The Place of Elastography for Liver Tumors Assessment

Abstract

Elastography is an ultrasound (US) based method widely used in the field of hepatology, particularly for liver stiffness assessment in patients with chronic liver disease. Elastography brings valuable information regarding tissue stiffness and could be considered a virtual biopsy. In the last years, the incidence of focal liver lesions (FLLs) has increased due to frequent detection during a routine abdominal US. The differential diagnosis of FLLs can be challenging, and it is important in terms of treatment options and prognosis. Currently, most FLLs require for diagnosis workup imaging methods with contrast (radiation exposure, potentially nephrotoxic contrast agents) and/or biopsy that are considered invasive procedures and could be contraindicated in particular cases. Avoidance of these invasive methods could be the main reason to perform elastography for FLLs evaluation as they are commonly first detected on US examination. Several studies showed that elastography could bring additional information regarding the stiffness of FLLs in order to predict their nature.

1. Introduction

In clinical practice, standard abdominal US is probably the most widely used imaging technique for liver examination due to the advantages of this method: non-invasive, availability, safe, low-cost. FLLs are often detected incidentally during routine US examinations [1, 2, 3]. The characterization and differential diagnosis of these lesions constitute a daily challenge for the practitioner. The continuous development of US tools (i.e., Color-Doppler; Tissue Harmonic Imaging; Contrast-Enhanced Ultrasound - CEUS, elastography) improved FLL characterization [4] and offered a new perspective for the clinician that led to a more complete evaluation of diffuse and focal liver disease.

US elastography is being widely used for liver stiffness assessment as a non-invasive marker of fibrosis useful for the management of patients with diffuse liver disease. Other clinical applications for liver elastography include diagnosing clinically significant portal hypertension and predicting high-risk varices, characterization of FLLs, and the prognosis of the clinical outcomes for chronic liver disease [5, 6, 7, 8, 9].

FLLs have different stiffness as the result of different histological structures. They can be classified as benign or malignant. The most frequent solid benign FLLs are hepatic hemangioma (HH), focal nodular hyperplasia (FNH), and hepatocellular adenoma (HA) [10]. Malignant FLLs can be primary liver tumors (hepatocellular carcinoma, HCC; cholangiocarcinoma, CC) or secondary lesions (metastases).

After detecting an FLL on the abdominal US, we must determine whether the tumor is benign or malignant; this is important for future follow-up, therapeutic management, and prognosis. In many cases, a second-line imaging method with contrast (CT/MRI) and/or biopsy is needed for a definite diagnosis. The need to develop less invasive methods to diagnose and characterize FLLs arises from the limitations of these currently used techniques that involve radiation exposure, potentially nephrotoxic contrast agents, limited availability, expensive and invasive methods.

Elastography can be added to a standard US and CEUS examination of an FLL, providing information regarding tissue stiffness and could be considered a virtual biopsy [11]. Several studies reported the possible role of different elastographic techniques to characterize diverse types of FLLs. They focused on the accuracy in discriminating between benign and malignant primary or secondary (metastases) liver tumors. The ability of US elastography to diagnose FLLs, including HCC, is still undergoing validation [12, 13]. In this chapter, we outline the recent advances regarding US elastography to evaluate FLLs.

2. Elastography for the evaluation of focal liver lesions in clinical practice

Currently, liver cancer is the sixth most common cancer and the fourth cause of cancer-related death worldwide [14]. Therefore, the clinical interest to rule out malignancy of FLLs is to diagnose liver cancer early and to allow prompt therapeutic intervention that can improve the prognosis of these patients. Starting from the premise that neoplastic disease can change the tissue structure/composition, elastography could help assess elasticity differences and predict the nature of an FLL [15, 16].

Elastographic assessment of an FLL must be performed knowing the clinical context and history of the patient (liver disease, previous cancer, medication, comorbidities, infections) [17, 18]. It is also essential to evaluate the liver parenchyma for steatosis or fibrosis, knowing the fact that some tumors are more common in particular clinical settings (i.e., cirrhosis represents the common underlying condition for HCC development).

US elastography is a noninvasive, noncontrast, rapid, cost-effective, easy to perform a method that can complete a standard US examination due to numerous elastographic techniques that are now available in different US machines.

According to elastography guidelines [13, 19, 20, 21], elastography techniques can be classified as qualitative (Strain elastography, SE) or quantitative (Shear Wave Elastography, SWE). Figure 1 shows the types of US-based elastography used in clinical practice. Both SE and SWE techniques can assess tissue stiffness but use different principles. Measurement of minimal displacements in the tissue caused by mechanical compression or an enforced acoustic impulse that acts as a wavefront represents the fundamental principle of US elastography techniques [21].

