.6% and 88.1%, respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 7.05 kPa (sensitivity 5 74.6%, specificity 5 100.0%), 9.45 kPa (sensitivity 5 78.8%, specificity 5 100.0%) and 11.1 kPa (sensitivity 5 83.1%, specificity 5 89.3%), respectively. We conclude that 2-D-SWE is a useful, accurate and non-invasive method for evaluating hepatic fibrosis in patients with liver tumors adapted to hepatectomy (ClinicalTrials.gov ID: NCT02958592). (E-mail: [email protected]) Ó 2017 World Federation for Ultrasound in Medicine & Biology. Key Words: Shear wave elastography, Hepatic fibrosis, Liver tumor, Hepatocellular carcinoma, Liver metastases.
remarkably improved in recent decades because of improvements in surgical techniques and peri-operative care (Cucchetti et al. 2011; Ramacciato et al. 2003; Wu et al. 2005), post-hepatectomy morbidity remains high, especially in patients with liver fibrosis and cirrhosis. In recent years, many studies have reported that there is a correlation between the degree of liver stiffness (measured using transient elastography [TE]) and posthepatectomy liver failure and morbidity (Fung et al. 2013; Nishio et al. 2016; Wong et al. 2013). It remains difficult to assess liver fibrosis before surgery without performing a traditional liver biopsy. Several emerging non-invasive techniques, including magnetic resonance (MR) elastography and ultrasonography (US)-based elastography, have recently been developed to estimate liver
INTRODUCTION Hepatic resection is an effective treatment for select patients with liver tumors, including those with hepatocellular carcinoma (HCC), liver metastases or various benign diseases (de Ridder et al. 2016; Dhir et al. 2016; European Association for the Study of the Liver 2016; Kazaryan et al. 2010). Although post-hepatectomy outcomes have
Address correspondence to: Zhongguo Zhou, Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, China. E-mail: [email protected] Conflict of interest disclosure: The authors declare that they have no conflicts of interest. 1
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stiffness in patients with a variety of liver diseases (Li et al. 2016; Myers et al. 2012; Oudry et al. 2009; Rustogi et al. 2012; Yoon et al. 2014). US-based elastography techniques, such as TE (Sandrin et al. 2003), acoustic radiation force impulse (ARFI) (Lupsor et al. 2009) and shear-wave elastography (SWE) (Li et al. 2016), are more convenient than MR elastography because they are relatively inexpensive to perform and have better portability. Hence, they are more commonly used in current clinical practice. Elastography provides a quantitative estimate of tissue stiffness based on the assumptions that the material is linear and symmetric and that the liver tissue is isotropic, homogeneous and incompressible (Muller et al. 2009). In SWE, a conventional ultrasound scanner is used to generate shear waves via US pulses. It provides a quantitative estimate of liver stiffness by estimating shear wave speed. Moreover, liver tissue stiffness can be imaged in real time using this modality, and a quantitative elastogram can be superimposed on an anatomic B-mode image. The region of interest can be measured by correlating the results with underlying conventional ultrasound imaging. Thus, an elastic modulus can be accurately measured, and these measurements are reproducible. Recently, an increasing number of studies have reported that there is a correlation between liver stiffness evaluated using 2-D-SWE and the degree of fibrosis determined using liver biopsy in patients with chronic liver disease (Ochi et al. 2012; Samir et al. 2015; Zheng et al. 2015). Liver tumors occur in various background parenchyma, including normal, fibrotic and cirrhotic livers. However, only a few studies have evaluated the utility of SWE for assessing the stiffness of the background liver parenchyma before surgery in patients with liver tumors (Lu et al. 2015; Tian et al. 2016; Zhuang et al. 2017). The aim of this study was to evaluate the diagnostic efficacy of 2-D-SWE for staging liver fibrosis in liver background parenchyma in patients with liver tumors who underwent hepatic resection. The pathology of the surgically resected tissue was used as a reference standard. METHODS Patient population A total of 121 consecutive patients were prospectively recruited from our center between June 2015 and March 2016. Written informed consent was obtained from all patients before their enrollment. All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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This prospective study was approved by the institutional review board at the Sun Yat-sen University Cancer Center and performed in accordance with the approved guidelines. The trial was registered at ClinicalTrials.gov as NCT02958592. The inclusion criteria were as follows: (i) patients with a solid focal liver lesion that was pathologically proven or diagnosed using imaging methods such as conventional US, CT or MRI; (ii) patients scheduled to undergo a hepatectomy; and (iii) patients with a lesion $1.0 cm in diameter. The exclusion criteria were as follows: (i) patients with a history of chemotherapy and (ii) patients unable to properly hold their breath. Performance of 2-D-SWE All patients underwent real-time 2-D-SWE at a frequency of 6 MHz using an Aixplorer ultrasound system (Super-Sonic Imaging S.A., Aix-en-Provence, France) equipped with an SC6-1 convex probe. The patients had fasted overnight and were asked to lie in a supine position with their upper arms maximally abducted to increase the intercostal space. A probe was placed in the intercostal space using gentle compression. First, measurements of the anteroposterior diameter of the right and left liver lobes, the length and thickness of the spleen, the inner diameters of the portal and spleen veins and the size and location of liver tumors were obtained as conventional B-mode images. Then, in an area free of tumor and large vessels, a section of liver parenchyma more than 2 cm away from the liver lesion was located after the imaging mode was changed to 2-D-SWE. Next, an elastography box was positioned at least 1 to 5 cm away from the liver capsule, and the patient was instructed to hold her or his breath for a few seconds to allow the 2-D-SWE signal to stabilize. A circular region of interest (ROI) with a fixed diameter of 20 mm was placed on the 2-D-SWE imaging area, and the 2-D-SWE image was defined and qualified when the elastography color map was more than 90% filled. The mean of the Young’s modulus of the liver tissue within the ROI was expressed in kilopascals (kPa) and recorded (Fig. 1). A 2-D-SWE image was acquired for three different sections per patient, and the mean of the three measurements was calculated. All 2-D-SWE procedures were performed by a doctor with 9 y of experience in the use of conventional US and 2 y of experience in performing 2-D-SWE. The doctor was blinded to the patients’ histologic and clinical data. Liver specimens and histology The pathologic results of all included liver tumors were as follows: 93 patients (76.8%) had hepatocellular carcinoma (HCC), 6 patients (5.0%) had intra-hepatic cholangiocarcinoma (ICC), 6 patients (5.0%) had mixed HCC and ICC and the remaining 16 patients (13.2%)
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levels, as well as a complete blood count (CBC) and prothrombin activity, were biochemically assessed on the same day as the SWE examinations (Table 1).
