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(Chest. 2001;119:1138-1142.)
© 2001 American College of Chest Physicians

Diagnostic Value of CYFRA 21–1 Tumor Marker and CEA in Pleural Effusion Due to Mesothelioma*

Michela Paganuzzi, PhD; Marina Onetto, MD; Paola Marroni, PhD; Rosa Filiberti, PhD; Elisabetta Tassara, MD; Stefano Parodi, PhD and Raffaella Felletti, MD

* From the Clinical Pathology Laboratory (Drs. Paganuzzi, Onetto, and Marroni), the Department of Environmental Epidemiology (Drs. Filiberti and Parodi), and the Thoracic Endoscopy Service (Dr. Tassara), National Institute for Cancer Research, Genoa, Italy; and the Department of Respiratory Disease (Dr. Felletti), A.O. San Martino Hospital, Genoa, Italy.

Correspondence to: Michela Paganuzzi, PhD, Clinical Pathology Laboratory, National Institute for Cancer Research, Largo R. Benzi 10, 16132 Genoa, Italy; e-mail: patclin{at}hp380.ist.unige.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: The aim of our study was to assess the clinical value of CYFRA 21–1 tumor marker and carcinoembryonic antigen (CEA) as diagnostic tools that are complementary to cytology in the diagnosis of malignant mesotheliomas.

Patients: We measured CEA and CYFRA 21–1 in the pleural effusions (PEs) and serum of 106 patients (benign lung disease, 34 patients; bronchogenic and metastatic carcinoma, 40 patients; mesothelioma, 32 patients).

Methods: CEA and CYFRA 21–1 levels were determined by means of two commercial enzyme immunoassays.

Results: The cutoff levels of CYFRA 21–1 and CEA in malignant PEs, selected on the basis of the best diagnostic efficacy, were 41.9 ng/mL and 5.0 ng/mL, respectively. In all neoplastic PEs, CYFRA 21–1 and CEA sensitivity was 78% and 30.6%, respectively, with a specificity of 80% and 91%, respectively. The sensitivity of CYFRA 21–1 and CEA in patients with mesothelioma was 87.5% and 3.1%, respectively. The results of the CYFRA 21–1 assay were positive in 17 of 19 cases of mesothelioma (89.5%) with a negative or uncertain cytology. The association of the tumor marker assay and the cytology allowed a correct diagnosis in 30 of 32 cases of mesothelioma (93.7%).

Conclusion: This study suggests that CYFRA 21–1 would provide a useful parameter for the differential diagnosis between benign and malignant PE from mesothelioma when the result of cytology is negative or uncertain and the clinical context does not allow a more aggressive approach. Moreover, the association of CYFRA 21–1 with CEA could provide details for a differential diagnosis between mesotheliomas and carcinomas. In fact, an elevated CYFRA 21–1 level with a low CEA level is highly suggestive of mesothelioma, whereas high levels of CEA alone or high levels of both the markers suggest a diagnosis of malignant PE, excluding mesothelioma.

Key Words: CEA • CYFRA 21–1 • mesothelioma • pleural effusion • tumor marker


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Malignant pleural effusion (PE) is a frequent occurrence in patients with cancer and may be either a sign of the disease or a complication of an already diagnosed malignancy.1

Virtually all primary malignancies have been reported to metastasize to the pleura. Some reports suggest that as many as 50% of patients with lung or breast cancer will develop PEs at some time during the course of their disease.2

The sine qua non condition for the diagnosis of malignant PE is the cytologic demonstration of malignant cells in pleural fluid; the absence of malignant cells, however, does not exclude malignancy. The difficulties arise in differentiating benign reactive mesothelial cells from malignant mesothelioma cells and metastatic carcinoma cells.3

Blind pleural biopsy, which is the alternative method in the case of negative cytology results, performs poorly and has a low sensitivity (from 35 to 65%).4 5 The recent introduction of videothoracoscopy has improved the efficacy of both the diagnosis and treatment of malignant PE.6 However, it is burdened with the risk for complications such as pneumothorax, pleural shock, hemothorax, and subcutaneous emphysema, as well as possible cancer implantation in 4% of patients.7 Furthermore, videothoracoscopy with multiple pleural biopsies is an aggressive and expensive method of investigation, and is not available everywhere.