Figure 1.

Scheme of US-based elastography types in clinical practice.

2.1 Strain elastography for FLLs evaluation

Strain imaging is a qualitative technique that allows the measurement of physical tissue displacement parallel to the normally applied stress. The applied force can be: (a) mechanically induced by either active displacement of tissue surface (strain elastography, SE) or passive internal physiological induced (strain-rate imaging, SRI); (b) ultrasound induced by using acoustic radiation force impulse (ARFI) [21]. SE can provide information about the relative stiffness value between one tissue and another. This technique is limited by interobserver variability and can be challenging to apply in particular situations (i.e., patients with ascites; deep localization of the lesion). Although SE is the least used method for liver examination, studies show the utility of strain techniques in FLL evaluation by characterizing the lesion as either soft or hard.

In a recent study [22], benign FLL had a low strain ratio (mean ratio 1.08 ± 0.40) compared to malignant lesions with a high strain ratio (mean ratio 4.14 ± 1.25). The cut-off value for malignant lesions was 1.7 with a sensitivity of 100% and specificity of 93.10. The highest strain index was for CC (6.25 ± 0.44), followed by hepatoblastoma, HCC, and liver metastases [22].

The utility of semiquantitative strain elastography for FLL characterization was also evaluated in a previous study by Onur et al. [23] that obtained a different cut-off to discriminate between benign and malignant FLL. The cut-off value of the strain index for FLL differentiation was 1.28, with a sensitivity of 78% and a specificity of 65%. No difference in strain values between malignant FLLs was found.

A comprehensive evaluation of FLLs on qualitative and quantitative ARFI techniques was assessed in a study by Nagula et al. showing that malignant lesions were stiffer and larger, while benign lesions were softer and similar in size (P < 0.05) [24]. Also, using ARFI strain imaging, another study found that 83.8% malignant and 55% benign FLLs appeared stiffer as compared with the surrounding liver parenchyma having statistically significant differences (P < 0.05) [25].

The intra-operative (IO) application of SE was also studied [26, 27, 28]. In one study that compared the diagnostic accuracy of IO-SE to IO-CEUS for the differentiation between malignant and benign FLLs, the authors concluded that IO-CEUS is useful for localization and characterization of FLLs prior to surgical resection. In contrast, IO-SE provided correct characterization only for a limited number of lesions. The calculated sensitivity of the SE was 70.5%, specificity 60%, PPV 94%, NPV 18.75%, and accuracy 69% [28].

Because SE is a qualitative method, we can obtain the relative stiffness of a lesion compared with the surrounding liver parenchyma. The stiffness of the background liver can be variable depending on the degree of fibrosis and could be considered a limitation of SE for FLL examination. Another confounding factor could be that both benign and malignant lesions can be soft or hard compared to normal liver.

2.2 Shear wave elastography for FLLs evaluation

SWE assesses quantitative information regarding tissue stiffness by evaluating shear wave attenuation. These methods use dynamic ultrasound-induced force to generate shear waves by acoustic radiation force impulses [21]. Measuring the shear wave speed, we can obtain quantitative measurements of tissue elasticity. The stiffness value is provided by the shear wave velocity (SWV) in meters per second (m/sec) or by converting Young’s modulus in kiloPascals (kPa) [21, 29]. The main three SWE techniques used in clinical practice are:

• Transient elastography (TE);

• Point shear wave elastography (pSWE);

• Two-dimensional shear wave elastography (2D-SWE).

TE is validated for liver fibrosis assessment [30]. However, it is not feasible for FLL stiffness evaluation because this method is used without direct B-mode US image guidance and cannot accurately where the lesion is localized.

2.2.1 Point shear wave elastography (pSWE): clinical applications for FLLs evaluation

Relied on ARFI technique, pSWE is available in different US machines and permits real-time non-invasive tissue stiffness assessment during US B-mode examination. Under US guidance, the operator can place the measurement box in any region of the hepatic parenchyma with no vasculature or in an FLL to a maximum depth of 8 cm from the skin plane, as shown in Figure 2. The SWV (m/sec) and depth (cm) of the region of interest (ROI) evaluated will be displayed.

Figure 2.

pSWE measurement in metastasis using Siemens Acuson-Sequoia US system.

Several meta-analysis focused on the performance of SWE in discriminating benign and malignant FLLs [31, 32, 33].

