Claudin-4 immunohistochemistry is a useful pan-carcinoma marker for serous effusion specimens

Our plain-English summary of Claudin-4 immunohistochemistry is a useful pan-carcinoma marker for serous effusion specimens, by M. Vojtek, M.D. Walsh, D.J. Papadimos, et al (Cytopathology, 2019).

The study

• Authors: M. Vojtek, M.D. Walsh, D.J. Papadimos, P.W. Shield
• Journal: Cytopathology
• Published: 2019;30(6):614-619
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: To evaluate the utility of claudin-4 as a pan-carcinoma marker in cell-blocks of effusion specimens and compare results with Ber-Ep4 staining.

Methods: Effusion cell-blocks (n = 284) were stained for claudin-4 and results compared with Ber-Ep4. Cases included 172 metastatic malignancies (137 adenocarcinomas, 20 small cell lung tumours, eight metastatic melanoma, four squamous cell carcinoma, three urothelial cell carcinoma), 49 benign reactive cases and 63 mesotheliomas.

Results: All 49 benign effusions were negative. Only 1/63 (1.6%) mesotheliomas was positive for claudin-4. Claudin-4 staining was positive in 131/137 (95.6%) adenocarcinoma cases. Cases negative for claudin-4 included single cases of metastases from breast, colon, stomach, prostate, kidney and ovary. Claudin-4 outperformed Ber-Ep4. Sensitivity (95.6% vs 85.4%), specificity (99.1% vs 86.6%), negative predictive value (94.9% vs 82.9%) and positive predictive value (99.2% vs 88.6%) were all higher for claudin-4 compared with Ber-Ep4, respectively. Only two cases were claudin-4-/Ber-Ep4+. Significantly (P < .0064) more cases of metastatic adenocarcinoma stained positive for claudin-4 (131/137; 95.6%) than Ber-Ep4 (117/137; 86.2%). Claudin-4 staining was present in 15/20 (75%) of neuroendocrine carcinomas, 3/4 (75%) squamous cell carcinoma and 3/3 (100%) urothelial cell carcinoma. All eight cases of melanoma were negative for both claudin-4 and Ber-Ep4.

Conclusions: Claudin-4 staining is a useful addition to IHC panels for effusions specimens with superior performance to Ber-Ep4.

© 2019 John Wiley & Sons Ltd.

In plain English

This laboratory study, from Queensland, Australia, tested whether a stain called claudin-4 helps pathologists tell cancer that has spread from elsewhere apart from mesothelioma and harmless mesothelial cells in fluid drained from around the lungs, abdomen or heart. The study did not look at asbestos exposure. The authors stained 284 fluid samples and compared claudin-4 with a commonly used stain, Ber-Ep4. All 49 benign samples were negative for claudin-4, and 1 of 63 mesotheliomas was positive. For Ber-Ep4 the figures were 1 of 49 benign samples and 14 of 63 mesotheliomas. Claudin-4 was positive in 131 of 137 adenocarcinomas, compared with 117 of 137 for Ber-Ep4. It was also positive in 29 of 30 breast cancers, against 19 of 30 for Ber-Ep4. For telling metastatic adenocarcinoma apart from the study's 63 mesotheliomas and 49 benign cases, claudin-4 had a sensitivity of 95.6% and a specificity of 99.1%. The authors concluded that the stain offers high sensitivity and specificity, better than Ber-Ep4. They noted that only small numbers of rarer tumour types were examined.

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: Laboratory diagnostic accuracy study comparing two immunohistochemistry stains (claudin-4 and Ber-Ep4) on stored effusion cell-blocks
• Who was studied: 284 effusion cell-blocks (200 pleural fluid, 81 peritoneal fluid, 3 pericardial): 137 metastatic adenocarcinomas, 20 small cell lung tumours, 8 melanomas, 4 squamous cell carcinomas, 3 urothelial carcinomas, 63 mesotheliomas and 49 benign reactive cases. Ethics approval came from Queensland University of Technology, Australia. Dates are not given.
• Exposure: Not an exposure study; asbestos exposure is not discussed. The test studied was claudin-4 staining (mouse monoclonal antibody, clone 3E2C1), compared with Ber-Ep4 staining.
• Main results:
  • Benign effusions: all 49 were negative for claudin-4.
  • Staining in mesothelial cells was seen in significantly fewer cases with claudin-4 (1/63 mesothelioma, 0/49 reactive) than with Ber-Ep4 (14/63 mesothelioma, 1/49 reactive); P less than 0.0001.
  • Metastatic adenocarcinoma: positive in 131/137 (95.6%) cases with claudin-4 versus 117/137 with Ber-Ep4; P less than 0.0064.
  • For detecting metastatic adenocarcinoma against the study's 63 mesothelioma and 49 benign cases, claudin-4 had sensitivity 95.6% and specificity 99.1%. Table 2 gives positive predictive value 99.2% versus 88.6% and negative predictive value 94.9% versus 82.9% for claudin-4 versus Ber-Ep4. All four measures were higher for claudin-4.
  • Breast cancer metastases: claudin-4 was significantly more sensitive than Ber-Ep4 (96.7% vs 63.3%); P less than 0.0025.
  • Other tumours: claudin-4 was positive in 3/4 squamous cell carcinomas, 15/20 small cell lung carcinomas and 3/3 urothelial carcinomas.
  • Melanoma: all 8 cases were negative for both stains.
  • Of 39 cases with both a fluid cell-block and matching tumour tissue, all but one gave the same claudin-4 result. The exception was a mesothelioma that was negative in the pleural biopsy but showed focal staining in the cell-block.
• The authors' conclusion: The authors concluded that claudin-4 offers high sensitivity and specificity, superior to Ber-Ep4, and would be a useful addition to staining panels for effusion specimens.
• Limitations the authors state:
  • Only limited numbers of the rarer non-glandular tumour types were examined.
  • The reason the one claudin-4-positive mesothelioma cell-block had a negative matched biopsy was uncertain.

Topics

Medical terms in this study, explained in our Lexicon: Claudin-4, Immunohistochemistry, Carcinoma, Ber-EP4, Adenocarcinoma, Squamous Cell Carcinoma, Mesothelioma.

Related studies

• Claudin-4 as a marker for distinguishing malignant mesothelioma from lung carcinoma and serous adenocarcinoma — Y. Ohta, Y. Sasaki, et al. (2013)
• Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology — V.Y. Jo, E.S. Cibas, et al. (2014)
• Immunocytochemical utility of claudin-4 versus those of Ber-EP4 and MOC-31 in effusion cytology — T. Oda, S. Ogata, et al. (2016)
• CD24 is highly useful in differentiating high-grade serous carcinoma from benign and malignant mesothelial cells — B. Davidson (2016)
• GATA3 is a useful immunohistochemical marker for distinguishing sarcomatoid malignant mesothelioma from lung sarcomatoid carcinoma and organizing pleuritis — Z.H. Piao, X.C. Zhou, et al. (2021)
• MMP-7 is a highly specific negative marker for benign and malignant mesothelial cells in serous effusions — B. Davidson, H.T. Stavnes, et al. (2016)

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