Diagnostic accuracy of Ber-EP4 for metastatic adenocarcinoma in serous effusions: a meta-analysis

Our plain-English summary of Diagnostic accuracy of Ber-EP4 for metastatic adenocarcinoma in serous effusions: a meta-analysis, by B. Wang, D. Li, X. Ou, et al (PloS One, 2014).

The study

• Authors: B. Wang, D. Li, X. Ou, Q. Yi, Y. Feng
• Journal: PloS One
• Published: 2014;9(9):e107741
• Type of article: Meta-analysis
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Numerous studies have investigated the utility of Ber-EP4 in differentiating metastatic adenocarcinoma (MAC) from malignant epithelial mesothelioma (MM) and/or reactive mesothelial cells (RM) in serous effusions. However, the results remain controversial. The aim of this study is to determine the overall accuracy of Ber-EP4 in serous effusions for MAC through a meta-analysis of published studies. Publications addressing the accuracy of Ber-EP4 in the diagnosis of MAC were selected from the Pubmed, Embase and Cochrane Library. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc 1.4 and STATA 12.0 softwares. 29 studies, based on 2646 patients, met the inclusion criteria and the summary estimating for Ber-EP4 in the diagnosis of MAC were: sensitivity 0.8 (95% CI: 0.78-0.82), specificity 0.94 (95% CI: 0.93-0.96), positive likelihood ratio (PLR) 12.72 (95% CI: 8.66-18.7), negative likelihood ratio (NLR) 0.18 (95% CI: 0.12-0.26) and diagnostic odds ratio 95.05 (95% CI: 57.26-157.77). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.91; the area under the curve was 0.96. Our findings suggest that BER-EP4 may be a useful diagnostic adjunctive tool for confirming MAC in serous effusions.

In plain English

This was a meta-analysis pooling 29 published studies (1993 to 2013, 14 countries, 2646 individuals) that tested a laboratory stain, Ber-EP4, on body-cavity fluid (serous effusions). The question was how well Ber-EP4 separates metastatic adenocarcinoma from malignant mesothelioma and/or reactive mesothelial cells. The article did not study asbestos exposure and did not report mesothelioma results separately. Pooled sensitivity (the share of adenocarcinoma samples staining positive) was 0.8 (95% CI 0.78 to 0.82), and pooled specificity (the share of mesothelioma or reactive mesothelial samples staining negative) was 0.94 (95% CI 0.93 to 0.96). The positive likelihood ratio was 12.72 (95% CI 8.66 to 18.7) and the negative likelihood ratio 0.18 (95% CI 0.12 to 0.26). Results varied widely between studies; whether studies enrolled consecutive or random patients was a statistically significant source of that variation. The authors concluded that Ber-EP4 may be a useful adjunct to conventional diagnostic tools, interpreted alongside morphology and clinical findings. They noted limitations including possible publication bias and verification bias, and differing cutoff values.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Meta-analysis (systematic review with pooled analysis) of published diagnostic accuracy studies
• Who was studied: 29 published studies (1993 to 2013) from 14 countries, covering 2646 individuals in total, with study sizes of 17 to 232. Studies compared metastatic adenocarcinoma with malignant mesothelioma and/or reactive mesothelial cells in serous effusions. The literature search ran to December 31, 2013.
• Exposure: No asbestos or other environmental exposure was studied. The 'test' evaluated was Ber-EP4 immunostaining, an antibody marking epithelial cells, applied to effusion fluid prepared as cell blocks or smears.
• Main results:
  • Across all 29 studies, pooled sensitivity of Ber-EP4 for metastatic adenocarcinoma was 0.8 (95% CI: 0.78 to 0.82) and pooled specificity was 0.94 (95% CI: 0.93 to 0.96).
  • Pooled positive likelihood ratio was 12.72 (95% CI: 8.66 to 18.7) and negative likelihood ratio was 0.18 (95% CI: 0.12 to 0.26).
  • Pooled diagnostic odds ratio was 95.05 (95% CI: 57.26 to 157.77).
  • On the summary ROC curve the Q-value was 0.91 and the area under the curve was 0.96, which the authors described as a high level of overall accuracy.
  • The authors found obvious heterogeneity between studies for all pooled measures, so they used a random effects model.
  • In meta-regression, whether studies enrolled a consecutive or random sample of patients was statistically significant (p = 0.0002). Test method (cell blocks or smears) was not a source of heterogeneity (p = 0.9046).
  • Deeks' test for publication bias was not statistically significant (p = 0.81), which the authors interpreted as no potential publication bias.
• The authors' conclusion: The authors concluded that Ber-EP4 may be a useful adjunct to conventional diagnostic tools for differentiating metastatic adenocarcinoma from malignant mesothelioma and/or reactive mesothelial cells, but that it should be interpreted alongside morphology and clinical findings. They called for further blinded, larger prospective studies.
• Limitations the authors state:
  • Only published studies were included, which may have led to publication bias.
  • Verification bias: some adenocarcinoma diagnoses were based only on clinical course, not on histological examination.
  • 6 studies made inappropriate exclusions, such as leaving out difficult-to-diagnose patients, which may overestimate accuracy.
  • Different cutoff values were used across studies, so an optimal cutoff could not be determined.
  • The original publications lacked the data needed to analyse laboratory infrastructure, assay expertise, patient spectrum and setting.

Topics

Medical terms in this study, explained in our Lexicon: Ber-EP4, Adenocarcinoma, Meta-Analysis, Mesothelioma, Reactive Mesothelial Hyperplasia, Odds Ratio.

Related studies

• Diagnostic accuracy of calretinin for malignant mesothelioma in serous effusions: a meta-analysis — D. Li, B. Wang, et al. (2015)
• The diagnostic utility of D2-40, calretinin, CK5/6, desmin and MOC-31 in the differentiation of mesothelioma from adenocarcinoma in pleural effusion cytology — T.S. Hyun, M. Barnes, et al. (2012)
• Cytological differential diagnosis among adenocarcinoma, epithelial mesothelioma, and reactive mesothelial cells in serous effusions by immunocytochemistry — X.Y. Su, G.D. Li, et al. (2011)
• Ber-EP4 for differentiating adenocarcinoma from reactive and neoplastic mesothelial cells in serous effusions. Comparison with carcinoembryonic antigen, B72.3 and Leu-M1 — M.E. Bailey, R.W. Brown, et al. (1996)
• Diagnostic value of monoclonal antibody B72.3 in detecting adenocarcinoma cells in serous effusions — A.F. Lauritzen (1989)
• Utility of Claudin-4 versus BerEP4 and B72.3 in pleural fluids with metastatic lung adenocarcinoma — A. Patel, A.C. Borczuk, et al. (2020)

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