The presence of a malignant pleural effusion (MPE) automatically classifies patients to advanced cancer stage and it is associated with significant mortality and morbidity (1). MPEs’ incidence is 660 per million population worldwide (2) accounting for more than 200,000 people diagnosed each year in the US (3) and over 100,000 people/year across Europe (2,3). Health Care Systems sustain a large burden due to hospital admissions for MPE. A retrospective analysis based on the Healthcare Cost and Utilization Project National Inpatient Sample database reported 126,825 hospital admissions for MPEs in 2012 and interestingly 72,240 included one or more pleural procedures which in the end were not expected to reduce the recurrence rate of MPEs (1). Lung and breast cancer are the most common causes of MPEs and hospitalizations related to them are more likely to include pleural procedures compared to hospitalizations for MPEs due to other types of cancer (1).
In this review, we examine diagnostic and therapeutic approaches in patients with primary lung cancer and pleural effusion and address clinical questions derived from practicing in pragmatic clinical health care settings.
Imaging plays an integral role in the diagnostic work up of pleural effusions especially on the background of suspected or confirmed lung cancer. Although chest X-rays have been historically used for the initial diagnosis of pleural effusions, thoracic ultrasound and enhanced chest CT scan have evolved the diagnostic work up. The traceable amount of pleural fluid varies depending on the imaging modality. Thoracic ultrasound is considerably more sensitive than Chest X-rays in detecting smaller volume of pleural fluid and it is independent of view/body posture while chest X-rays’ detection of pleural fluid is affected by the projected X-ray view and body posture (e.g., lateral decubitus) (4-8). Although there is published data on how to calculate the amount of pleural effusion identified in a chest CT scan (9,10), to the best of our knowledge there is no published data regarding minimum fluid volume quantity detected by chest CT scan (3-8). Table 1 summarizes the minimum amount of detectable fluid by each imaging modality (4-8).
All current guidelines for the diagnosis and management of MPEs suggest that pleural ultrasound guidance significantly increases the likelihood of successful pleural fluid aspiration and reduces the risk of complications such as pneumothorax or organ puncture (11-13). In the diagnostic pathway for MPEs secondary to lung cancer, contrast enhanced chest CT scans are the golden standard (11-13). They can provide valuable information on the lung tumor size and stage and the pleural cavity per se; they can distinguish benign and malignant effusions, identify pleural thickening, evaluate major and minor fissures and highlight findings which are suggestive of malignancy such as pleural rind, mediastinal pleural involvement, pleural nodularity, and pleural thickening greater than 1 cm (14,15).
Magnetic resonance imaging (MRI) is costlier than chest CT or thoracic ultrasound, it is not available in all centers and it is compromised by poor spatial resolutions and motion artefacts which make it less satisfactory in the diagnostic work-up of MPEs (14). It is also contraindicated for patients with metallic grafts. Recent evidence suggests that diffusion-weighted magnetic resonance imaging (DWI) can evaluate pleural diseases morphologically and qualitatively, and can identify pleural malignancy (16). However, this is a single institution experience and is based on a limited number of patients, which introduced selection bias and there is discrepancy in the literature concerning optimal DWI techniques and image analysis procedures (17,18). As outlined above, CT imaging with pleural phase contrast is the gold standard to assess MPEs. However, if contrast is contra-indicated (e.g., severe renal failure), MRI can be used to identify chest wall invasion or septation within pleural fluid. In the absence of contrast, T2-weighted images will demonstrate pleural nodularity, as both fluid and extrapleural fat will present high signal in comparison with the low signal pleura (19).
PET CT imaging is commonly used for staging of lung cancer, however its value in predicting benign vs. MPE is limited due to high false positive rates in patients with inflammation/infection (11,20). In a diagnostic pathway for suspected MPE secondary to lung cancer, PET CT may be helpful in identifying certain anatomical areas of the pleura to biopsy (21).
Thoracentesis, cytology and pathology acquisition
A common clinical scenario is suspected MPE in an asymptomatic patient. One of the questions arising in a pragmatic clinical setting is whether a pleural aspiration or a pleural drainage should be the next step in the diagnostic pathway. In this case, ATS/STS/STR Guidelines (12) recommend that pleural drainage should not be performed in asymptomatic patients however this is conditional recommendation supported by low evidence (26-28). Pleural aspiration is the recommended approach preferably with ultrasound guidance (11-13) unless the patient is symptomatic (dyspnea) where a pleural drainage is required to relieve breathlessness. Draining asymptomatic effusions would only subject the patient to the risks of the procedure without significant clinical beneﬁt. Mean sensitivity of pleural fluid cytology is 60% and this depends on the cytologist’s experience, samples’ preparation and underlying malignancy (11,29). A second specimen can increase the diagnostic yield by 27%, but more samples (i.e., >2) do not seem to influence the result, instead they increase related diagnostic costs (29,30).
