Ultrasound elastography: a novel tool for the differential diagnosis of pleural effusion

Study design

The study was conducted prospectively at the First Hospital of China Medical University (Shenyang, China) between October 2012 and October 2017. Patients with unilateral or bilateral pleural effusion were enrolled in this study. The inclusion criteria were as follows. 1) Patients with pleural effusion, as demonstrated by chest radiography; 2) undiagnosed effusions (malignant or otherwise) at the first patient encounter or presentation; 3) patients who did not undergo thoracentesis, drainage and analysis of pleural effusions before enrolment; and 4) patients who, in clinical practice, would have undergone further examination to establish the cause of pleural effusion. The exclusion criterion was inability or refusal to undergo further examination to establish the cause of pleural effusion. All enrolled patients were divided into a development set and a validation set based on the chronological order in which they presented to the hospital (figure 1). The primary outcome was the capacity of ultrasound elastography to identify MPE compared with traditional TUS. The secondary outcome was the influence of different aetiologies on the diagnostic performance of ultrasound elastography. This study was approved by the institutional ethical review board of the First Hospital of China Medical University (reference number: 201-9126-2), and written informed consent was obtained from all patients.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1

Flow chart of patient enrolment. ROC: receiver operating characteristic; TUS: traditional thoracic ultrasound.

To obtain the desired level of statistical power for evaluating the accuracy of the diagnostic test, the minimal sample size required was calculated based on the estimated sensitivity and specificity [7]:We estimated the sensitivity (Se) and specificity (Sp) for the mean elasticity index to diagnose MPE as 85% and 85%, respectively, according to our preliminary pilot study of a small sample of 20 cases; we estimated the prevalence of MPE in patients with pleural effusion as 43% according to data from our centre in 2012. For a maximum marginal error of the estimate not exceeding 10% with a 95% confidence level, the total required sample size was 114 patients. All 114 patients needed were enrolled in the development set to measure the accuracy of interest (the sensitivity/specificity and the area under the receiver operating characteristic (ROC) curve (AUC)), and another 130 patients were enrolled in the validation set.

Transthoracic ultrasound and ultrasound elastography

Before pleural ultrasound, a respiratory expert (GH) reviewed each patient's most recent chest radiographs to determine which side of the thorax to assess via ultrasound. In patients with bilateral pleural effusion, the side with the greater amount of effusion was assessed, since this was usually considered the clinically relevant side. Two operators with different seniority levels (the senior operator was a radiologist with >8 years of experience, while the junior operator was a radiologist with 3 years of experience) who were blinded to the patients' clinical history and thoracic imaging (computed tomography/magnetic resonance imaging) data performed all ultrasound examinations separately.

Greyscale ultrasound was performed with an Aixplorer ultrasound scanning system (SuperSonic Imagine, Aix-en-Provence, France) with a 4- to 15-MHz linear-array transducer, as described in previous studies [8–10]. The ultrasound imaging features of pleural nodules and focal pleural thickening are shown in figure 2a, b.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2

Ultrasound features of pleural nodules and focal pleural thickening and measurements of pleural stiffness by shear wave elastography. a) Pleural nodules appeared as hypoechoic nodular lesions with defined margins located in the parietal or visceral pleura, while b) focal pleural thickening was identified as an echogenic area of increased thickness in the parietal pleura with poorly defined margins. c) Images of pleural thickening or nodules are displayed together with the greyscale ultrasound images. After placing a box (frame) over the pleura, a coloured image appeared, revealing blue and red areas on an elastogram. Dark blue areas correspond to soft tissues, whereas red areas correspond to stiff tissues.

Measurements of pleural stiffness were performed using shear wave elastography (SWE) [11, 12] (figure 2c). Using the device's software (OsiriX, version 6.0; Pixmeo, Berne, Switzerland), a circular region of interest was placed inside the pleural elastogram, and the diameter of the circle was increased as much as possible to between 1 and 8 mm, taking care not to surpass the limits of the analysed pleurae. The default setting for the pleural 2D-SWE scale was used (range 0–100 kPa). A summary of the quantitative stiffness data was automatically displayed. The following parameters for the elasticity index, expressed in kPa, were provided by the system: the mean elasticity index (SWE_mean), the maximum elasticity index (SWE_max), the minimum elasticity index, and the elasticity index standard deviation [13]. Precise details of the TUS and ultrasound elastography technique are provided in the supplementary material.

Criteria for malignant pleural disease on TUS

The operators separately recorded an initial diagnosis of malignant or benign pleural disease pro forma on the basis of anonymised TUS data. If patients had any one of the following criteria upon TUS examination, then a TUS-based diagnosis of malignant disease was recorded: 1) diaphragmatic or parietal pleural nodule(s); 2) pleural thickening >1 cm; or 3) hepatic metastasis [14]. If patients had none of those three criteria, benign pleural effusion based on TUS would be recorded.

Pleural effusion types and the criteria for definitive diagnosis

The diagnosis of malignant pleural lesions was confirmed by the histocytological examination of biopsy samples obtained by semirigid thoracoscopy or closed pleural biopsy or by the cytopathological examination of pleural effusion samples using a liquid-based thin-layer cytopathology technique [1]. When disseminated malignancy was present with no alternative explanation for exudative effusion, probable MPE was diagnosed.

All definitive diagnoses of benign pleural effusion were determined based on comprehensive clinical data, including imaging, laboratory results and histocytological manifestations of disease. No patients with benign disease had any evidence of malignancy during the follow-up period of >12 months [15]. Benign pleural effusion was definitively diagnosed using pathogenic microorganism isolation methods, such as those used for diagnosing tuberculosis (TB) and empyema. Tubercular pleurisy was diagnosed based on a positive mycobacterial stain/culture of pleural fluid or pleural tissue or the presence of caseous granuloma on pleural biopsy. Empyema was diagnosed if thoracentesis yielded frank pus and/or bacteria were identified by Gram staining or the culture of pleural effusion samples [16]. Parapneumonic effusion was considered exudative effusion that occurred in the presence of clinical evidence of pneumonia and the exclusion of other suspicious diagnoses. The classification of the effusion as exudate or transudate was based on Light et al.'s criteria [17].

The methods used for determining the final diagnoses are shown in table 1. In 52 (48.15%) out of 108 patients, the definitive diagnosis of MPE was based on the pleural histocytological results. In addition, 56 (51.85%) out of 108 patients were diagnosed with probable MPE based on clinical criteria.

Statistical analysis

All data were collected and analysed using SPSS 17.0 (SPSS for Windows, version 17.0; SPSS, Chicago, IL, USA). For the ultrasound elastography and TUS data, we used paired t-tests and κ coefficients to determine the interobserver agreement between the two operators with different seniority levels, and the findings of the senior radiologist (BJ) were used for all subsequent analyses. Statistical analysis of the differences in diagnoses was performed using the exact binomial test. The elasticity indices of the development set, as continuous data, were used to construct ROC curves. The AUC was used as a performance measure. We attempted to establish the optimal cut-off values for SWE_mean and SWE_max using Youden's index [18]. In the validation set, we tested the universality of the cut-off values for differentiating MPE from benign pleural effusion. The diagnostic efficacy (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV)), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and Youden's index) of ultrasound elastography at fixed cut-off values was compared with that of traditional TUS. The 95% confidence interval of sensitivity, specificity, PPV, NPV, PLR and NLR was calculated using an online clinical calculator (http://vassarstats.net/clin1.html). Statistical significance was set at p<0.05.