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Clinical Chemistry 48: 1931-1937, 2002;
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(Clinical Chemistry. 2002;48:1931-1937.)
© 2002 American Association for Clinical Chemistry, Inc.

Carcinoembryonic Antigen, Squamous Cell Carcinoma Antigen, CYFRA 21-1, and Neuron-specific Enolase in Squamous Cell Lung Cancer Patients

Jan Kulpa1a, Ewa Wójcik1, Marian Reinfuss2 and Leszek Kolodziejski3

Departments of
1 Clinical Biochemistry,
2 Radiotherapy, and
3 Surgery, Center of Oncology, Cracow Division, 31-115 Cracow, Poland.

aAddress correspondence to this author at: Department of Clinical Biochemistry, Center of Oncology, Cracow Division, ul. Garncarska 11, 31-115 Cracow, Poland. Fax 48-012-422-8760; e-mail z5jkulpa{at}cyf-kr.edu.pl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), and CYFRA 21-1 are the most useful markers for non-small cell lung cancer (NSCLC), but neuron-specific enolase (NSE) is a tumor maker of choice for SCLC. The determination of NSE in NSCLC could allow selection of patients with neuroendocrine features. NSCLC patients whose tumors have neuroendocrine properties may be more responsive to chemotherapy; however, these tumors have been reported to be more aggressive. Tumor markers are not suitable for diagnosis; their principal applications are in monitoring of therapy and prognosis.

Methods: Tumor markers were measured in 200 untreated patients with squamous cell lung cancer (SQC) and a reference group (n = 220; 124 healthy persons and 96 patients with nonmalignant lung disease). CEA and SCC-Ag were measured by microparticle enzyme immunoassays on Abbott AxSYM and IMx analyzers. CYFRA 21-1 and NSE were measured by electrochemiluminescence immunoassays on the Roche Elecsys 2010.

Results: CEA, SCC-Ag, CYFRA 21-1, and NSE were increased above the cutoffs in 26%, 32%, 67%, and 28% of tested patients, respectively. The area under the ROC curve for CYFRA 21-1 was higher than those for CEA, SCC-Ag, and NSE (SQC vs controls). CYFRA 21-1 and CEA were significantly higher in advanced SQC than in early stages of disease (P <0.0001 and P <0.0004, respectively). In multivariate analysis of survival, CYFRA 21-1 was an independent but nonspecific prognostic factor in the operable group of SQC patients, whereas NSE was an independent prognostic factor in the advanced stages of disease.

Conclusion: CYFRA 21-1 is an independent prognostic factor in earlier stages and NSE in the advanced stages of SQC.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lung cancer presents one of the most serious problems of modern oncology. Despite the continual improvement and development of diagnostic methods, in 50–70% of lung cancer patients the disease is still diagnosed in advanced stages, excluding the possibility of radical therapy. Nearly one-half of non-small cell lung cancer (NSCLC)1 patients who undergo surgery relapse, with local growths and distant metastases developing a short time after treatment, and in patients with advanced disease, the reaction to radio- and/or chemotherapy differs considerably (1). These facts have stimulated the search for new diagnostic methods and clinical verification of the usefulness of different indicators. The results of such investigations could be helpful in recognizing disease, follow-up, and treatment; they may also provide additional information for a patient’s prognosis. One of the fields of particular interest in this respect includes tumor markers.

The usefulness of many tumor markers has been analyzed, but it seems that only some markers may gain a permanent position in the biochemical diagnosis of lung cancer. No marker has yet been found that would characterize specificity in relation to lung cancer or pulmonary tissues. NSCLC, as opposed to SCLC, is heterogeneous with respect to histology and, therefore, to biological properties (2), which is the reason that these investigations have concentrated, to some extent, on searching for markers with relatively high diagnostic sensitivity for a definite histologic type. Carcinoembryonic antigen (CEA) has been recognized as a marker for lung adenocarcinoma, whereas squamous cell carcinoma antigen (SCC-Ag) is considered a marker for squamous cell lung cancer (SQC). However, the diagnostic sensitivity of both markers is not satisfactory (3)(4). Important progress in biochemical diagnostics for NSCLC, especially for SQC, was made with the introduction of determinations for the serum-soluble fragments of cytokeratin 19, i.e., CYFRA 21-1 (5)(6)(7)(8). Nevertheless, opinions about the diagnostic utility of these markers vary. These differences in opinion concern the fact that diagnostic sensitivity and specificity are influenced by the structure of the analyzed group of patients as well as the composition of the reference group (9).