The evolution of targeted therapies for lung cancer has necessitated pleural tissue acquisition to be used in the diagnosis and genotyping. Blind biopsy of the pleura is not considered to be an option due to its low diagnostic yield and low sensitivity (33%) (31,32). Medical thoracoscopy is a reliable modality for pleural tissue acquisition (33,34); a meta-analysis of 17 individual trials studying this approach in 755 patients calculated an aggregate sensitivity of 91%, specificity of 100% and major complications rate of 1.5% (35). Rahman et al. (36) reported a mortality rate of 0.3% for medical thoracoscopy which is most likely linked with therapeutic interventions (talc pleurodesis) rather than the diagnostic process per se. Choosing between surgical and medical thoracoscopy for the diagnosis of a suspicious MPE has been a matter of debate. While surgical thoracoscopy is considered the gold standard, medical thoracoscopy is less invasive, cost-effective, it has a shorter hospital stay and it does not compromise the diagnostic yield. McDonald et al. (37) recently published a study comparing medical versus surgical thoracoscopy in the diagnosis of suspect MPE and Table 3 summarizes the comparison characteristics between the two.
Physician based ultrasound guided pleural biopsy is a safe alternative that can be used in patients that are not eligible for thoracoscopic approach (e.g., frail, with performance status >2, contraindications for general/conscious sedation/collapsed lung) and it presents a reliable diagnostic yield (94%) (38).
Abrams pleural biopsy has only 57% sensitivity for malignancy (11) therefore it is contraindicated as a procedure of choice in the diagnosis of suspected MPEs however it seems that its sensitivity is increased when the procedure is performed with ultrasound guidance and it can be comparable with the sensitivity of CT guided pleural biopsy. Sivakumar et al. (39) addressed the above and compared the diagnostic sensitivity and specificity of ultrasound guided Abrams pleural biopsy versus CT guided Tru-Cut pleural biopsy in the undiagnosed pleural effusions with a high suspicion of malignancy. Ultrasound guided Abrams biopsy presented comparable sensitivity with CT guided Tru-Cut biopsy (71.43% vs. 75% respectively) while specificity was 100% in both groups (39).
Routine diagnostic bronchoscopy should not be used routinely in the diagnosis of suspected MPEs and should only be considered when endobronchial lesion is suspected based on chest CT imaging (11).
Molecular markers in lung cancer related MPEs
Current guidelines do not support the routine use of molecular markers in the diagnosis guidance of targeted treatment of suspected lung cancer related MPEs due to the lack of solid supporting evidence (11-13). However, the detection of molecular markers in lung cancer related MPEs has been associated with prognosis and treatment response. Epidermal growth factor (EGFR) mutation status in cell blocks of lung adenocarcinoma MPEs confirmed by pathology is highly predictive of EGFR tyrosine kinase inhibitors (TKI) efficacy (40). Patients with EGFR mutation in their lung adenocarcinoma related MPE had a better progression free survival (7.33 months) than patients with wild-type EGFR (2.07 months, P=0.032) (40).
Anaplastic lymphoma kinase (ALK) rearrangement detection in lung adenocarcinoma related MPEs can be used as a complementary method for EML4 (echinoderm microtubule-associated protein-like 4)-ALK detection and can predict tumor responsiveness to crizotinib (41).
Dresler et al. (42) compared programmed death ligand 1 (PD-L1) expression in MPEs of lung adenocarcinoma with pleural biopsies and the positive expression in MPE was correlated with survival time after systemic anti-tumor treatment. Mean survival time with positive PD-L1 expression in MPE was shorter than that with the negative expression (17.370±1.827 vs. 29.944±2.671 months) (χ2=4.507, P=0.034).
Overall, the clinical implication of molecular markers is limited due to the inadequacy of the validation of the results by subsequent studies.
Therapeutic drainage and pleurodesis
Patients with large pleural effusion which is confirmed/suspected MPE secondary to lung cancer require therapeutic drainage (large volume thoracentesis) that will relieve the symptom of breathlessness and it will also provide information about the expansion of the underlying lung (12). Trapped lung (i.e., not expandable lung) occurs in 30% MPEs and it can be a contraindication for pleurodesis (11,42-44) and at this point clinicians should consider the option of indwelling pleural catheters (IPCs) that will be commented below (12,13). Patients with symptomatic MPE, expandable lung, and no prior deﬁnitive therapy, would benefit from chemical pleurodesis as ﬁrst-line deﬁnitive pleural intervention for management of breathlessness (12,13).
