|Year : 2018 | Volume
| Issue : 9 | Page : 400-404
Diagnostic value of CYFRA 21-1 and carcinoembryonic antigen in diagnosis of operable lung cancer from benign lung disease
Feng Chen1, Jia Li1, Xin Qi2, Jun Qi1
1 Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R, China
2 Department of Clinical Laboratory, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin, P.R. China
|Date of Web Publication||29-Jun-2018|
Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021
Source of Support: None, Conflict of Interest: None
Background: Lung cancer is sometimes difficult to differentiate from benign lung diseases with nodular shadow in imaging scan. In these cases, exploratory operation is needed for the patients with highly suspected malignant disease. Therefore, there is an urgent demand to differentiate the benign lung disease from malignant lung nodules rather than invasive method.
Aim: We evaluated the diagnostic value of two tumor markers in distinguishing operable lung cancer from benign lung disease.
Materials and Methods: The serum levels of carcinoembryonic antigen (CEA) and CYFRA 21-1 were retrospectively analyzed in 236 lung cancer patients and 44 patients with benign lung disease. These benign lung diseases were presented with evidence of a high likelihood of having lung cancer. After surgical operation, diagnosis of lung cancer and benign lung disease were confirmed by histological examination.
Results: We found that the average level of tumor marker in operable lung cancer patients was higher than those in patients with benign lung disease. CYFRA 21-1 sensitivity and specificity for lung cancer diagnosis was 37.3% and 90.9%, respectively, while that for CEA was 22.0% and 90.9%. The combined value for the sensitivity and specificity of these two tumor markers was 47.5% and 81.8%, respectively.
Conclusion: Our results indicate that the combination of these two tumor markers resulted in higher sensitivity compared to use CYFRA 21-1 or CEA along. Given its lower sensitivity and higher specificity, positive CYFRA 21-1 or positive CEA strongly supports lung cancer in patients with nodular shadow in imaging scan.
Keywords: Antigen CYFRA21.1, carcinoembryonic antigen, lung disease, lung neoplasms
|How to cite this article:|
Chen F, Li J, Qi X, Qi J. Diagnostic value of CYFRA 21-1 and carcinoembryonic antigen in diagnosis of operable lung cancer from benign lung disease. J Can Res Ther 2018;14, Suppl S2:400-4
|How to cite this URL:|
Chen F, Li J, Qi X, Qi J. Diagnostic value of CYFRA 21-1 and carcinoembryonic antigen in diagnosis of operable lung cancer from benign lung disease. J Can Res Ther [serial online] 2018 [cited 2019 Nov 11];14:400-4. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/400/174180
| > Introduction|| |
Lung cancer is a major cause of cancer-related mortality. Despite the ongoing improvement and development of diagnostic methods, the accurate diagnosis of lung cancer from benign lung disease is an important challenge. Currently, computed tomography (CT) has been proposed as an early detection tool., However, despite its high sensitivity, the specificity of CT in lung cancer diagnosis is poor.
Tumor markers are molecules occurring in blood or tissue that are produced by a tumor associated with a cancer or by the host in response to the cancer. Measurement or identification of tumor markers is useful for clinical diagnosis or patient management. Carcinoembryonic antigen (CEA), the first oncofetal antigens, consists of a large family of cell surface glycoprotein (molecular weight: 150–300 kDa). It is associated with plasma membrane of tumor cells, from which it may be released into the blood. Although CEA was first identified in colon cancer, the clinical usefulness of serum CEA in lung cancer has also been vigorously explored recently.,, The cytokeratin 19 fragmentation antigen, CYFRA 21-1, is a polypeptide that recognizes soluble cytokeratin 19 fragments and is a well-established biomarker for lung cancer. Cytokeratin 19 is an acidic type I cytokeratin that is found in both healthy epithelia and malignant cells, including lung cancer, and is reported to be useful in the diagnosis of lung malignant disease.,,
Because of their low sensitivity, tumor markers have not been generally recommended as a tool for the early detection of lung cancer in average-risk populations, while tumor markers may be used to diagnose operable lung cancer from benign lung disease such as those diseases with nodular shadow in imaging scan. In this study, we retrospectively investigated the serum levels of CYFRA 21-1 and CEA in operable lung cancer patients as well as in patients with various benign lung diseases. These benign lung diseases were presented with evidence of a high likelihood of having lung cancer and underwent surgical operation. After surgical operation, diagnosis of lung cancer and benign lung disease was confirmed by histological examination. Based on this, sensitivity and specificity for lung cancer diagnosis were calculated for CYFRA 21-1 and CEA with a cutoff level set at the standard cutoff level. For increasing the sensitivity, we also investigated the diagnostic value in combination with these two markers.