The aim of the present study was to determine the diagnostic sensitivity and specificity of the assays for the tumor markers CEA, SCC-Ag, CYFRA 21-1, and neuron-specific enolase (NSE) and the potential usefulness of their results in estimating prognosis for patients with SQC.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tumor marker concentrations were measured before treatment in 200 SQC patients with different clinical stages of the disease (25 with stage I, 26 with stage II, 34 with stage IIIA, 98 with stage IIIB, and 17 with stage IV) and in the reference group, which consisted of 124 healthy persons and 96 patients with benign lung diseases (sarcoidosis, tuberculosis, fibrosis, asthma, hamartoma, noncancerous tumors, or pneumonia; BLD group). The age and sex distributions and smoking status in both groups were comparable. The clinical diagnosis of SQC was confirmed each time by microscopic examination of the material obtained during bronchoscopy, biopsy, and/or surgery.

Blood specimens were obtained by a standard procedure between 0800 and 0900 in the morning. Serum was separated 30 min after collection, divided into four aliquots, and stored at -25 °C until assays. CEA and SCC-Ag concentrations were determined by microparticle enzyme immunoassays using Abbott reagent sets and AxSYM and IMx systems. CYFRA 21-1 and NSE were measured by electrochemiluminescent assays using Roche Diagnostics reagent sets and the ELECSYS 2010 analyzer.

The differences between groups were evaluated by Kruskal–Wallis one-way ANOVA. The correlation was determined by the Spearman method. ROC curves were used to assess the diagnostic sensitivity and specificity of the marker results, and differences between areas under curves (AUCs) were estimated by the Wilcoxon test. The prognostic value of tumor markers was examined by the Kaplan–Meier method and with the log-rank test; the choice of independent prognostic factors was performed in multivariate analysis with the Cox hazard model.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We observed significant differences for all tumor markers between SQC patients in particular stages compared with healthy persons as well as the BLD group (Table 1 ). The frequency of increased results was the highest for CYFRA 21-1, whereas the combination of this marker with CEA or SCC-Ag only slightly increased the percentage of pathologic results (Fig. 1 ). CYFRA 21-1 and CEA concentrations depended on disease stage (Figs. 2 and 3 ). SCC-Ag showed a tendency to increase in more advanced stages, but the differences were not significant. No significant differences were found for NSE. Only CYFRA 21-1 and CEA showed significant differences between operable and inoperable patients (Table 2 ).


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  		Table 1. Concentrations of CEA, SCC-Ag, CYFRA 21-1, and NSE in healthy persons, patients with benign lung diseases, and patients with SQC according to clinical stage.



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  		Figure 1. Diagnostic sensitivity of NSE, CEA, SCC-Ag, CYFRA 21-1, and the combination of CYFRA 21-1 and/or CEA and CYFRA 21-1 and/or SCC-Ag in SQC.



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  		Figure 2. CEA in healthy persons, patients with benign lung disease, and patients with SQC according to clinical stage.

The correlation coefficient (rS) for the relationship between CEA concentration and clinical stage was 0.289 (P <0.001). The percentages of increased results for patients with particular stages (st.) of SQC compared with the subgroups of the overall reference group [healthy persons and patients with benign lung disease (BLD)] were as follows (vs both reference subgroups): stage I, 11.5%; stage II, 20.0%; stage IIIA, 11.8%; stage IIIB, 33.7%; stage IV, 52.9%.



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  		Figure 3. CYFRA 21-1 concentrations in healthy persons, patients with benign lung disease, and patients with SQC according to clinical stage.

The correlation coefficient (rS) for the relationship between CYFRA 21-1 concentration and clinical stage was 0.374 (P <0.00001). The percentages of increased results for patients with particular stages of SQC compared with the subgroups of the reference group [healthy persons and patients with benign lung disease (BLD), respectively] were as follows: stage I, 61.4% and 30.8%; stage II, 80.0% and 52.0%; stage IIIA, 76.5% and 58.8%; stage IIIB, 85.7% and 68.4%; stage IV, 88.2% and 88.2%.


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  		Table 2. Concentrations of tumor markers in patients with operable (stages I + II + IIIA) and inoperable (stages IIIB + IV) SQC.