Pleurodesis is a parietal-to-visceral pleural fusion with concomitant obliteration of the pleural space. Complete drainage of the MPE allows parietal-to-visceral pleural apposition and at this point pleurodesis can be accomplished with chemical or mechanical means (30). A profound inflammatory response between the two pleural layers, follows the instillation of the chemical sclerosing agent and this progresses in fibrin accumulation and pleural fibrosis that prevents re-accumulation of fluid in the pleural space (30).
The choice of the sclerosing agent has been historically a matter of discussion in the literature. Various chemicals (talc, iodopovidone, bleomycin, tetracycline etc.) and bacterial products (derived from Streptococcus pyogenes, Staphylococcus aureus and others) have been mentioned in the literature and studies in clinical trials (30). Talc is an asbestos free trilayered magnesium silicate sheet which appears to have been used in pleurodesis since 1935 (45) and appears to be the most effective and least expensive sclerosing agent (46,47). In a Cochrane meta-analysis of 1,499 subjects, talc did not increase mortality post pleurodesis and was found to be the most efficacious agent (48). Dresler et al. reported the success rate of talc pleurodesis is approximately 75% at 1 month, but it is progressively reduced to approximately 50% at 6 months (42). The same study reported that talc poudrage is not superior to talc slurry with the exception of lung and breast cancer. However, there are no reliable data, regarding the optimal method for talc delivery, leading to variations in practice and recommendations (11-13). Bhatnagar et al. addressed this and performed a randomized controlled trial across 17 UK hospitals where they tested the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in inducing a successful pleurodesis (49,50). There was no difference in the rate of pleurodesis failure at 90 days in patients with MPE between thoracoscopic talc poudrage and talc slurry delivered via chest tube.
An IPC is a silicone tube giving long term access to the pleural cavity and it is tunneled subcutaneously. There is a one-way valve to the proximal end of the exposed tube which is used to connect to drainage bottles. Fluid drainage is patient driven and it is guided by patients’ symptoms offering a sense of intervention control to most patients. IPCs are suitable for patients with recurrent MPEs with both expandable and nonexpandable lungs, patients who failed pleurodesis in the past and have a short life expectancy. They are now considered an acceptable alternative option to pleurodesis in patients with expandable lung, no prior deﬁnitive therapy, and symptoms attributable to the effusion. They relieve breathlessness and improve quality of life while they give the opportunity of ambulatory management instead of prolonged hospital admissions (12,51). Symptomatic improvement occurs in 95.6% patients and 45.6% achieve spontaneous pleurodesis after a median of 52 days (52). The control of breathlessness and quality of life achieved is comparable to talc pleurodesis but with significantly shortened hospital stay (53,54) and importantly patients with IPC require fewer subsequent pleural interventions in comparison with the ones that underwent talc slurry pleurodesis via a chest drain (54). Improved quality of life in the community rather than in the hospital is of essence in this group of patients with limited survival. IPC use is safe with reported risk of death from pleural infection below 0.3% (55).
Clinical scores have been developed to improve our understanding of survival for patients with MPE and guide the selection of appropriate management strategies (56,57). LENT score (56) predicts survival in patients with MPEs and PROMISE score (57) combines biological and clinical parameters to accurately estimate 3-month mortality. Both are clinically relevant prognostic scores that can be applied immediately, and inform treatment decision making therefore avoiding invasive interventions and prolonged hospital stay in patients with limited survival that would prefer and benefit from spending their end of life in the community. Both scores can guide decision making process as to whether talc pleurodesis or IPC would be the intervention of choice tailored to patients’ needs.
It is an invasive surgical approach where part of the pleura is surgically removed. It can be safely performed and controls the symptoms of MPE secondary to malignant pleural mesothelioma (58). There is no indication for pleurectomy in MPEs secondary to confirmed lung cancer and as such it will not be further discussed in the current review.
MPE due to lung cancer is commonly encountered in pragmatic health care settings. Quality of life, symptom control and palliation are the paramount goal in its management. Diagnostic and therapeutic options and clinical prediction scores continue to expand with ongoing trials and clinical validation to further refine our management approaches. Formerly bed-ridden patients with MPE due to lung cancer are now treated in ambulatory care, have an improved quality of life in the community and spend less time in hospitals. Taking into account the amount of produced scientific evidence for MPEs, we need to re-evaluate our practice on a regular basis to ensure optimal outcomes are achieved.
Provenance and Peer Review: This article was commissioned by the Guest Editor (Dragan Subotic) for the series “Malignant Pleural Effusion” published in AME Medical Journal. The article was sent for external peer review organized by the Guest Editor and the editorial office.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2020.03.13). The series “Malignant Pleural Effusion” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Hardavella G, Karampinis I. Primary lung cancer and pleural effusion—diagnostic and therapeutic approach. AME Med J 2020;5:30.