| > Materials and Methods|| |
In this retrospective study, the clinical records of 236 newly diagnosed and previously untreated primary lung cancer patients and 44 benign lung diseases patients were enrolled in this study. All patients underwent segmentectomy, lobectomy, or wedge resection to determine the state of suspected lung cancer. Diagnosis of lung cancer was confirmed by histological examination of tumor tissue. Benign diseases were also diagnosed based on histological examination and each diagnostic criterion. The lung cancer diagnosis was established in accordance with the revised World Health Organization classification of lung tumors and was staged in accordance with the revised staging for lung cancer., Clinical, laboratory, pathological, and follow-up data for these patients were acquired from electronic oncology registries.
This study was approved by the Medical Ethics Committee and written informed consent was provided by all patients.
Blood samples were collected upon initial (pretreatment) diagnosis, prior to surgical treatment. Whole blood was collected by taking a 3 ml venous blood sample into a blood collection tube. Serum CYFRA 21-1 and CEA levels were determined with a CYFRA21-1 and CEA test kit (Roche Diagnostics Corp, China) using a cobas e601 analyzer. The standard cutoff values were set at 3.3 ng/mL for CYFRA 21-1 and 5.0 ng/mL for CEA, for 95% specificity, as recommended by the manufacturers of the assay kits. The cutoff values were set based on the data obtained from healthy adults.
Study analysis included information regarding tumor marker levels as a continuous and dichotomous variable (≤3.3 ng/mL or >3.3 ng/mL for CYFRA 21-1, ≤5.0 ng/mL or >5.0 ng/mL for CEA). t-test was used to compare the mean level of CFYRA 21-1 and CEA between the benign group and lung cancer group. Fisher's exact test was used to assess the difference between the normal group (≤3.3 ng/mL or ≤ 5.0 ng/mL for CFYRA 21-1 and CEA, respectively) and the elevated group (>3.3 ng/mL or >5.0 ng/mL for CFYRA 21-1 and CEA, respectively). Analysis of variance (ANOVA) results were used for differences between different clinical stages of lung cancer patients. P < 0.05 were considered statistically significant. Statistical analysis was carried out using SPSS (Statistical Package for the Social Sciences) 21.0 software (SPSS, Inc., Chicago, Illinois, USA).
Sensitivity for lung cancer was considered as 100 × (the number of lung cancer patients with positive tumor marker [true positive]/total number of lung cancer patients [true positive + false negative]) and specificity for lung cancer as 100 × (the number of benign lung disease patients with negative tumor marker [true negative]/total number of benign lung disease patients [true negative + false positive]).
| > Results|| |
The characteristics of 236 lung cancer patients and 44 patients with benign disease are shown in [Table 1]. Mean age (±standard deviation [SD]) in lung cancer patients was 61 ± 9 years old. Mean age (±SD) in benign lung disease patients was 54 ± 8 years old. Among the lung cancer patients, 100 patients (42.4%) were stage I, 76 patients (32.2%) were stage II, and 60 patients (25.4%) were stage III. Because only the operable patients were enrolled, there were no stage IV patients in this study. One hundred and seventy-two patients (72.9%) had adenocarcinoma and 64 patients (27.1%) had squamous cell carcinoma. Benign lung diseases, included benign sarcoidosis (n = 8), organizing pneumonia (n = 8), pulmonary tuberculosis (n = 4), pulmonary sclerosing hemangioma (n = 4), hamartoma (n = 4), lymphadenitis (n = 8), and others (n = 8). Moreover, the distribution of individual level in benign disease population and lung cancer population was shown in [Figure 1].