To assess the diagnostic utility of tumor markers in SQC, the cutoff values chosen were the 95% percentiles of, separately, healthy persons and patients with benign lung diseases (Table 3 ). With either reference group, the diagnostic sensitivity of CYFRA 21-1 was higher than that of the remaining markers. AUCs were higher for CYFRA 21-1 [0.87; confidence interval (CI), 0.83–0.90 for SQC vs benign lung disease] than for CEA (0.74; CI, 0.67–0.80), SCC-Ag (0.72; CI, 0.65–0.78), and NSE (0.68; CI, 0.62–0.74), which did not differ significantly from each other (Fig. 4 ). The AUCs were higher when the comparison group also included the healthy persons (Fig. 5 ).


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  		Table 3. Sensitivity, specificity, and positive and negative predictive values of tumor markers in SQC patients depending on control subgroup.



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  		Figure 4. ROC curves for the tumor marker assays for SQC patients (n = 200) in relation to patients with benign lung disease (n = 96).

AUC values are the mean ± SE. N.S., not significant.



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  		Figure 5. ROC curves for the tumor marker assays for SQC patients (n = 200) in relation to the reference group (both healthy persons and patients with benign lung disease; n = 220).

AUC values are the mean ± SE. N.S., not significant.

There was a tendency toward higher pretreatment concentrations for all tumor markers in the group of patients who died before 1 year compared with the group with longer survival. Significant differences were demonstrated only for CYFRA 21-1. Concentrations of this marker were increased in 75% of patients who died before 1 year after diagnosis and in 56% who survived >1 year (P <0.008).

To find the cutpoints that best indicated probability of survival, we checked many values and chose the one that produced the lowest P value in the log-rank test. Univariate analysis showed that all of the studied tumor markers and disease stages were statistically significant prognostic factors in SQC patients (Table 4 and Fig. 6 ). All these variables were included in a multivariate analysis in which Cox models were used. Disease stage and NSE remained significant determinants of survival in SQC (Table 4 ). When multivariate analysis was performed on groups selected on the basis of disease stage, CYFRA 21-1 was an independent prognostic factor in operable patients, whereas NSE was an independent prognostic factor in inoperable patients (Table 5 ).


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  		Table 4. Results of univariate survival analysis and multivariate Cox regression analysis.



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  		Figure 6. Probability of survival of SQC patients according to clinical stage (st.) of disease (A), pretreatment CYFRA 21-1 concentration (B), and pretreatment NSE concentration (C).


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  		Table 5. Multivariate Cox regression analysis according to clinical disease stages.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
CEA was one of the first markers measured in patients with NSCLC. The AUCs for CEA in the literature range from 0.69 to 0.79 (10)(11)(12)(13). In our study, for SQC patients, the AUC was 0.75, but CEA is known as a marker of choice for lung adenocarcinoma. Moreover, it should be pointed out that increased CEA concentrations are an indication of the presence of distant metastases. In the examined group of SQC patients with stage IIIB disease, CEA concentrations were >5.0 µg/L in 26.5% of patients and >50 µg/L in only 4% of patients, whereas in patients with stage IV disease, concentrations were >5.0 µg/L in 53% and >50 µg/L in 41%.

There are no unanimous opinions with respect to the prognostic value of CEA in NSCLC patients. According to Ochnio et al. (3) and Nisman et al. (10), pretreatment CEA concentrations have a prognostic value, but the studies by Shinkai et al. (14) and Buccheri et al. (15) do not confirm these data. Our results showed a worse prognosis for patients in whom the pretreatment CEA concentration was >6.0 µg/L.

In the present study, in SQC patients, the diagnostic sensitivity of SCC-Ag at 0.95 specificity was 0.32 and close to the values given by van der Gast et al. (7). We found no correlation between increased SCC-Ag results and extent of disease. Comparable observations have also been presented by others (7)(16). Ebert et al. (17) reported that the SCC-Ag concentration depends on tumor size, but there were no such dependencies between the concentration of this marker and nodal status. Contradictory results have been published concerning the prognostic effect of pretreatment SCC-Ag concentrations in patients with NSCLC, in particular in SQC patients. Whereas Moro et al. (13) concluded that SCC-Ag had no prognostic value, Sanchez de Cos et al. (18) found it to be a predictor of survival. In our study, SCC-Ag concentrations had prognostic value for survival of the SQC patients. De Bruijn et al. (19) suggested that determinant factor of the prognostic value of the SCC antigen may result from biochemical properties of this antigen as an inhibitor of proteases. Serine and cysteine proteases and their inhibitors are thought to be involved in the degradation of components of the extracellular matrix and play an important role in the process of tumor invasion and metastases.

