While imaging cannot provide a definitive diagnosis of MPE, the information gained is invaluable in formulating an accurate differential, directing investigations and staging the malignancy. In most LMICs there is extremely limited access (if any) to advanced imaging such as computed tomography (CT), magnetic resonance imaging and positron emission tomography (PET)-CT. Clinicians most often rely on chest radiographs, but even then may have to wait days for the result. Moderate to large free-flowing nonloculated pleural effusions can be visualised on an anteroposterior chest radiograph, with as little as 50 mL of fluid visible on a lateral radiograph [10]. Findings such as crowding of ribs, lung volume loss, an obvious lung mass, circumferential lobulated pleural thickening and a shifted mediastinum suggest a malignant cause of any associated effusion (figure 1a). The mediastinum may be shifted to the opposite side by a large effusion or mass, may remain in the midline or may be shifted toward the malignant mass if it obstructs a bronchus and causes lung collapse, or mediastinal infiltration [10].

Typical imaging findings in a malignant pleural effusion. a) A chest radiograph of a large right-sided malignant pleural effusion with an associated mass in the right upper zone; b) an axial slice from thoracic computed tomography (CT) in a patient with a large right-sided malignant pleural effusion, showing a thickened abnormal pleural with a distinct pleural-based mass lesion amenable to biopsy (arrow); c) a thoracic ultrasound image of large malignant effusion (E) with a markedly thickened parietal pleura (pleural thickening (PT)). Atelectatic lung (L) is seen in the effusion, and the highly echogenic diaphragmatic pleura (D) on the right.

Transthoracic ultrasound should be more readily available than other imaging modalities, as it is routinely used in antenatal medicine and emergency medicine. A basic low frequency (2–5 MHz) curvilinear probe with two-dimensional B-mode ultrasound image is more sensitive than chest radiography for detecting a pleural effusion. If a high-frequency linear probe is available, it can be used for a high-resolution image of the pleural surface, which may show findings strongly suggesting malignancy (figure 1c) [11, 12]. These include parietal pleural thickening >10 mm, diaphragmatic nodularity or thickening of >7 mm, visceral pleural thickening (only seen with a low-frequency probe when the effusion is moderate to large), pleural nodularity/irregularity and an adjacent lung mass [10, 11].

Contrast-enhanced thoracic CT remains the gold standard in evaluating MPE, and should be performed if available. It had a sensitivity and specificity of 97% and 89%, respectively, in one head-to-head comparison with thoracic ultrasound, which had a sensitivity and specificity of 79% and 100%, respectively; the latter mostly driven by pleural nodularity [13, 14]. It is the preferred way of visualising malignant pleural involvement, which usually looks thick or nodular, and may have underlying pulmonary masses or nodules (figure 1b). In addition, it is the best way to evaluate for coexistent liver or adrenal metastasis, although ultrasound may be of help here too [10]. In the case of mesothelioma, circumferential or mediastinal pleural thickening and involvement of the interlobar fissures, which is only visible on the CT, may be an important clue to the diagnosis [15].

If available, PET-CT can be used to detect pleural metastases as a guide to the biopsy site and to monitor treatment response. However, false positive findings can occur from other inflammatory conditions of the pleura, especially in settings with a high burden of communicable diseases [16].

The role of cytology in the diagnosis of MPE is perhaps underappreciated. A recent systematic review found the overall diagnostic sensitivity of pleural fluid cytology for MPE to be 58%, with the highest sensitivity for lung adenocarcinoma (84%), but low sensitivity for squamous cell carcinoma (24%) and mesothelioma (29%) [17]. Immunohistochemical staining dramatically improves our ability to accurately identify a malignancy from a fine-needle aspiration when the pleura is markedly thickened or there is a discrete pleural mass lesion [18]. The controversial exception may be mesothelioma, for which current guidelines still require histology for diagnosis and accurate subtyping [15, 19].

There are a few ways to optimise the yield of pleural fluid cytology. The 2022 guidelines from the British Thoracic Society strongly recommend sending a volume of ≥25 mL; ideally 25–50 mL in suspected MPE [20]. The correct handling of the specimen is important, and ideally it should be processed within 2 h. If not possible, cellular integrity may be preserved for up to 72 h with refrigeration at 2–8°C [21]. Furthermore, centrifuging the fluid sample and obtaining a cellblock for haematoxylin and eosin staining and immunohistochemistry should be done routinely to improve the overall diagnosis and establish the origin of metastatic cancers [18].

Performing a second thoracentesis where the first has failed to diagnose a pleural exudate is discouraged. The additional yield is only 7–17%, and repeat aspirations risk introducing infection into the effusion [22]. However, if the initial volume aspirated was small (<25 mL) and the suspected tumour type is one associated with a higher likelihood of cytological diagnosis from pleural fluid (such as adenocarcinoma), then re-aspiration under aseptic conditions could be considered [20].