Fig. 1. Two-dimensional shear-wave elastography (2-D-SWE) was performed on the liver of a 61-y-old man with stage F4 liver fibrosis who was diagnosed with hepatocellular carcinoma based on histopathologic examination of a surgically excised lesion. The 2-D-SWE value was 17.4 6 1.8 kPa. Min 5 minimum; Max 5 maximum; SD 5 standard deviation; Diam 5 diameter.
had liver metastases (n 5 10) and benign liver tumors (n 5 6). The primary cancers in the patients with liver metastases were colon cancer (n 5 4), breast cancer (n 5 2) and other malignancies (n 5 4). Benign liver tumors included focal nodular hyperplasia (n 5 4), cavernous hemangioma (n 5 1) and chronic granulomatous inflammation (n 5 1). A total of 121 liver parenchyma specimens were obtained after surgery at a distance greater than 2 cm away from the liver lesion. All samples were subjected to formalin fixation, paraffin embedding and hematoxylin– eosin, silver and Masson’s trichrome staining. Histology was reviewed by two experienced pathologists who were blinded to the 2-D-SWE results and patient clinical information. In cases where there was disagreement, the slides were re-examined using a two-headed microscope, and a consensus was reached by two blinded observers. Liver fibrosis was evaluated semiquantitatively and scored on a 5-point scale ranging from 0 to 4 according to the METAVIR scoring system, as follows: F0 indicated the absence of fibrosis, F1 indicated portal fibrosis without septa, F2 indicated portal fibrosis with few septa, F3 indicated septal fibrosis without cirrhosis and F4 indicated cirrhosis (Bedossa and Poynard 1996). In addition to 2-D-SWE and histopathologic examinations, anthropometric measurements were taken. These included measurements of weight, body height and body mass index (BMI). Serum albumin, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), g-glutamyltransferase (GGT) and total bilirubin (TBi)
Statistical analysis The Statistical Package for Social Sciences (SPSS) software, Version 20.0 (IBM, Armonk, NY, USA), was used for all statistical analyses, and two-sided p values , 0.05 were considered significant based on two-sided statistical tests. Continuous variables were compared using the Mann–Whitney and Kruskal–Wallis tests. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of 2-D-SWE. Then, we analyzed the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), positive likelihood ratio (LR1), negative likelihood ratio (LR–) and areas under the ROC curves (AUROCs) for the results of 2-D-SWE. The optimal diagnostic cutoff values were identified according to the Youden index (Youden 1950). Correlations between 2-D-SWE measurements and the histologically determined fibrosis stage were analyzed using Spearman’s correlation coefficient, and the correlation coefficients were compared using the Fisher Z-test. RESULTS Patient characteristics The median age of the patients was 53 y (range: 19– 79 y); 98 patients (81.0%) were male, and 23 patients Table 1. Clinical and histopathologic features of the 121 patients Males/females Median age (y) Body mass index Hepatitis (hepatitis B virus), yes/no Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase g-Glutamyltransferase Total bilirubin Albumin Prothrombin time International normalized ratio Pathology HCC ICC Mixed HCC and ICC Liver metastases Benign liver tumors Fibrosis score (METAVIR) F1 F2 F3 F4
98 (81.0%)/23 (19.0%) 53 (19–79) 22.59 (16.21–33.02) 104 (86.0%)/17 (14.0%) 29.7 (8.3–206.2) 27.9 (3–161.1) 83.1 (29.3–319.4) 47.0 (13.9–768.3) 12.9 (5.2–31.2) 44.1 (31.4–51.1) 11.4 (9.5–14.8) 0.99 (0.83–1.29) 93 (76.8%) 6 (5.0%) 6 (5.0%) 10 (8.2%) 6 (5.0%) 3 (2.5%) 33 (27.3%) 20 (16.5%) 65 (53.7%)
HCC 5 hepatocellular carcinoma; ICC 5 intra-hepatic cholangiocarcinoma. Values are expressed as the median (range) or median (percentage).
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Fig. 2. (a) Box-and-whisker plots of 2-D shear wave elastography (2-D-SWE) values for various diagnoses. The first and third quartiles are represented as the top and bottom of the boxes, respectively, and the line through each box represents the median. Error bars indicate minimum and maximum non-extreme values, circles indicate outside values and asterisks indicate outliers. (b) SWE values for the background liver parenchyma were significantly higher in patients with primary liver cancer, including hepatocellular carcinoma (HCC) and intra-hepatic cholangiocarcinoma (ICC), than in those with liver metastases (LM) and benign liver tumors (p , 0.001).
(19.0%) were female. The median BMI was 22.59 kg/m2 (range: 16.21–33.02 kg/m2). A total of 104 patients (86.0%) were chronically infected with hepatitis B, whereas the other 17 patients were not infected with hepatitis B. No patients were chronically infected with hepatitis C. According to the METAVIR scoring system, the histopathological results revealed that more than half of the patients (n 5 65, 53.7%) were in stage F4, a few patients (n 5 3, 2.5%) were in stage F1, 33 patients (27.3%) were in stage F2 and 20 (16.5%) patients were in stage F3 (Table 1). Liver stiffness measurement in background liver parenchyma Based on the measurements obtained using 2-DSWE, the median liver stiffness value for the entire cohort was 9.6 kPa (range: 3.3–46.2 kPa). The median values for the background liver parenchyma were 12.0 kPa (range: 5.1–46.2 kPa) in patients with HCC, 6.5 kPa (range: 5.3–13.1 kPa) in patients with ICC, 8.05 kPa (range, 5.3–13.1 kPa) in patients with mixed HCC and ICC and 5.85 kPa (range, 3.3–13.3 kPa) in patients with benign
liver tumors and liver metastases. The median values for the background liver parenchyma were significantly higher in the patients with primary liver cancer, including HCC and ICC, than in the patients with liver metastases and benign liver tumors (11.80 kPa vs. 5.85 kPa, respectively, p , 0.001) (Fig. 2, Table 2). Correlation of 2-D-SWE with pathologic liver fibrosis stage Median liver stiffness was assessed using 2-D-SWE and found to increase with liver fibrosis stage, except in measurements obtained in patients with stage F1 liver fibrosis because there was a small number of such cases (F1, 6.7 kPa; range: 3.7–7.0 kPa). In patients with F2, F3 and F4 fibrosis, the median liver stiffness values were 6.33 kPa (range: 3.3–9.4 kPa), 9.2 kPa (range: 5.9–33.4 kPa) and 13.7 kPa (range: 5.1–46.2 kPa), respectively. In a comparison of liver stiffness across various liver fibrosis stages (excluding stage F1), median liver stiffness values in the stage F4 patients were significantly higher than the corresponding values in the stage F3 and F2 patients (p 5 0.001 and p , 0.001,
Table 2. 2-D-SWE values according to pathologic diagnosis in all patients Parameter
HCC (n 5 93)
ICC (n 5 6)
Mixed HCC and ICC (n 5 6)
LM and BLT (n 5 16)
Mean Median Minimum Maximum 1st quartile 3rd quartile
13.07 12.0 5.10 46.20 8.25 17.10
7.50 6.50 5.30 13.10 5.53 9.28
8.82 8.05 5.40 14.60 6.60 11.00
6.09 5.85 3.30 13.30 5.25 6.38
HCC 5 hepatocellular carcinoma; ICC 5 intra-hepatic cholangiocarcinoma; LM 5 liver metastases; BLT 5 benign liver tumors.
