CLDN15 is a novel diagnostic marker for malignant pleural mesothelioma

Our plain-English summary of CLDN15 is a novel diagnostic marker for malignant pleural mesothelioma, by M. Watanabe, T. Higashi, K. Ozeki, et al (Scientific Reports, 2021).

The study

• Authors: M. Watanabe, T. Higashi, K. Ozeki, A.Y. Higashi, K. Sugimoto, H. Mine, H. Takagi, Y. Ozaki, S. Muto, N. Okabe, Y. Matsumura, T. Hasegawa, Y. Shio, H. Suzuki, H. Chiba
• Journal: Scientific Reports
• Published: 2021;11(1):12554
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90-100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.

In plain English

This laboratory study from Fukushima Medical University, Japan, tested whether a protein called claudin-15 (CLDN15) could help pathologists recognize malignant pleural mesothelioma (MPM). In mouse pleura and peritoneum, CLDN15 was the most abundant claudin detected. The authors made new antibodies against human CLDN15. They stained tumor tissue from 42 MPM patients diagnosed between 2003 and 2019. Of these patients, 27 were recorded as asbestos-exposed, but the study did not examine asbestos itself. Using a scoring cut-off of 3, 83% of MPM samples (35 of 42) were CLDN15-positive. The figures were 81% for calretinin, 50% for WT-1 and 81% for D2-40. Positivity was 93% in epithelioid, 75% in biphasic and 50% in sarcomatoid tumors. CLDN15 was positive in 4 of 50 lung adenocarcinomas (specificity 92%) and in 12 of 327 samples covering 24 other tumor types. The authors concluded that CLDN15 has high sensitivity and specificity for MPM tissue and is a potential positive marker for diagnosis. They noted small case numbers and low statistical power, and called for larger studies.

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-marker study. It combined RT-PCR screening of claudins in mouse mesothelial tissue, development of new monoclonal antibodies, and immunohistochemistry of archived human tumor samples scored with an immunoreactive score (IRS).
• Who was studied: Tissue from 42 malignant pleural mesothelioma cases diagnosed 2003 to 2019 at Fukushima Medical University Hospital and partner hospitals: 28 epithelioid, 8 biphasic, 6 sarcomatoid; 38 male, 4 female; median age 65.5. Also studied: 50 lung adenocarcinoma sections (40 for the comparison markers) and a purchased tissue microarray of 327 cases from 24 non-mesothelioma tumor types, plus mouse tissues.
• Exposure: Asbestos was not the exposure studied. Asbestos exposure was recorded only as patient background: 27 of 42 (64.3%) exposed, 15 (35.7%) non-exposed. No fiber types or doses were given.
• Main results:
  • In mouse pleura and peritoneum, Cldn15 was the most abundantly expressed claudin.
  • With an IRS cut-off of 3, 83% (35 of 42) of MPM samples were CLDN15-positive. For comparison: calretinin 81%, WT-1 50%, D2-40 81%.
  • Across all MPM samples, CLDN15 positivity was significantly higher than WT-1 positivity (p = 0.0057).
  • In epithelioid-type MPM, 93% (26 of 28) were CLDN15-positive.
  • In biphasic-type MPM, 75% (6 of 8) were CLDN15-positive.
  • In sarcomatoid-type MPM, 50% (3 of 6) were CLDN15-positive. Biphasic and sarcomatoid tumors combined were significantly less often positive than epithelioid tumors (p = 0.028).
  • Using two markers together raised sensitivity. For example, 93% (39 of 42) of MPM samples were positive for CLDN15 or calretinin.
  • Lung adenocarcinoma: 4 of 50 (8%) were CLDN15-positive, giving a specificity of 92%. For comparison: calretinin 4 of 40, WT-1 1 of 40, D2-40 0 of 40.
  • No lung squamous cell carcinomas were CLDN15-positive (n = 11).
  • In the tissue microarray of 24 non-mesothelioma primary tumor types, CLDN15 was positive in 12 of 327 (4%) cases.
• The authors' conclusion: The authors concluded that CLDN15 immunostaining has high sensitivity and specificity for MPM tissue. They wrote that the results support CLDN15 as a positive marker for the pathological diagnosis of MPM.
• Limitations the authors state:
  • Small case numbers in the biphasic and sarcomatoid types gave low statistical power (0.20 to 0.28). Differences in sensitivity between markers in these types could not be ruled out.
  • Comparisons of two-marker panels also lacked statistical power (0.20 to 0.35) because of the small sample size.
  • The tissue microarray result should be validated in a larger cohort.
  • MPM is rare, so few patients could be enrolled. The authors said larger studies are needed to validate the results.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Mesothelial Cells, Monoclonal Antibody, Immunohistochemistry, Calretinin, Wilms Tumor 1 (WT-1), Podoplanin (D2-40).

Related studies

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• Expression of Calretinin, Marker of Mesothelial Differentiation, in Pancreatic Ductal Adenocarcinoma: A Potential Diagnostic Pitfall — G. Askan, O. Basturk (2021)
• Tenascin XB Is a Novel Diagnostic Marker for Malignant Mesothelioma — K. Nakayama, M. Seike, et al. (2019)
• 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)
• RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma — T. Hiratsuka, T. Yamamoto, et al. (2022)
• Claudin 3, 4, and 15 expression in solid tumors of lung adenocarcinoma versus malignant pleural mesothelioma — S. Chaouche-Mazouni, A. Scherpereel, et al. (2015)

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