It must be acknowledged that cytology is rarely sufficient to identify the molecular markers required to guide targeted immunotherapy. However, considering the current exorbitant cost of these therapies, this is not likely to impact diagnostic pathways in LMICs.

Unguided or “blind” closed pleural biopsy has no place in current practice. The procedure has a high risk of organ injury; only yields a diagnosis of MPE in 47% of cases; and only increases the diagnostic yield over pleural fluid cytology by 7–27% [22, 23]. However, image-guided pleural biopsies provide a reasonable alternative for obtaining pleural tissue with minimal complications, especially in an underresourced setting [12]. The reported sensitivity in MPE varies slightly between studies, but is generally ∼87%; sometimes >95% when there is a gross pleural abnormality [20, 24, 25].

Various dedicated pleural biopsy needles are available. The Abrams or reverse-bevel needle (figure 2a and b) has been used since as far back as the 1950s and is still preferred in many LMICs, as it is reusable and lasts decades [26]. It is a large-bore metal needle, which consists of two cylinders with a stylet. The outer cylinder acts as a short trocar to puncture the chest wall through a small incision, with the fine-edged notch on the side used to hook pleura. The cutting edge of the inner cylinder is used to shear off a piece of tissue of up to 5 mm in diameter. Since the late 1980s, other needles (not specifically designed for pleural tissue sampling) have been validated, particularly core-cutting needles like the Tru-Cut needle (figure 2c) [27]. These were originally designed to be manually deployed, but numerous automated core needles are commercially available. Unfortunately, they are generally single use, which increases the cost of the procedure.

Needles for image-guided closed pleural biopsy. a) The traditional reusable Abrams pleural biopsy needle; the three parts of the needle are shown (from top to bottom): the outer cylinder, the inner cylinder with cutting edge, and the stylet. b) The assembled Abrams needle in the open position with the notch indicator on the grip in line with the specimen open notch (arrows). Below this is the needle in the closed position, as the inner cylinder has been rotated down into the outer cylinder. c) Typical core-cutting needles: on the left, an automated needle which will trigger a closing action after being primed; on the right, a manual needle.

A recent systematic review and meta-analysis found that there was no significant difference between the yield of CT- and ultrasound-guided biopsies in the diagnosis of pleural lesions [28]. Considering that ultrasound has no radiation exposure and is easily performed at the bedside, the authors concluded that ultrasound-guided biopsies should be the preferred approach in the presence of adequate skills. Only the most basic ultrasound equipment is needed to guide a biopsy in the presence of an effusion. A curvilinear probe on the “abdomen” preset, exactly as is used for obstetric services, is sufficient. If available, a linear probe for high-resolution scanning of the pleural surface is recommended when there is a small effusion or no effusion, and colour Doppler ultrasound to identify the intercostal vessels. Additionally, ultrasound allows the immediate detection of complications [12].

Most importantly, the biopsy needs to be performed in a safe and controlled environment where optimal patient positioning is possible [12]. It must be done with a full aseptic technique. So, the ideal environment is an elective theatre or clean procedure room. The patient should be seated upright, with their legs supported by a step, and their arms supported in front of them to lift the scapulae off the posterior chest wall. Once the patient is positioned properly and comfortable, the biopsy area is identified using the ultrasound, and marked on the patient's skin. Then the local anaesthetic agent is instilled. This may simply be 1% lignocaine given directly to the skin, subcutaneous tissues and intercostal structures over the planned biopsy site. Alternatively, a rib block can be done, which is very effective.

Techniques used for ultrasound-guided biopsy include the “free-hand” or “image-assisted” technique, and the “real-time” technique [29]. Most commonly, the image-assisted technique is used. The most suitable biopsy area is identified and marked, then the ultrasound probe is put down and the biopsy performed. In this case it is critical to assess the depth, correct plane and angle of the biopsy needle while the ultrasound is in use. A safe zone must be measured, to avoid injury to visceral structures, the diaphragm and intercostal neurovascular bundles [30]. The most suitable biopsy area is pleura that is thickened, nodular or a clearly visualised pleural mass. If there is no overtly abnormal pleura, the biopsy site should be as close as possible to the diaphragm and midline, as this is where most of the malignant deposits will occur. The real-time technique involves a second person holding the ultrasound probe in position throughout the procedure so that the needle is observed in real-time. This can be done with the needle in the long or short axis of the probe, although having the whole length of the needle visible during the procedure is preferred [29]. There are commercially available attachments for the ultrasound probe designed to hold a core needle, which may allow a single user to perform real-time ultrasound guidance [11].