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respectively), and median liver stiffness values in the stage F3 patients were also significantly higher than the corresponding values in the stage F2 patients (p , 0.001). Additionally, a specific association was observed between liver stiffness values and hepatic fibrosis stage (r 5 708, p , 0.001) (Fig. 3, Table 3). 2-D-SWE for assessment of fibrosis in patients who underwent hepatectomy Figure 4 illustrates the diagnostic performance of 2-D-SWE as assessed using ROC curves. The AUROCs for the ability of 2-D-SWE to predict significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 83.5% (95% confidence interval [CI]: 69.7–97.2), 91.6% (95% CI: 86.7–96.4) and 88.1% (95% CI: 81.3–94.8), respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 7.05 kPa (sensitivity 5 74.6%, specificity 5 100.0%), 9.45 kPa (sensitivity 5 78.8%, specificity 5 100.0%) and 11.1 kPa (sensitivity 5 83.1%, specificity 5 89.3%), respectively (Fig. 4, Table 4). DISCUSSION In this prospective study, we evaluated the diagnostic performance of 2-D-SWE when used to detect hepatic fibrosis in background liver parenchyma in patients with liver tumors who underwent hepatic resection. The pathology of the resected tissue was used as a reference standard. In our study, most HCCs occurred in fibrotic or cirrhotic background liver tissues, whereas most benign
Fig. 3. Box-and-whisker plot of 2-D shear wave elastography (2-D-SWE) values according to liver fibrosis stage. A specific association was found between 2-D-SWE values and hepatic fibrosis stage (r 5 708, p , 0.001). *Indicate outliers in Boxand-whisker plot.
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Table 3. 2-D-SWE values according to fibrosis stage in all patients Parameter
F1 (n 5 3)
F2 (n 5 33)
F3 (n 5 20)
F4 (n 5 65)
Mean Median Minimum Maximum 1st quartile 3rd quartile
5.80 6.70 3.70 7.00 3.70 NA
6.62 6.33 3.30 9.40 5.65 7.50
10.92 9.20 5.90 33.40 6.50 12.5
14.72 13.70 5.10 46.20 11.65 17.66
liver tumors and liver metastases occurred in normal background liver tissues. It is widely accepted that in the Chinese population, primary liver malignancies, including HCC and ICC, often develop in a background of chronic hepatitis B. Additionally, patients with chronic hepatitis B have a natural history of developing liver fibrosis. Previous studies have indicated that elevated liver stiffness is associated with a risk of developing HCC (Kim et al. 2015; Singh et al. 2013). Among the 121 patients included in our study, 99 of 105 patients (94.3%) with liver malignancies, including HCC and ICC, had chronic hepatitis B, whereas only 5 of 16 patients (31.3%) with benign liver tumors and hepatic metastases had chronic hepatitis B. Moreover, a significant difference was observed in the median liver stiffness value for background liver parenchyma between the primary liver cancer group and the benign liver tumor and liver metastasis group (11.80 kPa vs. 5.85 kPa, respectively, p , 0.001). These results are similar to those reported by Tian et al. (2016). The median liver stiffness value for the background liver parenchyma in the patients with HCC in our study was much greater than that reported in a recent study (12.0 kPa vs. 8.9 kPa) (Lu et al. 2015). This variation could be patient related. In the present study, median liver stiffness was measured according to the results of 2-D-SWE of the background liver parenchyma. In each fibrosis stage, the values observed in this study were much lower than those reported in a previous 2-D-SWE study of patients with chronic hepatitis B, in which the median values were 8.2, 11.3 and 18.1 for fibrosis stages F2, F3 and F4, respectively (Zeng et al. 2014). These differences might be explained by differences in the percentages of patients infected with hepatitis B among the patient populations examined in the two studies. Additionally, in a study by Ferraioli et al. (2012), patients with chronic hepatitis C had median values for fibrosis stages F2, F3 and F4 higher than those measured in our study (7.6 vs. 6.33 kPa, 10.0 vs. 9.2 kPa and 15.6 vs. 13.7 kPa, respectively) (Ferraioli et al. 2012). The different etiologies of chronic liver disease might explain this difference. Previous studies have found that SWE has good diagnostic
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Fig. 4. Receiver operating characteristic (ROC) curve analysis assessing the ability of 2-D-shear wave elastography to predict fibrosis stage. (a) Significant fibrosis ($F2), area under the curve (AUC) 5 0.835 (95% confidence interval [CI]: 0.697–0.972). (b) Severe fibrosis ($F3), AUC 5 0.916 (95% CI: 0.867–0.964). (c) Cirrhosis (5F4), AUC 5 0.881 (95% CI: 0.813–0.948).
performance for staging liver fibrosis in patients with different chronic liver diseases, including chronic hepatitis C infection, chronic hepatitis B infection and non-alcoholic fatty liver disease, when a liver biopsy is used as a reference standard (Ferraioli et al. 2012; Ochi et al. 2012; Zeng et al. 2014). A recent meta-analysis also indicated that SWE has high diagnostic accuracy for staging liver fibrosis in patients with chronic diseases of different etiologies (Li et al. 2016). To our knowledge, this study is the first to evaluate the value of using realtime 2-D-SWE to assess liver fibrosis in background liver parenchyma using resected tissue as a reference standard in patients with liver tumors. Our ROC curve analysis results revealed that the AUCs associated with 2-D-SWE when diagnosing significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 0.835, 0.916 and 0.881, respectively. These results indicate that 2-D-SWE has good diagnostic value for assessing hepatic fibrosis in patients with liver tumors. Compared with the results of a recent 2-D-SWE study conducted by Table 4. Diagnostic performance of 2-D-SWE in all patients Statistic
$F2
$F3
5F4
Area under the 83.5 (69.7–97.2) 91.6 (86.7–96.4) 88.1 (81.3–94.8) curve Cutoff value, 7.05 9.45 11.10 kPa Sensitivity, % 74.6 78.80 83.10 Specificity, % 100.0 100.0 89.30 PPV, % 100.0 100.0 90.00 NPV, % 9.0 66.7 82.00 Positive LR NA NA 7.77 Negative LR 0.25 0.21 0.19 PPV 5 positive predictive value; NPV 5 negative predictive value; LR 5 likelihood ratio.