|Figure 1: Distribution of tumor marker levels between patients with different types of underlying lung disease. Left: Benign lung disease group; right: Lung cancer group|
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The average level of tumor marker in lung cancer patients was higher than those in patients with benign lung disease.
The average levels of CYFRA 21-1 and CEA in benign and lung cancer patients were shown in [Table 2] (average score of CYFRA 21-1 in lung cancer: 4.7 ng/mL, 95% confidence interval [CI], 4.1–5.3 ng/mL, average score of CYFRA 21-1 in benign lung diseases: 2.4 ng/mL, 95% CI, 2.2–2.6 ng/mL, average score of CEA in lung cancer: 5.9 ng/mL, 95% CI, 4.6–7.2 ng/mL, average score of CEA in benign lung disease: 2.2 ng/mL, 95% CI, 1.4–3.0 ng/mL). CYFRA 21-1 level in lung cancer patients was clearly higher than patients with benign lung disease (t-test, P = 0.002). Although not statistically significant, CEA level in lung cancer patients also showed a tendency to score higher than patients with benign lung disease (t-test, P = 0.24).
|Table 2: Mean tumor marker levels were higher in patients with lung cancer compared with those with benign lung disease|
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The cutoff value in CYFRA 21-1 was set at the standard level (3.3 ng/mL) in this study. As shown in [Table 3], the percent of patients with CYFRA 21-1 levels greater than the standard cutoff level was 37.3% in lung cancer and 9.0% in benign lung disease, respectively (Fisher' exact test, P = 0.012). The cutoff value for CEA was also set at the standard level (5 ng/mL). The percent of patients with levels greater than the usual cutoff level was 22.0% in lung cancer and 9.0% in benign lung disease [Table 4], but the difference was not statistically significant (Fisher's exact test, P = 0.24).
Tumor marker levels were higher in patients with late-stage lung cancer than patients with early-stage lung cancer.
[Table 5] showed the CYFRA 21-1 levels according to the stage of lung cancer. Average scores of CYFRA 21-1 showed a tendency to be increased in the more advanced stages of lung cancer (average score of CYFRA 21-1 in the stage I group: 2.6 ng/mL, 95% CI, 2.4–2.8 ng/mL, average score of CYFRA 21-1 in the stage II group: 6.0 ng/mL, 95% CI, 4.5–7.5 ng/mL, average score of CYFRA 21-1 in the stage III group: 7.0 ng/mL, 95% CI, 5.5–8.5 ng/mL, ANOVA, P = 0.015). [Table 6] showed the CEA levels according to the stage of lung cancer. Average scores of CEA did not show a tendency to be increased in the more advanced stages of lung cancer (average score of CEA in the stage I group: 3.7 ng/mL, 95% CI, 3.0–4.3 ng/mL, average score of CEA in the stage II group: 8.4 ng/mL, 95% CI, 4.5–12.2 ng/mL, average score of CEA in the stage III group: 6.7 ng/mL, 95% CI, 5.1–8.3 ng/mL, ANOVA, P = 0.34).
|Table 5: Correlation between CYFRA 21-1 levels and clinical stage grouping|
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Combination of positive CYFRA 21-1 and positive CEA resulted in a higher sensitivity while remaining a relative higher specificity.