A meta-analysis performed by Jiao et al. [31] that included 9 prospective studies with a total of 1046 FLLs (malignant 679) showed a pooled sensitivity and specificity of 82.2% (95% CI: 73.4–88.5) and 80.2% (95% CI: 73.3–85.7), respectively. The positive likelihood ratio negative likelihood ratio and diagnostic odds ratio of SWE in differentiating malignant and benign liver lesions were 4.159 (95% CI: 2.899–5.966), 0.222 (95% CI: 0.140–0.352), and 18.749 (95% CI: 8.746–40.195), respectively. The area under the hierarchical summary receiver operating characteristic (HSROC) curve was 87% (95% CI: 84–90). The authors concluded that SWE complementary to the conventional US could be useful in FLL differentiation [31].

Another meta-analysis that included 8 studies with 590 lesions (228 benign and 362 malignant) showed that the cut-off value of SWV was different across studies, ranging from 1.5 to 2.7 m/sec. The sensitivity and specificity were 0.86 (95% CI 0.74–0.93) and 0.89 (95% CI 0.81–0.94). The HSROC curve was 0.94 (95% CI 0.91–0.96) [32].

Also, a recent meta-analysis of pSWE (12 studies) and 2D-SWE (3 studies) showed promising results for FLL evaluation [33]. The data included a total of 1894 FLLs from a large cohort (1728 patients). Comparing the methods, 2D-SWE had slightly higher sensitivity compared with pSWE (84% vs. 82%, P < 0.01) and no significant difference in the specificity for the two modalities (P = 0.18). SWE evaluation was useful for FLL differentiation with a mean sensibility of 0.72 (95% confidence interval [CI]: 0.59–0.83) and a mean specificity of 0.82 (95% CI: 0.43–0.97). The area under the operating curve (AUC) was 0.89 (95% CI: 0.86–0.91). The accuracy of the SWV ratio for the differentiation of benign and malignant FLLs was also assessed. The pooled sensitivity, specificity, PLR, and NLR, of the SWV ratio (FLL to surrounding liver parenchyma) for the differentiation of malignant and benign FLLs were 0.72 (95% CI: 0.59–0.83), 0.82 (95% CI: 0.43–0.97), 4.08 (95% CI: 0.88–18.89), and 0.33 (95% CI: 0.19–0.60), respectively. Using the Fagan plot demonstrated that SWE is fairly effective for FLL differentiation: 82% probability of malignant disease following a positive measurement, and the probability reduced to 18% when a negative measurement occurred [33].

Some published studies regarding FLL characterization using pSWE showed higher SWV in malignant tumors [34], and others showed similar SWV values in benign and malignant tumors [35, 36, 37, 38]. The overlapping results can be explained by the level of fibrous tissue in an FLL and the level of vascularization [34].

The studies demonstrated that malignant FLLs are generally stiffer than benign lesions, reporting the following descending stiffness order: Liver metastases > HCC > FNH (focal nodular hyperplasia) > Hemangioma [17, 32, 34, 39]. In the setting of liver cirrhosis, HCC lesions may appear softer than the surrounding liver parenchyma and also softer than other malignant FLLs (metastases and cholangiocarcinoma) [40, 41, 42], with SWV values varying from 2.16 ± 0.75 m/s [43] to 3.07 ± 0.89 m/s in the Guo study [44]. SWE assessment of a lesion must be interpreted, considering the patient’s clinical background [17, 33].

Table 1 shows the SWV mean values (m/sec) for different FLLS (HCC, Metastases, HH, FNH, and HA) and the cut-off values (m/sec) for discriminating between malignant and benign lesions obtained by different studies using pSWE for FLL evaluation.