Zeng et al. (2014) in patients with hepatitis B infection, our study resulted in slightly lower AUCs for detecting liver fibrosis stage (i.e., AUC 0.917-0.945). However, the cutoff values for staging significant fibrosis and severe fibrosis were similar for the two studies (7.05 kPa vs. 7.2 kPa and 9.45 kPa vs. 9.1 kPa, respectively), whereas the cutoff value for staging cirrhosis in our study was slightly lower than that used by Zeng et al. (2014) (11.1 kPa vs. 11.7 kPa, respectively). Furthermore, we obtained high PPVs for the cutoff values we used for various liver fibrosis stages, indicating the usefulness of SWE for confirming significant fibrosis ($F2) and severe fibrosis ($F3). However, the NPVs were low for significant fibrosis and severe fibrosis, indicating that 2-D-SWE does not capably exclude significant fibrosis and severe fibrosis. This result is inconsistent with those described in previous studies (Leung et al. 2013; Zeng et al. 2014). Differences in patient populations might explain these differences. Factors that affect assessments of liver stiffness may lead to incongruence in assessments of fibrosis stage and stiffness. Previous studies have found that inflammation and GGT, ALT, AST and serum ALP levels influence liver stiffness when measured using 2-D-SWE (Zeng et al. 2014; Zhuang et al. 2017). Other studies have indicated that inflammation, infiltrative diseases, cholestasis, venous congestion and excessive alcohol intake influence liver stiffness when measured using transient elastography (Arena et al. 2008; Coco et al. 2007; Friedrich-Rust et al. 2016; Millonig et al. 2008, 2010). These factors reflect the inflammatory status and function of liver, and they may therefore be associated with fibrosis progression. Currently, there is no consensus regarding the influence of liver steatosis on liver stiffness in patients with chronic liver disease
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(Boursier et al. 2014; Gaia et al. 2011; Petta et al. 2015). We did not assess the effect of hepatic steatosis on our 2D-SWE results because the number of patients with hepatic steatosis was small. Other factors, such as portal pressure, have been known to affect liver stiffness. The correlation between the hepatic venous pressure gradient (HVPG) and liver stiffness is reportedly good for HVPG values up to 10 or 12 mm Hg. However, it seems to be less optimal above these values, probably because of extrahepatic factors in advanced portal hypertension (Berzigotti 2017; Kumar et al. 2017). We did not assess the effect of portal pressure in this study because measurement of HVPG is invasive. Interestingly, the observed variability in liver stiffness measurements may also have affected variation in our shear wave speed estimates. In addition, in the present study, we used linear assumptions to develop an overall assessment of the liver modulus. However, non-linear models have been used in an attempt to distinguish inflammation and other factors from liver fibrosis stage (Talwalkar et al. 2008; Yin et al. 2017). Thus, the question of how to reduce the effects of confounding factors is important in clinical practice. The strength of this study was our use of surgically resected liver tissue as a reference standard. This allowed us to avoid potentially inadequate liver biopsy specimens. Our study also has several limitations. First, our sample population was relatively small, and the distribution of patients with various stages of liver fibrosis was not equal, especially in stage F1, for which we had a small number of patients. Therefore, further studies that include larger sample populations who are more equally distributed across fibrosis stages are needed. Second, the samples obtained in the liver parenchyma during liver resection may not have coincided with the ROI. Thus, it is possible that sampling may have affected the difference between fibrosis stage and stiffness more than in other studies. Hence, further study is needed to reduce sampling error. Third, our study population was Chinese, and most cases of HCC developed in patients infected with the hepatitis B virus. Our results may therefore not be generalizable to patients with liver fibrosis of other etiology. In conclusion, the results of this prospective study suggest that 2-D-SWE is a useful, accurate and noninvasive method for pre-operatively evaluating hepatic fibrosis in patients with liver tumors when adapted to hepatectomy. Acknowledgments—This study was supported by the National Natural Science Foundation of China (No. 81602143).
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Lu Q, Ling W, Lu C, Li J, Ma L, Quan J, He D, Liu J, Yang J, Wen T, Wu H, Zhu H, Luo Y. Hepatocellular carcinoma: Stiffness value and ratio to discriminate malignant from benign focal liver lesions. Radiology 2015;275:880–888. Lupsor M, Badea R, Stefanescu H, Sparchez Z, Branda H, Serban A, Maniu A. Performance of a new elastographic method (ARFI technology) compared to unidimensional transient elastography in the noninvasive assessment of chronic hepatitis C: Preliminary results. J Gastrointest Liver Dis 2009;18:303–310. Millonig G, Reimann FM, Friedrich S, Fonouni H, Mehrabi A, B€ uchler MW, Seitz HK, Mueller S. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008;48:1718–1723. Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, Stiefel P, P€ oschl G, B€uchler MW, Seitz HK, Mueller S. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010;52:206–210. Muller M, Gennisson JL, Deffieux T, Tanter M, Fink M. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: Preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219–229. Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Beaton M, Levstik M, Duarte-Rojo A, Wong D, Crotty P, Elkashab M. Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe. J Hepatol 2012;56: 564–570. Nishio T, Taura K, Koyama Y, Tanabe K, Yamamoto G, Okuda Y, Ikeno Y, Seo S, Yasuchika K, Hatano E, Okajima H, Kaido T, Tanaka S, Uemoto S. Prediction of posthepatectomy liver failure based on liver stiffness measurement in patients with hepatocellular carcinoma. Surgery 2016;159:399–408. Ochi H, Hirooka M, Koizumi Y, Miyake T, Tokumoto Y, Soga Y, Tada F, Abe M, Hiasa Y, Onji M. Real-time tissue elastography for evaluation of hepatic fibrosis and portal hypertension in nonalcoholic fatty liver diseases. Hepatology 2012;56:1271–1278. Oudry J, Chen J, Glaser KJ, Miette V, Sandrin L, Ehman RL. Cross-validation of magnetic resonance elastography and ultrasound-based transient elastography: A preliminary phantom study. J Magn Reson Imaging 2009;30:1145–1150. Petta S, Maida M, Macaluso FS, Di Marco V, Camma C, Cabibi D, Craxı A. The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease. Hepatology 2015;62:1101–1110. Ramacciato G, Mercantini P, Corigliano N, Cautero N, Masetti M, Di Benedetto F, Quintini C, Balducci G, Siniscalchi A, Begliomini B, Ziparo V, Pinna A. Hepatic resections for hepatocellular carcinoma (HCC): Short and long-term results on 106 cirrhotic patients. J Exp Clin Cancer Res 2003;22:233–241. Rustogi R, Horowitz J, Harmath C, Wang Y, Chalian H, Ganger DR, Chen ZE, Bolster BD Jr, Shah S, Miller FH. Accuracy of MR elastography and anatomic MR imaging features in the diagnosis of se-
Volume -, Number -, 2017 vere hepatic fibrosis and cirrhosis. J Magn Reson Imaging 2012;35: 1356–1364. Samir AE, Dhyani M, Vij A, Bhan AK, Halpern EF, Mendez-Navarro J, Corey KE, Chung RT. Shear-wave elastography for the estimation of liver fibrosis in chronic liver disease: Determining accuracy and ideal site for measurement. Radiology 2015;274:888–896. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–1713. Singh S, Fujii LL, Murad MH, Wang Z, Asrani SK, Ehman RL, Kamath PS, Talwalkar JA. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:1573–1584.e1. Talwalkar JA, Yin M, Fidler JL, Sanderson SO, Kamath PS, Ehman RL. Magnetic resonance imaging of hepatic fibrosis: Emerging clinical applications. Hepatology 2008;47:332–342. Tian WS, Lin MX, Zhou LY, Pan FS, Huang GL, Wang W, Lu MD, Xie XY. Maximum value measured by 2-D shear wave elastography helps in differentiating malignancy from benign focal liver lesions. Ultrasound Med Biol 2016;42:2156–2166. Wong JS, Wong GL, Chan AW, Wong VW, Cheung YS, Chong CN, Wong J, Lee KF, Chan HL, Lai PB. Liver stiffness measurement by transient elastography as a predictor on posthepatectomy outcomes. Ann Surg 2013;257:922–928. Wu CC, Cheng SB, Ho WM, Chen JT, Liu TJ, P’Eng FK. Liver resection for hepatocellular carcinoma in patients with cirrhosis. Br J Surg 2005;92:348–355. Yin M, Glaser KJ, Manduca A, Mounajjed T, Malhi H, Simonetto DA, Wang R, Yang L, Mao SA, Glorioso JM, Elgilani FM, Ward CJ, Harris PC, Nyberg SL, Shah VH, Ehman RL. Distinguishing between hepatic inflammation and fibrosis with MR elastography. Radiology 2017;160622. http://dx.doi.org/10.1148/radiol.2017160622. Yoon JH, Lee JM, Joo I, Lee ES, Sohn JY, Jang SK, Lee KB, Han JK, Choi BI. Hepatic fibrosis: Prospective comparison of MR elastography and US shear-wave elastography for evaluation. Radiology 2014;273:772–782. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32–35. Zeng J, Liu GJ, Huang ZP, Zheng J, Wu T, Zheng RQ, Lu MD. Diagnostic accuracy of two-dimensional shear wave elastography for the noninvasive staging of hepatic fibrosis in chronic hepatitis B: A cohort study with internal validation. Eur Rad 2014;24:2572–2581. Zheng J, Guo H, Zeng J, Huang Z, Zheng B, Ren J, Xu E, Li K, Zheng R. Two-dimensional shear-wave elastography and conventional US: The optimal evaluation of liver fibrosis and cirrhosis. Radiology 2015;275:290–300. Zhuang Y, Ding H, Zhang Y, Sun H, Xu C, Wang W. Two-dimensional shear-wave Elastography performance in the noninvasive evaluation of liver fibrosis in patients with chronic hepatitis B: Comparison with serum fibrosis indexes. Radiology 2017;283:873–882.