The clinical value of serum tumor markers for diagnosis, follow-up, and treatment monitoring of lung cancer patients already has been demonstrated in many studies.8 9 The measurement of tumor markers in PE represents an effort to improve effectiveness of the differential diagnosis of neoplastic effusions.

Several authors10 11 12 13 have demonstrated the clinical usefulness of measuring different tumor markers in the diagnosis of malignant PE. Those reported series, however, included mostly cases of adenocarcinoma and only a few cases of mesothelioma. The incidence of this neoplasia is relatively low, but it is increasing in certain geographic areas mostly because of an intensive occupational exposure to asbestos.14 In our region, the incidence of malignant mesothelioma is high, and it is one of the highest values in Europe, with an age-standardized rate of 5.0 per 100,000 men and 0.9 per 100,000 women.15

In the present study, we aimed to assess the clinical value of CYFRA 21–1 tumor marker and carcinoembryonic antigen (CEA) as diagnostic tools that are complementary to cytologic findings in the diagnosis of malignant mesotheliomas. For this purpose, we measured the tumor markers in the serum and PE of patients with mesothelioma and compared them with those of patients with pleural metastatic carcinoma and benign pathologic conditions.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
We measured CEA and CYFRA 21–1 in the serum and PE of 106 consecutive patients admitted for diagnosis to the Department of Respiratory Disease of San Martino Hospital and to the Thoracic Endoscopy Service of the National Institute for Cancer Research of Genoa from 1995 to 1997. Informed consent was obtained from all the subjects.

Thirty-four patients had benign PE, and 72 patients had malignant PE. Of these latter patients, 32 malignant PEs were from mesothelioma (Table 1 ). All the PEs were examined through cytologic analysis. When the result of the cytologic examination was negative or in doubt, patients underwent blind pleural biopsies and/or thoracoscopic-guided biopsies. The PEs were considered to be positive according to the presence of malignant cells as determined by cytologic analysis and/or pleural biopsy. The diagnosis of benign disease was confirmed on the basis of instrumental investigations (CT scan), bacteriologic examination, response to therapy, and clinical follow-up.


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  		Table 1.. Description of Patients

 
Tumor Marker Assays
PEs and blood samples were centrifuged, and aliquots of supernatants and sera were stored at -80°C until tested. CYFRA 21–1 and CEA were measured using two commercially available immunoenzymatic kits. CYFRA 21–1 was measured with a semiautomated system (model ES 300; Boehringer Mannheim; Mannheim, Germany) using a two-step sandwich method with the streptavidin-biotin technique. The assay utilized two mouse monoclonal antibodies, KS 19–1 and BM 19–21, that were directed against two different epitopes of a soluble fragment of cytokeratin 19. CEA was measured using a kit (AXSYM CEA kit; Abbott Laboratories; Abbott Park, IL) that is based on the microparticle enzyme immunoassay technology. The assay of each marker was performed according to the protocol recommended by the manufacturer. Results were expressed in nanograms per milliliter.