[Table 7] showed the sensitivities and specificities of CYFRA 21-1 and CEA in the diagnosis of lung cancer. Sensitivity and specificity of CYFRA 21-1 for detecting malignant nodules in patients with lung disease was 37.3% and 90.9%, respectively, using standard cutoff level (3.3 ng/mL). The sensitivity and specificity of CEA for detecting malignant nodules in patients with lung disease was 22.0% and 90.9%, respectively, using standard cutoff level (5.0 ng/ml). Then, we analyzed the sensitivity and specificity with the combination of positive CYFRA 21-1 and positive CEA at the standard cutoff level; this resulted in a higher specificity (47.5%), but in a lower sensitivity (81.8%) compared with either CYFRA 21-1 or CEA alone.
|Table 7: Sensitivity and specificity of CYFRA 21-1, CEA, and the combination of CYFRA 21-1 and CEA|
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| > Discussion|| |
This study evaluated the role of tumor markers in the diagnostic differentiation of operable lung cancer from benign lung diseases. Our results showed that mean tumor marker levels were higher in patients with lung cancer compared with those with benign lung disease [Table 1]. Moreover, tumor marker levels were higher in patients with late-stage lung cancer than patients with early-stage lung cancer. Although specificities of the tumor markers at the standard cutoff level for lung cancer diagnosis were high, the sensitivities were at a low level. However, the sensitivity of the combination of positive CEA and positive CYFRA 21-1 was greater than CEA or CYFRA 21-1 alone [Table 7].
By carrying out the study in a specialized oncology center, we enrolled a relatively larger percentage of patients with highly suspected malignant disease and further confirmed by surgery and pathology. However, a little number of patients were diagnosed with benign lung disease. There is an urgent need to differentiate the benign lung disease from malignant lung nodules rather than surgical operation. In lung cancer diagnosis, imaging studies are also very important., The sensitivity of dynamic CT imaging for identifying a malignant solitary pulmonary nodule is 98–100% and the specificity is 54–93% across studies. In accordance with the former studies, our results show that tumor markers exhibit lower sensitivity than dynamic CT imaging, but the specificity is higher than CT scanning [Table 7]. While the combination of positive CEA and positive CYFRA 21-1 increased the sensitivity from 37.3% (positive CYFRA 21-1) and 22.0% (positive CEA) to 47.5% (positive CYFRA 21-1 or positive CEA), meanwhile remain a relative higher specificity (81.8%). Therefore, the combination of tumor markers might be helpful in distinguishing lung cancer from benign lung disease.
There have been many reports concerning CYFRA 21-1 and CEA in lung cancer management,,,, and several researchers have suggested that these markers may be useful in diagnosing lung cancer. In addition, elevation of tumor markers has also been found in certain benign lung diseases,,, but these report used healthy peoples, patients with obstructive respiratory diseases, or inflammatory pulmonary diseases as controls.,, In contrast, our studies mainly focused on the differentiation between the lung cancer and benign lung disease, which is highly suspected as lung cancer. These benign lung diseases were diagnosed by pathology after surgical operation. Therefor, our study may be more useful for the diagnostic differentiation of lung cancer from benign lung diseases which is highly suspected as lung cancer.
Some tumor marker levels increase according to the progression of cancer and their sensitivity depends on tumor stage. Higher level of CYFRA 21-1 or CEA was identified in more advanced stages., In our study, both tumor markers showed a tendency to increase according to the stages of lung cancer [Table 5] and [Table 6]. Because it is not difficult to differentiate late-stage (stage IV) patients from benign lung diseases, and the aim of our study is to diagnose operable lung cancer from benign lung disease, we did not include stage IV patients in our study. This may decrease the sensitivity of tumor marker in our study. However, our data showed that the sensitivity was increased after the combination of positive CEA and CYFRA 21-1 (47.5%), while maintaining a high specificity (81.8%).
| > Conclusion|| |
We retrospectively investigated the diagnostic value of two tumor markers, CYFRA 21-1 and CEA, in operable lung cancer patients and patients with benign lung disease. Tumor marker levels were higher in patients with lung cancer than benign lung disease. The combination of these two tumor markers resulted in higher sensitivity compared to use CYFRA 21-1 and along with CEA. Given its lower sensitivity and higher specificity, positive CYFRA 21-1 or positive CEA strongly supports lung cancer. While negative CYFRA 21-1 or negative CEA may not exclude malignant disease.