http://dx.doi.org/10.1016/j.ultrasmedbio.2017.07.003
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Original Contribution ASSESSING HEPATIC FIBROSIS USING 2-D SHEAR WAVE ELASTOGRAPHY IN PATIENTS WITH LIVER TUMORS: A PROSPECTIVE SINGLE-CENTER STUDY ZHONGXI HUANG,*y WEI ZHENG,*z YAO-JUN ZHANG,*y LI XU,*y JIN-BIN CHEN,*y JIAN-CONG CHEN,*y MIN-SHAN CHEN,*y and ZHONGGUO ZHOU*y * Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; y Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; and z Department of Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China (Received 21 January 2017; revised 27 June 2017; in final form 7 July 2017)
Abstract—The purpose of this study was to investigate the diagnostic performance of 2-D shear wave elastography (2-D-SWE) in evaluations of liver stiffness in patients with liver tumors before resection. A total of 121 consecutive patients with hepatocellular carcinoma (HCC) (n 5 93), intra-hepatic cholangiocarcinoma (n 5 6), mixed hepatocellular carcinoma and intra-hepatic cholangiocarcinoma (n 5 6), liver metastases (n 5 10) and benign tumors (n 5 6) were prospectively enrolled in this study from June 2015 to March 2016. Three valid 2-D-SWE measurements for each patient and median liver stiffness values were calculated. Fibrosis staging was evaluated according to the METAVIR scoring system. A receiver operating characteristic curve analysis was used to assess diagnostic performance. In this study, we found that median liver stiffness values were significantly higher in patients with primary liver tumors than in those with liver metastases and benign tumors (11.80 kPa vs. 5.85 kPa, p , 0.001). In addition, liver stiffness, assessed using 2-D-SWE, was highly correlated with pathologically confirmed liver fibrosis stage. Liver fibrosis stage and liver stiffness values were analyzed using Spearman’s correlation (0.708, p , 0.001). The median liver stiffness values were as follows: F1, 6.7 kPa; F2, 6.33 kPa; F3, 9.2 kPa; F4, 13.7 kPa. The area under the receiver operating characteristic curves of the liver stiffness values that predicted significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 83.5%, 91.6% and 88.1%, respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 7.05 kPa (sensitivity 5 74.6%, specificity 5 100.0%), 9.45 kPa (sensitivity 5 78.8%, specificity 5 100.0%) and 11.1 kPa (sensitivity 5 83.1%, specificity 5 89.3%), respectively. We conclude that 2-D-SWE is a useful, accurate and non-invasive method for evaluating hepatic fibrosis in patients with liver tumors adapted to hepatectomy (ClinicalTrials.gov ID: NCT02958592). (E-mail: [email protected]) Ó 2017 World Federation for Ultrasound in Medicine & Biology. Key Words: Shear wave elastography, Hepatic fibrosis, Liver tumor, Hepatocellular carcinoma, Liver metastases.
remarkably improved in recent decades because of improvements in surgical techniques and peri-operative care (Cucchetti et al. 2011; Ramacciato et al. 2003; Wu et al. 2005), post-hepatectomy morbidity remains high, especially in patients with liver fibrosis and cirrhosis. In recent years, many studies have reported that there is a correlation between the degree of liver stiffness (measured using transient elastography [TE]) and posthepatectomy liver failure and morbidity (Fung et al. 2013; Nishio et al. 2016; Wong et al. 2013). It remains difficult to assess liver fibrosis before surgery without performing a traditional liver biopsy. Several emerging non-invasive techniques, including magnetic resonance (MR) elastography and ultrasonography (US)-based elastography, have recently been developed to estimate liver
INTRODUCTION Hepatic resection is an effective treatment for select patients with liver tumors, including those with hepatocellular carcinoma (HCC), liver metastases or various benign diseases (de Ridder et al. 2016; Dhir et al. 2016; European Association for the Study of the Liver 2016; Kazaryan et al. 2010). Although post-hepatectomy outcomes have
Address correspondence to: Zhongguo Zhou, Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, China. E-mail: [email protected] Conflict of interest disclosure: The authors declare that they have no conflicts of interest. 1
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stiffness in patients with a variety of liver diseases (Li et al. 2016; Myers et al. 2012; Oudry et al. 2009; Rustogi et al. 2012; Yoon et al. 2014). US-based elastography techniques, such as TE (Sandrin et al. 2003), acoustic radiation force impulse (ARFI) (Lupsor et al. 2009) and shear-wave elastography (SWE) (Li et al. 2016), are more convenient than MR elastography because they are relatively inexpensive to perform and have better portability. Hence, they are more commonly used in current clinical practice. Elastography provides a quantitative estimate of tissue stiffness based on the assumptions that the material is linear and symmetric and that the liver tissue is isotropic, homogeneous and incompressible (Muller et al. 2009). In SWE, a conventional ultrasound scanner is used to generate shear waves via US pulses. It provides a quantitative estimate of liver stiffness by estimating shear wave speed. Moreover, liver tissue stiffness can be imaged in real time using this modality, and a quantitative elastogram can be superimposed on an anatomic B-mode image. The region of interest can be measured by correlating the results with underlying conventional ultrasound imaging. Thus, an elastic modulus can be accurately measured, and these measurements are reproducible. Recently, an increasing number of studies have reported that there is a correlation between liver stiffness evaluated using 2-D-SWE and the degree of fibrosis determined using liver biopsy in patients with chronic liver disease (Ochi et al. 2012; Samir et al. 2015; Zheng et al. 2015). Liver tumors occur in various background parenchyma, including normal, fibrotic and cirrhotic livers. However, only a few studies have evaluated the utility of SWE for assessing the stiffness of the background liver parenchyma before surgery in patients with liver tumors (Lu et al. 2015; Tian et al. 2016; Zhuang et al. 2017). The aim of this study was to evaluate the diagnostic efficacy of 2-D-SWE for staging liver fibrosis in liver background parenchyma in patients with liver tumors who underwent hepatic resection. The pathology of the surgically resected tissue was used as a reference standard. METHODS Patient population A total of 121 consecutive patients were prospectively recruited from our center between June 2015 and March 2016. Written informed consent was obtained from all patients before their enrollment. All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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This prospective study was