The easiest way of diagnosing malignant pleural effusion (MPE) is to demonstrate the presence of tumor cells in the cytological examination of pleural fluid (PF).1 Unfortunately, pleural cytology has a maximum yield of around 60%, and figures are much lower in some tumor types, such as squamous cell lung cancer or mesothelioma (25%–30%).2 For this reason, extensive research has been conducted into obtaining a diagnosis of malignancy in patients with false negative results on pleural cytology, without the need to resort to invasive procedures such as biopsy by thoracoscopy. In this respect, measuring the concentrations of certain conventional tumor markers in pleural fluid is an attractive option, as this specimen is easy to obtain in clinical practice. However, there is no consensus on the most useful tumor markers and the most appropriate cutoff points to use.

Carcinoembryonic antigen (CEA) has been by far the most widely studied marker in PF, followed by others such as CYFRA 21-1 and carbohydrate antigen 15-3 (CA 15-3). Although evidence has shown that these markers can offer valuable information in some situations, neither the British3 nor the Spanish1 guidelines recommend their routine use in PF.

This study reports the largest single-center series published to date on the potential utility of determining CEA and CA 15-3 in PF for identifying malignancy in the context of non-purulent exudate. This validates our previous experience4 and shows the added value of determining these tumor markers in addition to pleural cytology.

A retrospective review was conducted of all consecutive patients with pleural effusion referred by their treating physician to the Pleural Medicine Department of our hospital between August 2003 and August 2016 to undergo diagnostic thoracentesis with determination of CEA or CA 15-3 in the PF. The study was approved by the local ethics committee (CEIC-1713).

This study shows that the determination of CEA and CA 15-3 in PF can identify the tumor origin of over one third of MPE with negative cytology studies. These markers are more useful in the case of gastrointestinal, ovarian or lung adenocarcinomas that metastasize to the pleura, and negligible in the case of lymphomas and mesotheliomas.

CEA has been the most widely studied tumor marker in PF. Three metaanalyses have been published on the potential utility of these biomarkers in diagnostics, comprising 15, 45, and 49 studies each.7–9 The results, along with those from another 3 metaanalyses on the use of pleural CA 15-3,9–11 are summarized in Table 5. Recently, a Chinese study of 601 patients with MPE and 538 with BPE found pleural CEA to have 69% sensitivity and 82% specificity, with an AUC of 0.740.12

Taken together, the pooled sensitivities of these markers are very similar to those of PF cytology, but unlike the latter, they achieve absolute specificities with the (various) cutoff points proposed. This creates a margin of uncertainty in the interpretation of the CEA and CA 15-3 values that reduces their clinical applicability. Moreover, in previous studies, the BPE group has always included a considerable percentage of cardiac transudates and empyemas, effusions which, in practice, do not confound the differential diagnosis with MPE. These 2 limitations, the selection of tumor marker cutoffs that do not have absolute specificity and the inclusion of effusions with etiologies easily identifiable from a clinical point of view, have been resolved in this study. Nevertheless, the selection of 100% specific cutoffs reduces the sensitivity of any test; in this case, the percentage of patients with MPE who exceeded the established threshold for each individual tumor marker was around 40%. However, the combined use of either one or other of the 2 tumor markers raised sensitivity for detecting MPE up to 60%.

Finally, very few studies have provided data on the value of CEA and CA 15-3 in PMPE or MPE with negative cytology results.4,13,14 Indeed, this is the subset of patients in which measuring tumor markers in PE is of practical interest, since in patients with positive pleural cytologies, the diagnosis of malignancy is definitively established. In this respect, the behavior of the tumor markers was similar in MPE with negative pleural cytology and in PMPE: a combination of either CEA or CA 15-3 in PF led to 41% and 35% of these cases being classified as malignant, respectively.

The strengths of this study do not conceal its limitations. This was a retrospective evaluation performed in a single center, and the results must be validated in independent populations in other centers. Nevertheless, we have been able to confirm the data that we obtained from a previous study conducted previously,4 and this, in a way, can be seen as a validation. Another potential limitation is the possibility that a “paramalignant” effusion (i.e., effusion not directly related with the tumor invading the pleura of a cancer patient) might have been erroneously included in the PMPE group. Although the clinical definition of PMPE was strict in order to avoid this occurrence, this patient group did not undergo a confirmatory pleuroscopy. In any case, similarities in the behavior of PF tumor markers in the MPE group with negative cytology and the PMPE group suggests that the classification of the latter was largely correct.

In conclusion, the determination of CEA and CA 15-3 in PF using 100% specific cutoffs contributes valuable clinical information by increasing our ability to identify MPE, notwithstanding the need for cytohistological confirmation in patients who may be candidates for receiving active oncological treatment.

Study conception and design: J.M. Porcel. Data collection and analysis: C. Civit, A. Esquerda, A. Salud, S. Bielsa. Data interpretation: J.M. Porcel, S. Bielsa. Manuscript draft: J.M. Porcel. Critical review and approval of the final version of the manuscript: J.M. Porcel, C. Civit, A. Esquerda, A. Salud, S. Bielsa.

The authors state that they have no conflict of interests.