Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma

Abstract

Rationale: The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain.

Objectives: To determine the clinical value of measuring mesothelin levels in pleural effusion supernatant to aid diagnosis of MM.

Methods and measurements: Pleural effusion samples were collected prospectively from 1331 consecutive patients. Mesothelin levels were determined by commercial ELISA in effusions and their relationship to concurrent pathology reporting and final clinical diagnosis was determined.

Results: 2156 pleural effusion samples from 1331 individuals were analysed. The final clinical diagnosis was 183 MM, 436 non-MM malignancy, and 712 nonmalignant effusions. Effusion mesothelin had a sensitivity of 67% for MM at 95% specificity. Mesothelin was elevated in over 47% of MM cases in effusions obtained before definitive diagnosis of MM was established. In the setting of inconclusive effusion cytology, effusion mesothelin had a positive predictive value of 79% for MM and 94% for malignancy.

Conclusions: A mesothelin-positive pleural effusion, irrespective of the identification of malignant cells, indicates the likely presence of malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis.

Figure 1

Soluble mesothelin concentrations in pleural effusion (PE) supernatants. Results presented for the single, most recent sample per individual against final clinical diagnosis (n = 1331). Dashed horizontal line indicates upper limit of normal threshold for effusion mesothelin (i.e., 20 nM).

Figure 2

Receiver operating characteristic (ROC) curve showing accuracy of effusion mesothelin concentrations in the most recent sample per individual in differentiating all patients with MM (n = 183) from all other cases (n = 1148).

Figure 3

Pleural effusion soluble mesothelin concentrations: results for single, most recent sample per individual (n = 1331) plotted against the diagnosis reported by cytopathology for that sample.

Figure 4

Flow diagram of the study. Number of cases for each category as defined by key (to the left of figure).

Figure 5

Soluble mesothelin concentrations in pleural effusion supernatants of patients with (a) a final clinical diagnosis of non-MM malignancy (n = 124) and (b) MM (n = 43), relative to the time of diagnosis. (×) Effusion samples with cytopathology report of normal or nondiagnostic; (⚪) effusion samples reported as being associated with inflammation or containing immune infiltrating cells.

Figure 6

Soluble mesothelin concentrations in pleural effusion supernatants reported by cytopathology as being atypical (⋄) or suspicious of malignancy (◆) in patients with a final clinical diagnosis of (a) non-MM malignancy (n = 23) and (b) MM (n = 34), relative to the time of clinical diagnosis.

Figure 7

Pleural effusion soluble mesothelin concentrations in samples received from patients diagnosed with MM. (a) Mesothelin concentrations plotted relative to the time of diagnosis for MM patients with tumors of different histologies (×) sarcomatoid; (▲) biphasic; and (⚪) epithelial or nonspecified histology. Multiple samples per patient shown (n = 271). (b) Mesothelin concentrations plotted relative to the cytopathology report for each specimen. Multiple samples per patient shown (n = 271). (c) Mesothelin levels in effusions from 77 individuals with a biopsy confirmation of MM diagnosis. The pathology report for samples was (×) normal or nondiagnostic; (⚪) associated with inflammation or containing immune infiltrating cells; (⋄) atypical or suspicious of malignancy or (◆) MM.

Figure 8

Suggested diagnostic flowchart. Suggested clinical role of effusion mesothelin estimation in patients with pleural effusions in whom malignancy, particularly mesothelioma, forms part of the differential diagnosis.