approved by the institutional review board at the Sun Yat-sen University Cancer Center and performed in accordance with the approved guidelines. The trial was registered at ClinicalTrials.gov as NCT02958592. The inclusion criteria were as follows: (i) patients with a solid focal liver lesion that was pathologically proven or diagnosed using imaging methods such as conventional US, CT or MRI; (ii) patients scheduled to undergo a hepatectomy; and (iii) patients with a lesion $1.0 cm in diameter. The exclusion criteria were as follows: (i) patients with a history of chemotherapy and (ii) patients unable to properly hold their breath. Performance of 2-D-SWE All patients underwent real-time 2-D-SWE at a frequency of 6 MHz using an Aixplorer ultrasound system (Super-Sonic Imaging S.A., Aix-en-Provence, France) equipped with an SC6-1 convex probe. The patients had fasted overnight and were asked to lie in a supine position with their upper arms maximally abducted to increase the intercostal space. A probe was placed in the intercostal space using gentle compression. First, measurements of the anteroposterior diameter of the right and left liver lobes, the length and thickness of the spleen, the inner diameters of the portal and spleen veins and the size and location of liver tumors were obtained as conventional B-mode images. Then, in an area free of tumor and large vessels, a section of liver parenchyma more than 2 cm away from the liver lesion was located after the imaging mode was changed to 2-D-SWE. Next, an elastography box was positioned at least 1 to 5 cm away from the liver capsule, and the patient was instructed to hold her or his breath for a few seconds to allow the 2-D-SWE signal to stabilize. A circular region of interest (ROI) with a fixed diameter of 20 mm was placed on the 2-D-SWE imaging area, and the 2-D-SWE image was defined and qualified when the elastography color map was more than 90% filled. The mean of the Young’s modulus of the liver tissue within the ROI was expressed in kilopascals (kPa) and recorded (Fig. 1). A 2-D-SWE image was acquired for three different sections per patient, and the mean of the three measurements was calculated. All 2-D-SWE procedures were performed by a doctor with 9 y of experience in the use of conventional US and 2 y of experience in performing 2-D-SWE. The doctor was blinded to the patients’ histologic and clinical data. Liver specimens and histology The pathologic results of all included liver tumors were as follows: 93 patients (76.8%) had hepatocellular carcinoma (HCC), 6 patients (5.0%) had intra-hepatic cholangiocarcinoma (ICC), 6 patients (5.0%) had mixed HCC and ICC and the remaining 16 patients (13.2%)
2-D SWE assessment of hepatic fibrosis d Z. HUANG et al.
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levels, as well as a complete blood count (CBC) and prothrombin activity, were biochemically assessed on the same day as the SWE examinations (Table 1).
Fig. 1. Two-dimensional shear-wave elastography (2-D-SWE) was performed on the liver of a 61-y-old man with stage F4 liver fibrosis who was diagnosed with hepatocellular carcinoma based on histopathologic examination of a surgically excised lesion. The 2-D-SWE value was 17.4 6 1.8 kPa. Min 5 minimum; Max 5 maximum; SD 5 standard deviation; Diam 5 diameter.
had liver metastases (n 5 10) and benign liver tumors (n 5 6). The primary cancers in the patients with liver metastases were colon cancer (n 5 4), breast cancer (n 5 2) and other malignancies (n 5 4). Benign liver tumors included focal nodular hyperplasia (n 5 4), cavernous hemangioma (n 5 1) and chronic granulomatous inflammation (n 5 1). A total of 121 liver parenchyma specimens were obtained after surgery at a distance greater than 2 cm away from the liver lesion. All samples were subjected to formalin fixation, paraffin embedding and hematoxylin– eosin, silver and Masson’s trichrome staining. Histology was reviewed by two experienced pathologists who were blinded to the 2-D-SWE results and patient clinical information. In cases where there was disagreement, the slides were re-examined using a two-headed microscope, and a consensus was reached by two blinded observers. Liver fibrosis was evaluated semiquantitatively and scored on a 5-point scale ranging from 0 to 4 according to the METAVIR scoring system, as follows: F0 indicated the absence of fibrosis, F1 indicated portal fibrosis without septa, F2 indicated portal fibrosis with few septa, F3 indicated septal fibrosis without cirrhosis and F4 indicated cirrhosis (Bedossa and Poynard 1996). In addition to 2-D-SWE and histopathologic examinations, anthropometric measurements were taken. These included measurements of weight, body height and body mass index (BMI). Serum albumin, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), g-glutamyltransferase (GGT) and total bilirubin (TBi)
Statistical analysis The Statistical Package for Social Sciences (SPSS) software, Version 20.0 (IBM, Armonk, NY, USA), was used for all statistical analyses, and two-sided p values , 0.05 were considered significant based on two-sided statistical tests. Continuous variables were compared using the Mann–Whitney and Kruskal–Wallis tests. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of 2-D-SWE. Then, we analyzed the sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), positive likelihood ratio (LR1), negative likelihood ratio (LR–) and areas under the ROC curves (AUROCs) for the results of 2-D-SWE. The optimal diagnostic cutoff values were identified according to the Youden index (Youden 1950). Correlations between 2-D-SWE measurements and the histologically determined fibrosis stage were analyzed using Spearman’s correlation coefficient, and the correlation coefficients were compared using the Fisher Z-test. RESULTS Patient characteristics The median age of the patients was 53 y (range: 19– 79 y); 98 patients (81.0%) were male, and 23 patients Table 1. Clinical and histopathologic features of the 121 patients Males/females Median age (y) Body mass index Hepatitis (hepatitis B virus), yes/no Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase g-Glutamyltransferase Total bilirubin Albumin Prothrombin time International normalized ratio Pathology HCC ICC Mixed HCC and ICC Liver metastases Benign liver tumors Fibrosis score (METAVIR) F1 F2 F3 F4
98 (81.0%)/23 (19.0%) 53 (19–79) 22.59 (16.21–33.02) 104 (86.0%)/17 (14.0%) 29.7 (8.3–206.2) 27.9 (3–161.1) 83.1 (29.3–319.4) 47.0 (13.9–768.3) 12.9 (5.2–31.2) 44.1 (31.4–51.1) 11.4 (9.5–14.8) 0.99 (0.83–1.29) 93 (76.8%) 6 (5.0%) 6 (5.0%) 10 (8.2%) 6 (5.0%) 3 (2.5%) 33 (27.3%) 20 (16.5%) 65 (53.7%)
HCC 5 hepatocellular carcinoma; ICC 5 intra-hepatic cholangiocarcinoma. Values are expressed as the median (range) or median (percentage).
