Combined ultrasound-guided cutting-needle biopsy and standard pleural biopsy for diagnosis of malignant pleural effusions

Pleural effusions are a common clinical problem with more than 50 recognised causes [1]. In the UK, an estimated 50,000 diagnoses of MPE are made each year [2]. While fluid tumor markers may help in making a probable diagnosis of malignancy, they are not disease-specific [3], and cytological examination of pleural fluid for malignant cells establishes a positive diagnosis of malignancy in only 60% of carcinomatous effusions [4‐6]. Immunostaining substantially improves the diagnostic yield [7] but this falls to 30% in effusions associated with malignant mesothelioma [8]. Thus, the role and value of fluid biomarkers and cytology are hotly debated [9].

The definitive diagnosis of pleural malignancy depends upon histological proof obtained via pleural biopsy. SPB, US-CNB and thoracoscopy are techniques commonly utilised for the acquisition of pleural tissue [10‐15]. Thoracoscopy has a superior diagnostic yield for pleural effusions [16, 17] but it is relatively complicated to perform, especially in frail patients. With the lower diagnostic yields, SPB and US-guided CNB are now being neglected. However, given the ease of use of these procedure and their lesser costs, SPB or US-guided CNB may be considered the initial diagnostic step in undiagnosed pleural effusions. Currently, the most efficient and cost-effective approach for a definitive diagnosis remains difficult to establish and is controversial among chest physicians [18].

To our knowledge, no prospective studies have been undertaken to assess the utility of a combination of US-guided CNB and SPB performed sequentially in the same setting and by the same operator. Consequently, in this prospective study, we evaluated the value of a combination of US-guided CNB and SPB for diagnosis of MPEs.

The definitive diagnosis of pleural diseases, particularly malignancy, depends upon histological analysis of tissue obtained via pleural biopsy. Adequate pleural tissues, which are crucial for a definitive diagnosis, can be obtained by SPB, thoracoscopy or CNB under the guidance of CT or US. Thoracoscopy allows direct visualisation of the pleura and biopsy from abnormal sites [20]. In a study of patients with pleural tuberculosis, Koegelenberg et al [21]. found that US-assisted Abrams’ needle biopsy specimens were more likely to contain pleural tissue than specimens obtained using US-assisted Tru-Cut biopsies (91.0 vs 78.7%; p = 0.015). In 2014, Hallifax et al [22]. reported that US-guided CNB successfully obtained pleural tissue in a high proportion of patients (94.0%) with pleural disease, including cases where thoracoscopy had failed. The present study is the first prospective investigation of a combination of US-guided CNB and SPB for the diagnosis of MPE. Our results showed that US-guided CNB and SPB provided adequate specimens for histological analysis in 90.7 and 93.0% of cases, respectively (p = 0.577), while the combination of both techniques provided adequate specimens in 96.5% of cases; however, the latter result was not significantly superior to the two techniques alone (p = 0.119 or 0.304).

Current guidelines on the investigation of pleural effusions emphasise the use of a diagnostic algorithm or recommend the use of a stepwise approach [6, 23‐25]. However, pleural effusion analyses and biomarkers are not disease-specific [3, 26‐28]. Previous biopsy investigations have mostly focused on the advantages and limitations of each individual technique, and to our knowledge, no studies have investigated a combination of CNB and SPB at the same time. Our results indicate that a combination of the two techniques is more effective than either technique alone for the diagnosis of malignant pleural disease. The size of this advantage is considerable. The combination of CNB and SPB led to a correct diagnosis of MPE in 88.6% of patients, and the sensitivity (88.6%) was only slightly lower than published sensitivities from large thoracoscopy series [29, 30]. Thoracoscopy has the advantage of undertaking some therapeutic options, such as talc poudrage, at the same time, but has the disadvantages of being more costly, more invasive, and hazardous in very frail patients. The combination of CNB and SPB performed sequentially by same operator in the same setting can avoid the need for repeated procedures (since the sensitivities of the combination of US-guided CNB and SPB and the two techniques alone for diagnosis of pleural malignancy were 88.6, 51.2 and 63.4%, respectively, 37 or 25% of patients compared with CNB or SPB alone could avoid the need for repeated procedures), and it would decrease both medical costs and the time required for evaluation of pleural malignancy.

