Claudin-4 as a marker for distinguishing malignant mesothelioma from lung carcinoma and serous adenocarcinoma

Our plain-English summary of Claudin-4 as a marker for distinguishing malignant mesothelioma from lung carcinoma and serous adenocarcinoma, by Y. Ohta, Y. Sasaki, M. Saito, et al (International Journal of Surgical Pathology, 2013).

The study

• Authors: Y. Ohta, Y. Sasaki, M. Saito, M. Kushima, M. Takimoto, A. Shiokawa, H. Ota
• Journal: International Journal of Surgical Pathology
• Published: 2013;21(5):493-501
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We compared claudin-4 with Ber-EP4 and carcinoembryonic antigen as markers to distinguish mesothelioma from lung adenocarcinoma, poorly differentiated lung squamous cell carcinoma, and serous adenocarcinoma of the uterus or ovary. All mesothelioma specimens were negative for claudin-4, but 3 of 18 specimens were focally positive for Ber-EP4. In contrast, lung adenocarcinoma including poorly differentiated adenocarcinoma was highly positive for claudin-4, but expression of Ber-EP4 and carcinoembryonic antigen varied widely. Claudin-4 in poorly differentiated squamous cell carcinoma had a lower positive expression rate than in adenocarcinoma. Granular claudin-4 immunoreactivity was conspicuous in poorly differentiated squamous cell carcinoma; this immunoreactive pattern was also observed in mesothelioma. Claudin-4 was thus considered very useful marker for distinguishing mesothelioma and adenocarcinoma, even if histological specimens are small, as in biopsies that contain limited numbers of tumor cells. However, it should be mentioned that claudin-4 has a limit in discrimination between squamous cell carcinoma from mesothelioma.

In plain English

This laboratory study from Japan tested whether a tissue stain for the protein claudin-4 could help tell malignant mesothelioma apart from cancers that can look similar under the microscope. It compared claudin-4 with two existing stains, Ber-EP4 and CEA. The authors examined 18 mesothelioma specimens (12 pleural, 6 peritoneal), 34 lung adenocarcinomas, 10 poorly differentiated lung squamous cell carcinomas, 15 serous adenocarcinomas of the ovary or uterus, and 8 biopsies of carcinoma in the pleura or peritoneum. Asbestos exposure was not studied. All 18 mesotheliomas were negative for claudin-4, while 3 of 18 showed small areas of Ber-EP4 staining. All 34 lung adenocarcinomas were claudin-4 positive, 32 of them in 80% to 100% of tumor cells, while Ber-EP4 and CEA staining varied widely. Serous adenocarcinomas stained similarly for claudin-4. Squamous carcinomas stained less, often with a grainy pattern that was not counted as positive. The same pattern was also seen in 14 of 18 mesotheliomas. The authors concluded that claudin-4 is a very useful marker for separating mesothelioma from adenocarcinoma but has a limit with squamous cell carcinoma.

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: Diagnostic laboratory study comparing immunohistochemical stains on tumor specimens identified from medical records
• Who was studied: 18 malignant mesothelioma specimens (12 pleural, 6 peritoneal; all epithelioid), 34 lung adenocarcinomas (6 poorly differentiated), 10 poorly differentiated lung squamous cell carcinomas, 15 serous adenocarcinomas of the ovary or uterus, and 8 biopsy specimens of carcinoma in the pleura or peritoneum (5 adenocarcinoma, 3 squamous cell carcinoma). Authors are at Showa University, Japan. Dates not given.
• Exposure: No asbestos or fiber exposure was studied. What was compared were tissue stains for claudin-4, Ber-EP4 and carcinoembryonic antigen (CEA), scored by the proportion of stained tumor cells, with 1% or more counted as positive.
• Main results:
  • Mesothelioma: all 18 specimens were negative for claudin-4 (score 0). 14 of 18 showed granular claudin-4 staining inside the cell, which was not counted as positive.
  • Mesothelioma: 3 of 18 specimens showed score 1 (1% to 25% of cells) for Ber-EP4.
  • Lung adenocarcinoma: for claudin-4, 32 of 34 specimens stained in 80% to 100% of tumor cells (score 4). The remaining 2 stained in 60% (score 3).
  • Lung adenocarcinoma: Ber-EP4 scores varied, with 16 of 34 at score 4, 8 at score 3, 7 at score 2 and 3 at score 1. CEA scores ranged from 4 to 0.
  • Poorly differentiated lung adenocarcinoma: each case showed membrane claudin-4 staining with score 4.
  • Serous adenocarcinoma: for claudin-4, 13 of 15 specimens were score 4 and 2 were score 3. All but one were negative for CEA.
  • Poorly differentiated lung squamous cell carcinoma: claudin-4 scores were lower, with 3 of 10 at score 4, 2 at score 3, 2 at score 2 and 3 at score 1.
  • Granular claudin-4 staining was seen in more tumor cells in poorly differentiated squamous cell carcinoma than in lung adenocarcinoma.
  • Pleural or peritoneal biopsies: all 5 metastatic adenocarcinomas were positive for claudin-4, Ber-EP4 and CEA. Of the 3 squamous cell carcinoma biopsies, 1 scored 2 for claudin-4 and the other 2 scored 0.
• The authors' conclusion: The authors concluded that claudin-4 is a very useful marker for distinguishing malignant mesothelioma from adenocarcinoma, including poorly differentiated adenocarcinoma. They considered that p63 or Ber-EP4 should be used to distinguish mesothelioma from poorly differentiated squamous cell carcinoma.
• Limitations the authors state:
  • The authors stated that claudin-4 has a limit in telling mesothelioma from poorly differentiated squamous cell carcinoma in small specimens. Both showed similar granular staining, and 2 of 3 squamous carcinoma biopsies had no claudin-4-positive cells.

Topics

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

Medical terms in this study, explained in our Lexicon: Claudin-4, Malignant Mesothelioma, Carcinoma, Adenocarcinoma, Ber-EP4, Carcinoembryonic Antigen (CEA), Mesothelioma, Lung Adenocarcinoma.

Related studies

• Value of PAX8, PAX2, claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas — 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)
• Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology — V.Y. Jo, E.S. Cibas, et al. (2014)
• Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum — R.L. Attanoos, R. Webb, et al. (2002)
• Is PAX2 a reliable marker in differentiating diffuse malignant mesotheliomas of peritoneum from serous carcinomas of müllerian origin? — F.F. Gao, A.M. Krasinskas, et al. (2012)
• Hepatocyte nuclear factor-1β is not a specific marker of clear cell carcinoma in serous effusions — B. Davidson (2014)

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