Statistical Analysis
Differences in the median values between the groups under study were checked using the Kruskall-Wallis test, while the Mann-Whitney U test was used for comparison of the two groups. Spearman rank correlation coefficients for the tumor markers were calculated separately for the serum and the PE. The threshold for each marker was selected on the basis of the best diagnostic efficacy (ie, on the basis of the more equilibrated combination of sensitivity and specificity). In order to compare the performance of the tumor markers, receiver operating characteristic (ROC) curves were constructed.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The median concentration and range of CEA and CYFRA 21–1 in the serum and PE of patients with malignant and benign disease are reported in Table 2 . The PE CYFRA 21–1 concentration was significantly higher in patients with mesothelioma than in those with benign pleurisy (p < 0.001) and with carcinoma (p = 0.02). In serum, a significant difference was observed between patients with mesotheliomas and benign diseases (p < 0.0001), but not those with carcinomas. The CEA values both in the serum and in PE were significantly higher in patients with carcinomas than in those with mesotheliomas (p < 0.001). The distribution of CYFRA 21–1 and CEA in PEs is shown in Figure 1 .


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  		Table 2.. CYFRA 21-1 and CEA Levels in PE and Serum in Neoplastic and Benign Diseases*

 


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  		Figure 1.. Distribution of CEA and CYFRA 21–1 concentrations in PEs from carcinomas (•), mesotheliomas ({blacktriangleup}), and benign diseases ({circ}). The cutoff values (CEA, 5.0 ng/mL; CYFRA 21–1, 41.9 ng/mL) are denoted by horizontal and vertical lines, respectively.

 
The ROC curves analysis showed the performance of PE CYFRA 21–1 and CEA in mesotheliomas (Fig 2 ).



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  		Figure 2.. ROC curves of CEA and CYFRA 21–1 in the differential diagnosis between mesotheliomas and benign PEs.

 
We evaluated the diagnostic efficacies in serum and PE for CYFRA 21–1 and CEA in all malignancies at different cutoff levels. The sensitivity of the two markers was higher in PEs than in sera (not significant) at any cutoff level. The best diagnostic efficacy of CYFRA 21–1 in PEs (78%) was observed at the cutoff value of 41.9 ng/mL, which achieved a sensitivity of 78% and a specificity of 80%. The sensitivity in patients with carcinomas was 67.5%, and in those with mesotheliomas it was 87.5%. For CEA, we chose the diagnostic accuracy (49%) obtained with the conventional cutoff of 5.0 ng/mL. The sensitivity was 30.6% in all malignancies, 52.5% in carcinomas, and 3.1% in mesotheliomas, with a specificity of 91% (Table 3 ).


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  		Table 3.. Diagnostic Sensitivity of CEA and CYFRA 21-1 in PEs*

 
The performance of CEA and CYFRA 21–1 in PEs was compared with the cytologic analysis.

Forty of the 72 patients with neoplastic disease (55.6%) had negative results of cytologic analysis, 26 patients (36.1%) had positive results, and 6 patients (8.3%) had uncertain behavior. The positivity of CEA and CYFRA 21–1 in the 46 patients with negative or uncertain cytologic analysis results is reported in Table 4 .


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  		Table 4.. Cases Showing CEA and/or CYFRA 21-1 Values Higher Than the Cutoff Threshold in the 46 Malignant PEs With Negative or Uncertain Cytology Results*

 
Considering mesotheliomas alone, 13 patients (41%) had positive results of cytologic analysis, 16 patients (50%) had negative results, and 3 patients (9%) had uncertain behavior. Seventeen of 19 patients (89.5%) with negative or uncertain results of cytologic analysis showed positive CYFRA 21–1 concentrations.

The cytologic examination combined with the measurement of PE CEA and CYFRA 21–1 increased the detection rate of mesotheliomas to 93.7%.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The differential diagnosis between benign and malignant effusions represents a critical clinical problem. Cytologic analysis is the method usually adopted to identify malignant cells in a PE, but it seems not to be sensitive enough (40 to 60%).3 In the case of uncertainty, blind or thoracoscopic-guided biopsy should be used. This procedure is highly sensitive, but, unfortunately, it is also invasive and limited to specialized centers.

