In addition, the sensitivity, specificity, PPV, NPV, +LR, and −LR of ProGRP for distinguishing SCLC from squamous cell carcinoma were 71.2%, 93.2%, 94.0%, 68.9%, 10.5, and 0.3, respectively (Table 2). All of these evaluation indexes were better than those of NSE. Furthermore, ProGRP also indicated better diagnostic utility in terms of higher AUC than NSE and CEA (Fig. 2B, 0.859 vs 0.669 vs 0.534, P < .05). Besides, combination of ProGRP with NSE (CDM1) also gave a comparatively ideal predictive value in the discrimination between SCLC and squamous cell carcinoma and yielded an AUC of 0.894 (95% CI: 0.833–0.955), but it did not significantly differ from ProGRP (P = .15).
In discriminating SCLC from adenocarcinoma, serum ProGRP offered a sensitivity, specificity, PPV, NPV, +LR, and −LR of 71.2%, 93.1%, 90.4%, 78.2%, 10.5, and 0.3, respectively (Table 2). Interestingly, CEA exhibited a higher sensitivity of 74.2%. Of note, the sensitivity and NPV increased markedly reaching 100% when these 2 biomarkers were assessed together. ROC analysis (Fig. 2C) showed that ProGRP was most efficiently used to identify the SCLC patients with an AUC of 0.835 (95% CI: 0.760–0.910), followed by CEA (AUC 0.693, 95% CI: 0.606–0.780) and NSE (AUC 0.670, 95% CI: 0.576–0.765). The combination of ProGRP and CEA (CDM2) further increased the diagnostic capacity indicated by a high AUC of 0.928 (95% CI: 0.886–0.0.970), which was close to the AUC concerning the combinations of ProGRP with NSE and CEA (CDM4 0.929, 95% CI: 0.888–0.970, P = .75). To further analyze the diagnostic capacity of ProGRP and CEA in SCLC versus adenocarcinoma, we divided the patients with SCLC and adenocarcinoma into 4 groups according to serum levels of these 2 markers (Table 3). Intriguingly, none of the patients with SCLC were in group B (ProGRP ≤ 66 pg/mL, CEA > 5 ng/mL), that is, in this group 100% of the patients were diagnosed with adenocarcinoma. Besides, the patients with SCLC accounted for 96.8% and 85% in groups C (ProGRP > 66 pg/mL, CEA ≤ 5 ng/mL) and D (ProGRP > 66 pg/mL, CEA > 5 ng/mL), respectively.
In this study, serum ProGRP was analyzed by ECLIA technique and we evaluated the role of ProGRP in this new detection system for the differential diagnosis of benign pulmonary diseases and lung cancer histological subtypes (especially SCLC vs squamous vs adenocarcinoma), as well as its use in combination with CEA and NSE.
Our study revealed that ProGRP serum level was significantly higher in SCLC than in benign pulmonary diseases and NSCLC (adenocarcinoma and squamous). In the ECLIA detection system, ProGRP showed the sensitivity of 71.2% in the patients with SCLC, which was similar to those determinated by ELISA in other groups (65%–80%).[19,23–26] Likewise, Tang et al assessed the diagnostic value of serum ProGRP detected by ELISA in the diagnosis of SCLC using meta-analysis and proved that ProGRP had the pooled sensitivity of 72% (95% CI: 70%–75%) and pooled specificity of 93% (95% CI: 92%–94%), which was comparable to the values of ProGRP analyzed by ECLIA in our study. With the combination of ProGRP and NSE, the diagnostic sensitivity of SCLC further increased, reaching 81.8%.
Comparing with NSE and CEA, ProGRP exhibited the strongest sensitivity–specificity relationship in discriminating SCLC from benign lung diseases. Its sensitivity, specificity, PPV, and +LR were up to 71.2%, 91.1%, 92.1%, and 8.0, respectively. Whereas the corresponding indexes of NSE were 56.1%, 73.3%, 75.5%, and 2.1, respectively. However, there was no significant difference in AUC–ROC between ProGRP and NSE (0.815 vs 0.713). Moreover, both of them were found to be more superior to CEA for detecting SCLC and benign lung diseases. Notablely, the combination of ProGRP and NSE could significantly enhance the diagnostic performance of NSE alone, while this improvement over ProGRP alone was not obvious. Shibayama et al found that NSE showed a higher specificity and PPV than ProGRP in the discrimination of SCLC and benign lung diseases (specificity: 100% vs 93.2%; PPV: 100% vs 91.4%), but our findings reflected a discrepancy: ProGRP possessed a better specificity and PPV. One of the probable reasons was that in our study serum samples were not separated from the clot within 1 hour after sampling strictly according to formulary requirement and might lead to a false increase of NSE.[14,16] Since NSE may leak from platelets and erythrocytes, collecting a suitable sample seems not easy. Alternatively, ProGRP might be a promising tumor marker.