Study	HCC	Metastases	HH	FNH	HA	Cut-off value malignant vs benign; P value
Dong et al. [35]	2.63 (range 1.84–5.68)	2.78 (range 1.02–3.15)	1.5 (range 0.79–2.61)	1.35 (range 0.69–2.94)	—	2.06 p < 0.005
Zhang et al. [36]	2.59 ± 0.91	3.20 ± 0.62	1.33 ± 0.38	1.90 ± 0.45	—	2.16 p < 0.01
Yu et al. [37]	2.49 ± 1.07	2.73 ± 0.89	1.75 ± 0.80	2.18 ± 0.84	1.79 ± 0.14	2.72 p < 0.01
Heide et al. [38]	2.63 ± 1.09	2.88 ± 1.16	2.36 ± 0.77	3.11 ± 0.93	2.23 ± 0.97	- p = 0.23
Akdoğan et al. [40]	2.75 ± 0.53	3.59 ± 0.51	2.15 ± 0.73	3.22 ± 0.18	—	2.32 p > 0.05
Kim et al. [41]	2.66 ± 0.94	2.82 ± 0.96 3.70 ± 0.61	1.80 ± 0.57	—	—	2.73 p > 0.05
Gallotti et al. [42]	2.17 ± 0.85	2.87 ± 1.13	2.30 ± 0.95	2.75 ± 0.95	1.25 ± 0.37	- p < 0.05
Ghiuchici et al. [43]	2.16 ± 0.75	—	—	—	—	- p < 0.001
Guo et al. [44]	3.07 ± 0.89	2.74 ± 1.06	1.48 ± 0.70	2.30 ± 1.18	—	2.13 p < 0.001
Galati et al. [45]	2.47 ± 1.42	3.29 ± 1.23	1.34 ± 0.91	—	—	2.0 -

Table 1.

Shear wave velocity values (m/sec, range) for FLLs in different studies using pSWE. Cut-off values (m/sec) for discriminating malignant versus benign FLLs.

2.2.2 Two-dimensional shear wave elastography (2D-SWE): clinical applications for FLLs evaluation

2D-SWE is another quantitative elastographic technique used in clinical practice to discriminate between malignant and benign lesions in the prostate [46], thyroid [47, 48], breast [49], and FLLs [50, 51, 52, 53, 54]. This method allows real-time visualization of a color quantitative elastogram superimposed on a B-mode image. Figures 3 and 4 show examples of 2D-SWE FLL evaluation implemented on different US devices.

Figure 3.

2D-SWE elastogram in a large HCC using SSI–SuperSonic imagine, Aixplorer US system.

Figure 4.

2D-SWE.GE evaluation for a HCC using Logiq E9, GE Healthcare US system.

Grgurevic et al. [52] aimed in a recent study to describe the stiffness of the most common benign and malignant FLLs by means of RT-2D-SWE (real-time 2-dimensional share-wave elastography), to analyze the ratio between the stiffness of FLL and surrounding liver parenchyma, and to determine the accuracy of RT-2D-SWE in differentiating benign and malignant FLLs. The authors developed a liver elastography malignancy prediction score (LEMP) for non-invasive characterization of FLLs that enabled correct differentiation of benign and malignant FLL in 96% of patients. This study concluded that RT-2D-SWE could be a reliable method for differentiating malignant from benign liver lesions with a comprehensive approach.

Two other 2D-SWE studies found no significant differences between malignant and benign FLL stiffness [51, 55]. Both studies showed that FNHs were significantly stiffer than HA. Regarding HCC nodules, studies showed 2D-SWE values that varied from19.6 kPa to 44.8 kPa (range 15.8 kPa–97 kPa) [51, 53]. This variability can be explained by many factors, including lesion dimensions and ROI positioning. Additionally, the background liver can influence the diagnostic capability of 2D-SWE [52, 54].

2.3 Limitations of elastography for FLL evaluation

Elastographic evaluation of FLLs has several limitations:

• Lesion position and size;

• Motion artifacts and patients features;

• Wide range of stiffness values in FLLs;

• The number of SWE measurements.

The location of the lesion can limit SWE evaluation; the maximum depth of SWE examination is limited to 8 cm from the skin [56]. The size of the lesion can lead to higher variability of elastographic values [43]. Patient-related limitations are connected to poor image acquisition due to poor intercostal window, obesity, and the patient’s inability to hold respiration. Another confounding factor that must be mentioned is that the SWE values overlap between malignant and benign lesions, leading to diagnostic confusion. There is no consensus regarding the necessary number of elastographic measurements in FLLs [8, 18].

Nevertheless, elastography remains a powerful and essential diagnostic tool for FLL evaluation that can be added complementary to routine US examinations.

3. Conclusions

Elastography is a noninvasive, US-based, real-time imaging modality that can be a valuable tool in orienting the diagnosis and can be integrated into imaging protocols already involving the standard US to obtain a multiparametric approach. Although SWE has excellent potential in characterizing FLLs, further research is needed to evaluate the accuracy of these methods and set specific cut-off values.

Published studies have conflicting results, and no consensus has been so far established. This is the main reason that the WFUMB [13] and EFSUMB [21] guidelines do not recommend the use of elastography for differentiation between malignant and benign FLLs. Further multicentric studies with larger and homogenous cohorts are required for these techniques to be appropriately used routinely in a clinical setting.

Conflict of interest

The authors declare no conflict of interest.