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Fig. 2. (a) Box-and-whisker plots of 2-D shear wave elastography (2-D-SWE) values for various diagnoses. The first and third quartiles are represented as the top and bottom of the boxes, respectively, and the line through each box represents the median. Error bars indicate minimum and maximum non-extreme values, circles indicate outside values and asterisks indicate outliers. (b) SWE values for the background liver parenchyma were significantly higher in patients with primary liver cancer, including hepatocellular carcinoma (HCC) and intra-hepatic cholangiocarcinoma (ICC), than in those with liver metastases (LM) and benign liver tumors (p , 0.001).
(19.0%) were female. The median BMI was 22.59 kg/m2 (range: 16.21–33.02 kg/m2). A total of 104 patients (86.0%) were chronically infected with hepatitis B, whereas the other 17 patients were not infected with hepatitis B. No patients were chronically infected with hepatitis C. According to the METAVIR scoring system, the histopathological results revealed that more than half of the patients (n 5 65, 53.7%) were in stage F4, a few patients (n 5 3, 2.5%) were in stage F1, 33 patients (27.3%) were in stage F2 and 20 (16.5%) patients were in stage F3 (Table 1). Liver stiffness measurement in background liver parenchyma Based on the measurements obtained using 2-DSWE, the median liver stiffness value for the entire cohort was 9.6 kPa (range: 3.3–46.2 kPa). The median values for the background liver parenchyma were 12.0 kPa (range: 5.1–46.2 kPa) in patients with HCC, 6.5 kPa (range: 5.3–13.1 kPa) in patients with ICC, 8.05 kPa (range, 5.3–13.1 kPa) in patients with mixed HCC and ICC and 5.85 kPa (range, 3.3–13.3 kPa) in patients with benign
liver tumors and liver metastases. The median values for the background liver parenchyma were significantly higher in the patients with primary liver cancer, including HCC and ICC, than in the patients with liver metastases and benign liver tumors (11.80 kPa vs. 5.85 kPa, respectively, p , 0.001) (Fig. 2, Table 2). Correlation of 2-D-SWE with pathologic liver fibrosis stage Median liver stiffness was assessed using 2-D-SWE and found to increase with liver fibrosis stage, except in measurements obtained in patients with stage F1 liver fibrosis because there was a small number of such cases (F1, 6.7 kPa; range: 3.7–7.0 kPa). In patients with F2, F3 and F4 fibrosis, the median liver stiffness values were 6.33 kPa (range: 3.3–9.4 kPa), 9.2 kPa (range: 5.9–33.4 kPa) and 13.7 kPa (range: 5.1–46.2 kPa), respectively. In a comparison of liver stiffness across various liver fibrosis stages (excluding stage F1), median liver stiffness values in the stage F4 patients were significantly higher than the corresponding values in the stage F3 and F2 patients (p 5 0.001 and p , 0.001,
Table 2. 2-D-SWE values according to pathologic diagnosis in all patients Parameter
HCC (n 5 93)
ICC (n 5 6)
Mixed HCC and ICC (n 5 6)
LM and BLT (n 5 16)
Mean Median Minimum Maximum 1st quartile 3rd quartile
13.07 12.0 5.10 46.20 8.25 17.10
7.50 6.50 5.30 13.10 5.53 9.28
8.82 8.05 5.40 14.60 6.60 11.00
6.09 5.85 3.30 13.30 5.25 6.38
HCC 5 hepatocellular carcinoma; ICC 5 intra-hepatic cholangiocarcinoma; LM 5 liver metastases; BLT 5 benign liver tumors.
2-D SWE assessment of hepatic fibrosis d Z. HUANG et al.
respectively), and median liver stiffness values in the stage F3 patients were also significantly higher than the corresponding values in the stage F2 patients (p , 0.001). Additionally, a specific association was observed between liver stiffness values and hepatic fibrosis stage (r 5 708, p , 0.001) (Fig. 3, Table 3). 2-D-SWE for assessment of fibrosis in patients who underwent hepatectomy Figure 4 illustrates the diagnostic performance of 2-D-SWE as assessed using ROC curves. The AUROCs for the ability of 2-D-SWE to predict significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 83.5% (95% confidence interval [CI]: 69.7–97.2), 91.6% (95% CI: 86.7–96.4) and 88.1% (95% CI: 81.3–94.8), respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 7.05 kPa (sensitivity 5 74.6%, specificity 5 100.0%), 9.45 kPa (sensitivity 5 78.8%, specificity 5 100.0%) and 11.1 kPa (sensitivity 5 83.1%, specificity 5 89.3%), respectively (Fig. 4, Table 4). DISCUSSION In this prospective study, we evaluated the diagnostic performance of 2-D-SWE when used to detect hepatic fibrosis in background liver parenchyma in patients with liver tumors who underwent hepatic resection. The pathology of the resected tissue was used as a reference standard. In our study, most HCCs occurred in fibrotic or cirrhotic background liver tissues, whereas most benign
Fig. 3. Box-and-whisker plot of 2-D shear wave elastography (2-D-SWE) values according to liver fibrosis stage. A specific association was found between 2-D-SWE values and hepatic fibrosis stage (r 5 708, p , 0.001). *Indicate outliers in Boxand-whisker plot.
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Table 3. 2-D-SWE values according to fibrosis stage in all patients Parameter
F1 (n 5 3)
F2 (n 5 33)
F3 (n 5 20)
F4 (n 5 65)
Mean Median Minimum Maximum 1st quartile 3rd quartile
5.80 6.70 3.70 7.00 3.70 NA
6.62 6.33 3.30 9.40 5.65 7.50
10.92 9.20 5.90 33.40 6.50 12.5
14.72 13.70 5.10 46.20 11.65 17.66
liver tumors and liver metastases occurred in normal background liver tissues. It is widely accepted that in the Chinese population, primary liver malignancies, including HCC and ICC, often develop in a background of chronic hepatitis B. Additionally, patients with chronic hepatitis B have a natural history of developing liver fibrosis. Previous studies have indicated that elevated liver stiffness is associated with a risk of developing HCC (Kim et al. 2015; Singh et al. 2013). Among the 121 patients included in our study, 99 of 105 patients (94.3%) with liver malignancies, including HCC and ICC, had chronic hepatitis B, whereas only 5 of 16 patients (31.3%) with benign liver tumors and hepatic metastases had chronic hepatitis B. Moreover, a significant difference was observed in the median liver stiffness value for background liver parenchyma between the primary liver cancer group and the benign liver tumor and liver metastasis group (11.80 kPa vs. 5.85 kPa, respectively, p , 0.001). These results are similar to those reported by Tian et al. (2016). The median liver stiffness value for the background liver parenchyma in the patients with HCC in our study was much greater than that reported in a recent study (12.0 kPa vs. 8.9 kPa) (Lu et al. 2015). This variation could be patient related. In the present study, median liver stiffness was measured according to the results of 2-D-SWE of the background liver parenchyma. In each fibrosis stage, the values observed in this study were much lower than those reported in a previous 2-D-SWE study of patients with chronic hepatitis B, in which the median values were 8.2, 11.3 and 18.1 for fibrosis stages F2, F3 and F4, respectively (Zeng et al. 2014). These differences might be explained by differences in the percentages of patients infected with hepatitis B among the patient populations examined in the two studies. Additionally, in a study by Ferraioli et al. (2012), patients with chronic hepatitis C had median values for fibrosis stages F2, F3 and F4 higher than those measured in our study (7.6 vs. 6.33 kPa, 10.0 vs. 9.2 kPa and 15.6 vs. 13.7 kPa, respectively) (Ferraioli et al. 2012). The different etiologies of chronic liver disease might explain this difference. Previous studies have found that SWE has good diagnostic
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Fig. 4. Receiver operating characteristic (ROC) curve analysis assessing the ability of 2-D-shear wave elastography to predict fibrosis stage. (a) Significant fibrosis ($F2), area under the curve (AUC) 5 0.835 (95% confidence interval [CI]: 0.697–0.972). (b) Severe fibrosis ($F3), AUC 5 0.916 (95% CI: 0.867–0.964). (c) Cirrhosis (5F4), AUC 5 0.881 (95% CI: 0.813–0.948).