The histological diagnosis of lung cancer is of great importance for the initiation of treatment and prognostic implications. However, the diagnosis is not always easy, especially for the patients with advanced tumors. Thus, how to improve the histological diagnosis using serum tumor markers is still a challenging issue worthy of special consideration. Our study paid more attention to the roles of serum ProGRP, NSE, CEA, and their combinations in the discrimination between SCLC and NSCLC (especially squamous cell carcinoma and adenocarcinoma).
Against the squamous cell carcinoma of lung cancer, the diagnostic sensitivity of serum ProGRP and NSE for SCLC were, respectively, estimated to be 93.0% and 40.9% at a set specificity of 75.0%. Our results demonstrated that the tumor markers with the highest discriminatory capacity between SCLC and squamous cell carcinoma were ProGRP, followed by NSE (AUC–ROC 0.859 vs 0.669, P = .008), which further confirmed the superiority of ProGRP to NSE for diagnosis of SCLC and was in line with earlier reports on ProGRP analyzed by ELISA.[25,26,28–30] However, the AUC–ROC of ProGRP was not significantly increased by the addition of NSE, no significant differences were found in the comparison. In view of the cost savings for patients, ProGRP still might be an optimal choice for discriminating SCLC from squamous cell carcinoma, and NSE might add additional value to ProGRP.
In the discrimination of SCLC and adenocarcinoma, serum ProGRP showed a much higher sensitivity compared with NSE at a specificity of 76.0% (93.2% vs 41.1%). Serum level of CEA was significantly lower in the SCLC patients compared with the adenocarcinoma cases. Our present results further validated previous findings.[18,23,26] Moreover, the combination of ProGRP and CEA improved the diagnostic performance in comparison with ProGRP alone (AUC–ROC 0.928 vs 0.835, P = .04). In the present study, we found an interesting phenomenon: 100% of the patients were diagnosed with adenocarcinoma in the group of ProGRP ≤ 66 pg/mL and CEA > 5 ng/mL when analyzing the cases with SCLC and adenocarcinoma. That is to say, when ProGRP was less than 66 pg/mL, CEA was of significant value in discriminating SCLC from adenocarcinoma. If CEA was less than 5 ng/mL, the patient was considered SCLC with a great possibility. On the contrary, the patient was more likely to be identified as adenocarcinoma. In addition, the combined mode of ProGRP + NSE + CEA provided almost equivalent AUC compared with ProGRP + CEA (0.929 vs 0.928), which suggested that the former mode was not appropriate as a routine clinical protocol and might lead to unnecessary expenditure for patients.
In summary, our study provided valid information about the 3 biomarkers with respect to their diagnostic values for discriminating SCLC from benign pulmonary diseases and NSCLC (adenocarcinoma and squamous cell carcinoma). Among these studied markers, ProGRP was the most efficient in identifying SCLC. Moreover, ProGRP and NSE were demonstrated to have approximately equivalent diagnostic performance in discriminating SCLC from benign lung diseases. For the patients with squamous cell carcinoma, we recommended the use of ProGRP; however, for those with adenocarcinoma, ProGRP, and CEA were preferred.
We thank all the participants who consented to participate in this study. Especially, we sincerely thank Xiaohui Li who helped us collect the samples.
LSH and HYY wrote the paper. LSH, LQZS, YX and DHC carried out the experiments and interpreted the data. XHL and XLC collected the samples. CHD and XHL participated in study design and supervised the study. All authors approved the final version of the paper.
This work was supported by the Guangdong Natural Science Foundation (grant number S2013010014007, 2014A030313070) and Guangdong Province Science & Technology Project Plan & Social Development Foundation (grant number 2010A030400006). The funders did not participate in data collection and analysis, article writing or submission.
Institutional review board statement
The study was developed under the principles of Declaration of Helsinki and approved by the Ethics Committee of Sun Yat-sen Memorial Hospital and Sun Yat-sen University Cancer Center.
Conflicts of interest
The authors declare that they have no conflicts of interest.
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Keywords:Copyright © 2018 The Chinese Medical Association. Published by Wolters Kluwer Health, Inc.
carcinoembryonic antigen; differential diagnosis; histological diagnosis; lung cancer; neuron-specific enolase; progastrin-releasing peptide; small cell lung cancer