The results of previous studies have suggested that a pool of different markers in the PE can improve the diagnostic power of cytologic analysis in detecting malignant PEs.16 17 18 CEA was found to be a complementary tool to immunohistochemical studies for differentiating between PEs resulting from metastatic tumors and from malignant mesothelioma.13 19 The CYFRA 21–1 assay, which detects a soluble fragment of cytokeratin 19 that is expressed by all histologic types of lung cancer,20 was indicated as the most available tumor marker in PEs from epithelial carcinomas, especially squamous cell carcinomas.11 21

Overall, our findings agree with those of other authors. No correlation was found between CEA and CYFRA 21–1 values, thus confirming that the two molecules provide different information on tumor behavior. Both CEA and CYFRA 21–1 showed a higher sensitivity in PE than in serum, probably because in a limited district tumor markers have concentrations higher than those in the blood stream. Therefore, the diagnosis of malignant PEs could be better achieved by measuring tumor markers in pleural fluid than in serum. The sensitivity of CEA was 30.6% in all malignant effusions and 52.5% in carcinomatous effusions. These percentages of sensitivity were lower than those described in some previous studies,19 22 23 probably because of the prevalence in our series of patients with mesotheliomas over those with carcinomas. Only one of the mesothelioma patients (3.1%) showed CEA levels higher than the cutoff level.

The cytologic analysis in a mesothelioma PE can be challenging even for a trained pathologist. Reviewing the literature, we could find only a few studies on tumor markers in PEs from mesothelioma, which were based on very small groups of patients13 24

Because of a large number of mesothelioma cases in our series (32 patients), we were better able to define the diagnostic significance of CYFRA 21–1 and CEA in such a difficult diagnosis.

CYFRA 21–1 sensitivity was significantly higher in patients with mesotheliomas than in those with carcinomas. In agreement with our results, other authors24 25 have reported that mesothelioma cells expressed very high levels of cytokeratin 19 and that high levels of tissue polypeptide antigen (cytokeratins 8, 18, and 19) were present in the pleural fluid of patients with mesotheliomas. Salama et al,24 in a series of nine mesothelioma patients, attributed a great clinical value to CYFRA 21–1 in the diagnosis of the disease. As reported by this author and others,26 27 we found that high CYFRA 21–1 levels and low CEA levels are associated with mesothelioma. Because some lung carcinomas showed a similar behavior, the diagnosis of mesothelioma on the basis of this profile should be made with extreme caution. However, in our study, all the mesothelioma patients, except one, showed very low levels of CEA in all PEs. Consequently, we infer that high CYFRA 21–1 levels with low CEA levels are suggestive of mesothelioma, whereas high levels of CEA alone or high levels of both markers can show evidence of malignant PEs, excluding mesothelioma.

As reported in the literature,24 our findings indicated that CEA and CYFRA 21–1 are complementary tools to cytologic analysis in the clinical assessment of malignant PEs, in particular those resulting from mesothelioma. In our study, the cytologic diagnostic sensitivity in mesothelioma PEs was 40.6%. In 19 mesotheliomas with a false-negative or uncertain cytology, the CYFRA 21–1 diagnostic sensitivity was 89%, while no cases showed CEA values higher than the cutoff level. The association of cytology with the measurement of PE CEA and CYFRA 21–1 levels allowed a correct diagnosis of 30 of 32 mesotheliomas (93.7%).

In conclusion, when the cytologic analysis does not allow a final PE diagnosis, increased CYFRA 21–1 and/or CEA concentrations may represent, for the clinician, a useful decisional criterion before embarking on a more aggressive approach to treatment.

When patients are in good performance status, pleural biopsy and/or thoracoscopy are necessary in order to stage the cancer and plan a correct therapeutic approach. In patients with poor clinical conditions, because of age or low performance status, diagnosis should be made on the basis of tumor markers alone, avoiding more aggressive diagnostic techniques.


   Footnotes
 
Abbreviations: CEA = carcinoembryonic antigen; PE = pleural effusion; ROC = receiver operating characteristic

Received for publication February 10, 2000. Accepted for publication October 17, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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