The biopsy procedure is different depending on the needle used. An Abrams needle should be slowly inserted through a small skin incision until within the pleural space, angled infero-laterally (away from the usual position of the neurovascular bundle), until the specimen notch is against the pleura. The needle is opened by twisting the grip of the outer cylinder. When pushed against the pleura and closed, a piece of pleura will be sheared off inside the notch. The needle is then removed. A core needle also enters the skin through a small incision and is angled lengthwise against the pleura. The cutting sheath is then either manually closed over the specimen notch, or having been “primed”, triggered to close automatically. The clinician must stabilise the needle when the cutting sheath is closed, as the needle tends to push back [30].

The yield of ultrasound-guided biopsy is ∼84% for all pathologies; possibly a bit lower (∼70%) for malignant effusions [20]. Important factors which improve the yield of ultrasound-guided biopsy include a larger needle gauge, thicker pleura and nodular pleura [31]. The number of samples taken in one procedure also matters: we recommend that at least six cores be sent for the highest likelihood of a diagnosis [32, 33].

The most common complication of a closed pleural biopsy is a pneumothorax. When image guidance is used, pneumothorax is more often caused by air moving into the pleural space through the needle than by visceral pleura and lung injury. Fortunately, only a minor proportion of these patients will require intervention to manage this complication. Other rare complications include haemothorax (<2%), local haemorrhage and haematoma (<1%), site pain (1–15%) and transient fever (<1%) [22]. Life-threatening haemorrhage is a potential risk, which is most often due to injury of an intercostal vessel. The risk of introducing infection into the pleural space is theoretical, with data suggesting that the only preventative measure needed is an aseptic technique [34]. Procedure tract metastasis has a variable incidence between 4% and 24%. It is more common in mesothelioma, and more likely with larger bore procedures, with the highest incidence reported in surgical biopsies [35, 36].

In a prospective study preformed at our institution, we validated a previously suggested algorithm to guide both the biopsy technique and device based on pleural imaging, and reported a 90% diagnostic yield for all diagnoses, including malignancy [25]. Patients were stratified into three groups: 1) those with an associated mass lesion; 2) those with diffuse pleural thickening (>10 mm) and/or nodularity; and 3) those with insignificant pleural thickening (irrespective of the size of the effusion). Where there was an overt pleural-based mass lesion, transthoracic fine needle aspiration (TTFNA) cytology with cell block was performed with rapid on-site evaluation (ROSE) of specimens by an experienced pathologist. In cases where ROSE showed insufficient material, Tru-Cut core biopsies (six passes) were performed. ROSE allowed immediate feedback from the pathologist to the clinician performing the TTFNA, so that if needed, a biopsy could be done during the same visit. In cases where there was uniform pleural thickening of <1–2 cm in depth, we used an Abrams needle closed biopsy with ultrasound guidance. In cases of marked pleural thickening of >1–2 cm depth, we proceeded with a core needle for biopsy. In the case of insignificant pleural thickening, an Abrams needle was performed in basal region of the pleural surface as identified by ultrasound.

Considering that ROSE and cytopathology services are not available in many LMICs, we propose an alternative ultrasound-based algorithm, summarised in figure 3.

A practical approach to the diagnosis of a malignant pleural effusion in a severely resource-constrained setting. Transthoracic fine-needle aspiration (TTFNA) with rapid on-site evaluation (ROSE) by a pathologist may not be available, in which case an image-guided biopsy would the first investigation after thoracentesis in an effusion with an overt pleural-based mass lesion. Where thoracoscopy, video-assisted thoracoscopic surgery (VATS) and surgical biopsy are unavailable, then we suggest obtaining either computed tomography (CT) or ultrasound, depending on what has already been done. Then stratify according to this imaging and repeat the biopsy with a new target. Figure created using BioRender.com.

Where available, undiagnosed cases should be referred for either medical or surgical thoracoscopy or video-assisted thoracoscopic surgery (VATS), which provides a higher diagnostic yield of ∼98% [37]. However, most countries in sub-Saharan Africa have either no or extremely limited access to any form of thoracoscopy.

Medical thoracoscopy, or pleuroscopy, is done under conscious sedation through a single port in a spontaneously breathing patient, usually in a bronchoscopy suite. In contrast, traditional VATS needs three chest ports and general anaesthesia. While both procedures allow for biopsy of visually abnormal parietal pleura, adhesiolysis and pleurodesis, VATS is associated with longer hospital stay (median 5.8–10.7 days) and inpatient mortality (1–8%) [38]. Recently, techniques have improved to uniportal VATS as well as VATS under conscious sedation, blurring the boundaries with medical pleuroscopy [39].