The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas

Our plain-English summary of The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas, by L. Bernardi, T. Bizzarro, F. Pironi, et al (Cancer Cytopathology, 2021).

The study

• Authors: L. Bernardi, T. Bizzarro, F. Pironi, S. Szymczuk, R. Buda, E. Fabbri, G. Di Claudio, G. Rossi
• Journal: Cancer Cytopathology
• Published: 2021;129(4):275-282
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The distinction between mesothelioma with epithelioid features and metastatic carcinoma may be challenging, particularly on cytology. A novel 2-hit Claudin-4 and BRCA-associated protein 1 (BAP1) panel was investigated.

Methods: The objective of this study was to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the panel on cytology from pleural effusions and matched biopsies, including 49 malignant mesotheliomas on cytology with 43 matched biopsies, 49 normal/reactive mesothelial proliferations, and 49 pleural metastatic carcinomas from different primaries with 21 matched pleural biopsies. The diagnostic role of the 4 categories obtained by crossing the immunostaining results was analyzed.

Results: Claudin-4 strongly stained all metastatic carcinomas and tested completely negative in normal mesothelium, benign reactive mesothelial hyperplasia, and malignant mesothelioma. All normal and benign mesothelial proliferations and all carcinomas except 1 were immunoreactive for BAP1, whereas BAP1 loss was observed in 88% of malignant mesotheliomas. The expression of Claudin-4 alone excluded all benign and malignant mesothelial growth, consistently characterizing all metastatic carcinomas. Double negativity was evident in all malignant mesotheliomas, and double positivity was observed in all metastatic carcinomas. BAP1-positive/Claudin-4-negative status was observed only in malignant mesotheliomas and benign mesothelial proliferations. A single metastatic anal squamous cell carcinoma had BAP1-negative/Claudin-4-positive staining.

Conclusions: Claudin-4 expression was completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations. BAP1 staining characterized 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity was observed almost exclusively in mesotheliomas. This 2-hit panel is probably the best compromise for differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.

© 2020 American Cancer Society.

In plain English

This study, from pathology units in Ravenna and Rimini, Italy, tested whether two laboratory stains, Claudin-4 and BAP1 (which the authors call the "Brescia panel"), can tell pleural malignant mesothelioma apart from cancers that have spread to the pleura from elsewhere (metastatic carcinomas). The authors examined samples from 2017 to 2020. They included fluid samples (cell blocks) from 49 mesotheliomas (43 epithelioid, 6 biphasic) and 49 metastatic carcinomas, with matched biopsies for 43 and 21 of them. For comparison there were 14 normal mesothelium biopsies and 35 reactive mesothelial hyperplasia samples (fluid cell blocks with matched biopsies). The study did not look at asbestos exposure. Claudin-4 stained all 49 metastatic carcinomas and none of the mesotheliomas or comparison samples. BAP1 staining was lost in 43 of 49 mesotheliomas (88%) but present in 48 of 49 carcinomas. The one exception was an anal squamous cell carcinoma. Results agreed between fluid samples and biopsies. The authors concluded that Claudin-4 staining rules out mesothelioma. They called this a preliminary pilot study needing larger confirmation. Some counts in the article do not match each other.

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: Retrospective and prospective diagnostic laboratory study of immunostaining on pleural fluid cell blocks and biopsies
• Who was studied: Samples collected 2017 to 2020 at the pathology units of Ravenna and Rimini, Italy. They comprised 49 cell blocks of pleural metastatic carcinoma from various primary sites (25 women, 24 men, mean age 74.4) with 21 matched biopsies, and 49 cell blocks of primary pleural malignant mesothelioma (41 men, 8 women, mean age 78.5; 43 epithelioid, 6 biphasic) with 43 matched biopsies. A further 49 comparison samples were included: 14 biopsies of normal mesothelium from lung cancer resections, and 35 cell blocks with concurrent biopsies from reactive pleural hyperplasia.
• Exposure: No asbestos or fiber exposure was studied. The study tested two immunostains, Claudin-4 and BRCA-associated protein 1 (BAP1), used alone and together.
• Main results:
  • All metastatic carcinomas stained positive for Claudin-4.
  • Among malignant mesotheliomas, 43 samples (88%) were BAP1-negative and 6 (12%) were BAP1-positive, including 3 of the 6 biphasic tumors.
  • 48 metastatic carcinomas were positive for both stains. One anal squamous cell carcinoma was BAP1-negative and Claudin-4-positive.
  • The BAP1-positive, Claudin-4-negative group contained 6 mesotheliomas (3 epithelioid, 3 biphasic) and benign mesothelial proliferations. The group negative for both stains contained only mesotheliomas (43 cases).
  • All normal mesothelial samples (14) and reactive mesothelial hyperplasia samples (35) were BAP1-positive and Claudin-4-negative.
  • Staining results agreed completely between cell blocks and matched biopsies.
  • For distinguishing malignant mesothelioma from metastatic carcinoma, Claudin-4 alone had 100% sensitivity, specificity, PPV, NPV and diagnostic accuracy.
  • BAP1 alone had 87.8% sensitivity, 99% specificity, 97.7% PPV, 94.2% NPV and 95.2% diagnostic accuracy.
  • The two stains combined had 93.9% sensitivity, 100% specificity, 100% PPV, 89.1% NPV and 95.9% diagnostic accuracy.
• The authors' conclusion: The authors concluded that Claudin-4 is the best pan-carcinoma marker and its expression rules out malignant mesothelioma, while loss of BAP1 is almost uniquely restricted to mesothelioma. They called the two-stain panel highly effective for this differential diagnosis, even in cell blocks from pleural effusions.
• Limitations the authors state:
  • The authors describe this as a preliminary pilot study with some limitations.
  • Further validation is needed in larger series with significant numbers of metastatic carcinomas from each primary site.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Claudin-4, Differential Diagnosis, Mesothelioma, Epithelioid, Carcinoma, Cytology, BAP1, Pleural Effusion.

Related studies

• Differential Diagnosis of Malignant Pleural Mesothelioma on Cytology: A Gene Expression Panel versus BRCA1-Associated Protein 1 and p16 Tests — R. Bruno, G. Alì, et al. (2020)
• Utility of Claudin-4 versus BerEP4 and B72.3 in pleural fluids with metastatic lung adenocarcinoma — A. Patel, A.C. Borczuk, et al. (2020)
• BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study — L. Righi, E. Duregon, et al. (2016)
• Value of PAX8, PAX2, napsin A, carbonic anhydrase IX, and claudin-4 immunostaining in distinguishing pleural epithelioid mesothelioma from metastatic renal cell carcinoma — N.G. Ordóñez (2013)
• Claudin-4 immunohistochemistry is a useful pan-carcinoma marker for serous effusion specimens — M. Vojtek, M.D. Walsh, et al. (2019)
• A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair — R. Parrotta, A. Okonska, et al. (2017)

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