performance for staging liver fibrosis in patients with different chronic liver diseases, including chronic hepatitis C infection, chronic hepatitis B infection and non-alcoholic fatty liver disease, when a liver biopsy is used as a reference standard (Ferraioli et al. 2012; Ochi et al. 2012; Zeng et al. 2014). A recent meta-analysis also indicated that SWE has high diagnostic accuracy for staging liver fibrosis in patients with chronic diseases of different etiologies (Li et al. 2016). To our knowledge, this study is the first to evaluate the value of using realtime 2-D-SWE to assess liver fibrosis in background liver parenchyma using resected tissue as a reference standard in patients with liver tumors. Our ROC curve analysis results revealed that the AUCs associated with 2-D-SWE when diagnosing significant fibrosis ($F2), severe fibrosis ($F3) and cirrhosis (5F4) were 0.835, 0.916 and 0.881, respectively. These results indicate that 2-D-SWE has good diagnostic value for assessing hepatic fibrosis in patients with liver tumors. Compared with the results of a recent 2-D-SWE study conducted by Table 4. Diagnostic performance of 2-D-SWE in all patients Statistic
$F2
$F3
5F4
Area under the 83.5 (69.7–97.2) 91.6 (86.7–96.4) 88.1 (81.3–94.8) curve Cutoff value, 7.05 9.45 11.10 kPa Sensitivity, % 74.6 78.80 83.10 Specificity, % 100.0 100.0 89.30 PPV, % 100.0 100.0 90.00 NPV, % 9.0 66.7 82.00 Positive LR NA NA 7.77 Negative LR 0.25 0.21 0.19 PPV 5 positive predictive value; NPV 5 negative predictive value; LR 5 likelihood ratio.
Zeng et al. (2014) in patients with hepatitis B infection, our study resulted in slightly lower AUCs for detecting liver fibrosis stage (i.e., AUC 0.917-0.945). However, the cutoff values for staging significant fibrosis and severe fibrosis were similar for the two studies (7.05 kPa vs. 7.2 kPa and 9.45 kPa vs. 9.1 kPa, respectively), whereas the cutoff value for staging cirrhosis in our study was slightly lower than that used by Zeng et al. (2014) (11.1 kPa vs. 11.7 kPa, respectively). Furthermore, we obtained high PPVs for the cutoff values we used for various liver fibrosis stages, indicating the usefulness of SWE for confirming significant fibrosis ($F2) and severe fibrosis ($F3). However, the NPVs were low for significant fibrosis and severe fibrosis, indicating that 2-D-SWE does not capably exclude significant fibrosis and severe fibrosis. This result is inconsistent with those described in previous studies (Leung et al. 2013; Zeng et al. 2014). Differences in patient populations might explain these differences. Factors that affect assessments of liver stiffness may lead to incongruence in assessments of fibrosis stage and stiffness. Previous studies have found that inflammation and GGT, ALT, AST and serum ALP levels influence liver stiffness when measured using 2-D-SWE (Zeng et al. 2014; Zhuang et al. 2017). Other studies have indicated that inflammation, infiltrative diseases, cholestasis, venous congestion and excessive alcohol intake influence liver stiffness when measured using transient elastography (Arena et al. 2008; Coco et al. 2007; Friedrich-Rust et al. 2016; Millonig et al. 2008, 2010). These factors reflect the inflammatory status and function of liver, and they may therefore be associated with fibrosis progression. Currently, there is no consensus regarding the influence of liver steatosis on liver stiffness in patients with chronic liver disease
2-D SWE assessment of hepatic fibrosis d Z. HUANG et al.
(Boursier et al. 2014; Gaia et al. 2011; Petta et al. 2015). We did not assess the effect of hepatic steatosis on our 2D-SWE results because the number of patients with hepatic steatosis was small. Other factors, such as portal pressure, have been known to affect liver stiffness. The correlation between the hepatic venous pressure gradient (HVPG) and liver stiffness is reportedly good for HVPG values up to 10 or 12 mm Hg. However, it seems to be less optimal above these values, probably because of extrahepatic factors in advanced portal hypertension (Berzigotti 2017; Kumar et al. 2017). We did not assess the effect of portal pressure in this study because measurement of HVPG is invasive. Interestingly, the observed variability in liver stiffness measurements may also have affected variation in our shear wave speed estimates. In addition, in the present study, we used linear assumptions to develop an overall assessment of the liver modulus. However, non-linear models have been used in an attempt to distinguish inflammation and other factors from liver fibrosis stage (Talwalkar et al. 2008; Yin et al. 2017). Thus, the question of how to reduce the effects of confounding factors is important in clinical practice. The strength of this study was our use of surgically resected liver tissue as a reference standard. This allowed us to avoid potentially inadequate liver biopsy specimens. Our study also has several limitations. First, our sample population was relatively small, and the distribution of patients with various stages of liver fibrosis was not equal, especially in stage F1, for which we had a small number of patients. Therefore, further studies that include larger sample populations who are more equally distributed across fibrosis stages are needed. Second, the samples obtained in the liver parenchyma during liver resection may not have coincided with the ROI. Thus, it is possible that sampling may have affected the difference between fibrosis stage and stiffness more than in other studies. Hence, further study is needed to reduce sampling error. Third, our study population was Chinese, and most cases of HCC developed in patients infected with the hepatitis B virus. Our results may therefore not be generalizable to patients with liver fibrosis of other etiology. In conclusion, the results of this prospective study suggest that 2-D-SWE is a useful, accurate and noninvasive method for pre-operatively evaluating hepatic fibrosis in patients with liver tumors when adapted to hepatectomy. Acknowledgments—This study was supported by the National Natural Science Foundation of China (No. 81602143).
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