SPB was described more than 50 years ago and became the most widely utilised method for blind biopsy [31]. This procedure has some advantages, including a relatively low cost and ease of usage, but it generally demonstrates a modest diagnostic accuracy of less than 60% for MPE [5, 6],although a higher diagnostic accuracy for pleural tuberculosis (80–87%) [17, 32]. In recent years, US-guided CNB has been increasingly used for pleural biopsy. The most obvious advantage of this procedure is its ability to ensure that biopsy samples are obtained from areas characterised by abnormal pleural tissue. While US-guided CNB increases the diagnostic accuracy and minimises the risk compared with SPB [33, 34], its diagnostic accuracy is lower than that of thoracoscopy [6, 35]. However, the use of thoracoscopy is not always possible in frail patients or when pleural fluid is heavily loculated or the lung is adherent to the chest wall.

To overcome these limitations, a combination of CNB and SPB was used in this study. All procedures were performed sequentially by an experienced operator (JW) according to standardised guidelines. Several possible factors could be responsible for the diagnostic advantage of the combination in comparison with the individual techniques. During SPB, an incision in the skin in the direction of the chosen intercostal space above the lower rib was made, especially in overweight/obese patients. During the biopsy procedure, the assistant pressed the skin between the ribs, which allowed the distal tip of the needle to have sufficient contact with the pleura. A limitation of SPB is the blindness of the procedure, although an experienced operator can obtain adequate tissues for a histological diagnosis. We found that the number of adequate specimens was higher with SPB than with CNB (93.0 vs 90.70%, respectively), and, as previously reported [17, 32‐36], the diagnostic accuracy was also higher (81.3 vs 74.4%, respectively). In addition, for patients with a pleural thickness <3 mm, the diagnostic accuracy of SPB was also significantly higher than with CNB (p < 0.05).

For CNB, we performed the procedures using relatively supradiaphragmatic biopsy sites or the most thickened pleural sites. Pleural malignancy is characteristically patchy and preferentially basal, or is found on the diaphragm and results in focal involvement [36]. In addition, a large angle may be essential to obtain adequate samples, especially from thin pleura. The cutting needle was cautiously introduced at an angle of more than 55° through an incision in the skin made toward the direction of the chosen intercostal space under the guidance of a high-frequency probe. However, as has previously been reported [17, 32‐36], our results showed that the diagnostic accuracy of CNB was lower than that of SPB (74.4 vs 81.3%, respectively). When our results were analysed according to the degree of pleural thickening, the diagnostic accuracy of CNB in patients with pleural thickening <3 mm was significantly lower than in patients with pleural thickening ≥3 mm (p < 0.05), and significantly lower than with SPB (p < 0.05). A possible reason for this finding may be that the diagnostic accuracy is affected by pleural thickening. When a US-guided pleural biopsy is performed in patients with minor pleural thickening, there may be a lower probability of obtaining adequate specimens. However, SPB may be capable of acquiring a larger number of adequate samples.

Both biopsy procedures were well tolerated in the patients we studied, and no serious complications were observed. However, we concerned with that although four significant pain and two moderate haemoptysis required no intervention, there were about 3.5% complications (four significant pain and two chest wall haematoma) required further intervention following CNB. Following SPB, four patients (2.3%) suffered from a slight pneumothorax, but which recovered spontaneously. Though neither procedure was abandoned for the complication, management must be to improve to avoid it, such as, better preparation for reducing syncope or significant pain, skilled procedures for avoiding haemoptysis, chest wall haematoma or pneumothorax. Reported complication rates of SPB or image-guide CNB vary widely [16, 37, 38]. There was 11% had a new pneumothoraces visible on CT following CT-guided CNB [38], but major complication was rare. Thoracoscopy has demonstrated a low rate of complications, but mortality rates resulting from major complications (including air leak and pneumonia) have been reported to be 0.34–1.8% [2, 39]. So, the combined approach was safe. In addition, compared with the suggested stepwise approach and thoracoscopy [6, 16], the combination was finished in the same operation sequentially, it shortened the days of hospitalization, decreased the cost and it was convenience. In our study, one patient was found to have an implantation metastasis at the biopsy site after 3 months of follow-up. Whether prophylactic radiotherapy of the site can reduce the likelihood of this complication is controversial [4, 40].

Use of a combination of US-guided CNB and SPB afforded a high sensitivity to diagnose MPEs, it is a convenient and safe approach.