Recently, in the biochemical diagnosis of patients with neoplasm, great attention has focused on cytokeratins 8, 18, and 19, proteins of intermediate filaments of the cells cytoskeleton (20). The CYFRA 21-1 assay is a test that has been developed for detection of cytokeratin 19 fragment in serum, especially in patients with NSCLC (5)(10)(21). According to Sugama et al. (22), increased serum CYFRA 21-1 is the result not only of cytokeratin release as a consequence of cell lysis or necrosis, but also of the degradation of cytokeratin filaments by activated protease in tumor cells.

In our study the AUC for CYFRA 21-1 (0.907) was significantly larger than the AUCs for all other analyzed tumor markers. It was comparable to the values reported by Nisman et al. (10) and Rastel et al. (5), but higher than the AUC reported by Pujol et al. (21). In the present study, the concentration of CYFRA 21-1 as well as the frequency of increased results showed a tendency to increase with the extent of disease. In concordance with other studies, we found that CYFRA 21-1 may discriminate between patients with operable (stages I–IIIA) and inoperable (stage IIIB-IV) SQC (9)(10). Although the literature contains much information about the influence of pretreatment serum concentrations of CYFRA 21-1 on the survival of patients with NSCLC, the data for SQC patients are limited. Our study showed that patients with serum CYFRA 21-1 concentrations >3.6 µg/L had a significantly shorter survival than those with lower serum concentrations of this marker. The results presented here for CYFRA 21-1 were similar to those reported by Niklinski et al. (23).

NSE is the tumor marker of first choice for SCLC, but increased serum NSE has been reported in 11.7–28% of patients with NSCLC (24). NSE expression is an unfavorable symptom because SQCs with neuroendocrine differentiation are more aggressive than others. At the same time, those patients may have a better response to chemotherapy (25). According to some authors, neuroendocrine properties may be expressed in various histologic types of lung cancer because both NSCLC and SCLC derive from a common cell lineage and their differentiation occurs at a later stage of oncogenetic development (26).

In the present study, the AUC for NSE was 0.74, which is lower than the AUC reported by Wieskopf et al. (8) for NSCLC patients. This may be explained by different histologic types and various proportions of patients with early and advanced disease stages. In the present study, the diagnostic sensitivity of NSE was 0.275 at 0.95 specificity, and the concentration of this tumor marker did not show dependence on disease stage. Similar to the findings of van Zandwijk et al. (27), high pretreatment concentrations of NSE were associated with shorter survival.

Several observations in our study, including the lack of a relationship between the frequency of increased NSE and extent of disease and the doubled frequency of deaths before 1 year during follow-up of patients with increased NSE, indicate that of this marker may be useful in the estimation of prognosis. This suggestion was confirmed by the results of multivariate analysis including all analyzed determinants. We found that, apart from disease stage, NSE was an independent, but nonspecific, prognostic factor in SQC. Moreover, NSE was an independent prognostic factor in the patients with stages IIIB–IV, which may be treated with chemotherapy, whereas CYFRA 21-1 was a prognostic factor at early stages, when surgery may be used to treat patients.

Metaanalysis has indicated that "classic" biochemical and hematologic factors (e.g., albumin, lactate dehydrogenase, leukocytes, and hemoglobin) may be helpful in the assessment of a SQC patient’s prognosis (28). The utility of tumor markers for this same purpose has been the subject of numerous discussions. Currently, a prevailing opinion is that the pretreatment concentrations of these markers may offer some additional information in evaluating patient prognosis. The results of the present study seem to confirm this suggestion.

In conclusion, pretreatment serum concentrations of CYFRA 21-1 and NSE appear to offer additional information to that presented by classic prognostic factors regarding SQC.


   Footnotes
 
1 Nonstandard abbreviations: NSCLC, non-small cell lung cancer; CEA, carcinoembryonic antigen; SCC-Ag, squamous cell carcinoma antigen; SQC, squamous cell lung cancer; NSE, neuron-specific enolase; AUC, area under the ROC curve; and CI, confidence interval.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Neuron-specific enolase in non-small cell lung cancer
Joseph C. Watine
Clinical Chemistry Online, 10 Dec 2002 [Full text]
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