Financial support and sponsorship
This study was supported by the grants from the Beijing hope run special fund of cancer foundation of China (LC2015B13). No other financial relationships relevant to this publication were disclosed.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
Diederich S, Wormanns D. Impact of low-dose CT on lung cancer screening. Lung Cancer 2004;45 Suppl 2:S13-9.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al.
Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.
Wang B, He YJ, Tian YX, Yang RN, Zhu YR, Qiu H. Clinical utility of haptoglobin in combination with CEA, NSE and CYFRA21-1 for diagnosis of lung cancer. Asian Pac J Cancer Prev 2014;15:9611-4.
Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012;76:138-43.
Yang ZM, Ding XP, Pen L, Mei L, Liu T. Analysis of CEA expression and EGFR mutation status in non-small cell lung cancers. Asian Pac J Cancer Prev 2014;15:3451-5.
Lai RS, Hsu HK, Lu JY, Ger LP, Lai NS. CYFRA 21-1 enzyme-linked immunosorbent assay. Evaluation as a tumor marker in non-small cell lung cancer. Chest 1996;109:995-1000.
Wieskopf B, Demangeat C, Purohit A, Stenger R, Gries P, Kreisman H, et al.
Cyfra 21-1 as a biologic marker of non-small cell lung cancer. Evaluation of sensitivity, specificity, and prognostic role. Chest 1995;108:163-9.
Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol 2005;40:90-7.
Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of lung cancer: Diagnosis and management of lung cancer, 3rd
ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143 5 Suppl: e191S-210S.
Dhopeshwarkar MR, Roberts HC, Paul NS, Dong Z, Tsao M, Menezes RJ. Screen-detected lung cancer: A retrospective analysis of CT appearance. Acad Radiol 2011;18:1270-6.
Gould MK, Fletcher J, Iannettoni MD, Lynch WR, Midthun DE, Naidich DP, et al.
Evaluation of patients with pulmonary nodules: When is it lung cancer? ACCP evidence-based clinical practice guidelines (2nd
edition). Chest 2007;132 3 Suppl: 108S-30S.
Patz EF Jr, Campa MJ, Gottlin EB, Kusmartseva I, Guan XR, Herndon JE 2nd
. Panel of serum biomarkers for the diagnosis of lung cancer. J Clin Oncol 2007;25:5578-83.
Hanagiri T, Sugaya M, Takenaka M, Oka S, Baba T, Shigematsu Y, et al.
Preoperative CYFRA 21-1 and CEA as prognostic factors in patients with stage I non-small cell lung cancer. Lung Cancer 2011;74:112-7.
Schneider J. Tumor markers in detection of lung cancer. Adv Clin Chem 2006;42:1-41.
Molina R, Auge JM, Filella X, Viñolas N, Alicarte J, Domingo JM, et al.
Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: Comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer. Anticancer Res 2005;25:1773-8.
Oremek GM, Sauer-Eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer. Anticancer Res 2007;27:1911-5.
Szturmowicz M, Sakowicz A, Rudzinski P, Zych J, Wiatr E, Zaleska J, et al.
The clinical value of Cyfra 21-1 estimation for lung cancer patients. Int J Biol Markers 1996;11:172-7.
Kanazawa H, Yoshikawa T, Yamada M, Shoji S, Fujii T, Kudoh S, et al.
CYFRA 21-1, a cytokeratin subunit 19 fragment, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Clin Sci (Lond) 1998;94:531-5.
Kulpa J, Wójcik E, Reinfuss M, Kolodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem 2002;48:1931-7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]