High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma

Our plain-English summary of High mesothelin expression by immunohistochemistry predicts improved survival in pleural mesothelioma, by G.J. Chu, A. Linton, S. Kao, et al (Histopathology, 2023).

The study

• Authors: G.J. Chu, A. Linton, S. Kao, S. Klebe, S. Adelstein, D. Yeo, J.E.J. Rasko, W.A. Cooper
• Journal: Histopathology
• Published: 2023;83(2):202-210
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aims: Mesothelin (MSLN) is a cancer-associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody-drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti-mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical-score (H-score).

Methods And Results: The MN1 anti-MSLN antibody was used to stain a formalin-fixed paraffin-embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H-score were evaluated. The correlation of H-score with prognosis was investigated. Sixty-six per cent of epithelioid tumours were MSLN-positive (with expression in > 5% tumour cells). Of MSLN-expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H-score as a continuous variable and an H-score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively).

Conclusions: MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin-targeted personalised therapies, such as chimeric antigen receptor T cells.

© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.

In plain English

This Australian laboratory study examined mesothelin in pleural mesothelioma. Mesothelin is a protein targeted by experimental treatments. The authors stained stored tumour samples from 75 consecutive patients who had pleurectomy with or without decortication in Sydney between 1992 and 2007. 67 could be analysed. The article does not report on asbestos exposure. With a cut-off of staining in at least 5% of tumour cells, 23 of 35 epithelioid tumours (66%) were positive, versus nine of 32 non-epithelioid tumours (28%). All 10 sarcomatoid tumours were negative. Among epithelioid tumours, those with an H-score (combining staining intensity and extent) of 33 or more had a median survival of 21.5 months (95% CI 17 to 40), versus 7 months (95% CI 5 to 15) for lower scores. After adjustment for age, sex and tumour type, an H-score of 33 or more was linked to longer survival (hazard ratio 0.25, 95% CI 0.117 to 0.516). Positivity alone was not statistically significant. The authors concluded that staining should be used in future clinical trials to select patients for mesothelin-targeted therapies. They recommended confirming the findings in a prospective trial.

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 study of stored tumour tissue from a past series of consecutive patients: immunohistochemistry on a tissue microarray, with survival analysis (Kaplan–Meier and Cox multivariate analysis)
• Who was studied: 75 consecutive patients with pleural mesothelioma who had pleurectomy with or without decortication at Royal Prince Alfred Hospital, Sydney, Australia, between 1992 and 2007. 67 were analysable: 35 epithelioid, 22 biphasic, 10 sarcomatoid.
• Exposure: Not asbestos. The factor studied was mesothelin (MSLN) protein in tumour tissue, measured with the MN1 anti-mesothelin antibody and scored by staining intensity (0 to 3+), percentage of positive tumour cells, and H-score (out of 300). No asbestos exposure or fiber type data are reported.
• Main results:
  • Of the 75 patient specimens, eight could not be analysed for technical reasons, leaving 67 patients.
  • Using a threshold of staining in at least 5% of tumour cells, 32 of 67 samples (48%) were MSLN-positive. This included 23 of 35 epithelioid tumours (66%) versus nine of 32 non-epithelioid tumours (28%) (P = 0.003). All 10 sarcomatoid tumours were negative.
  • Among MSLN-staining epithelioid tissues, 70.4% showed moderate or strong intensity, but only 37% had expression in at least 50% of tumour cells.
  • In epithelioid tumours, the MSLN-high group (H-score 33 or more) had a median survival of 21.5 months (95% CI 17 to 40 months). The MSLN-low group had a median survival of 7 months (95% CI 5 to 15 months) (log-rank P less than 0.001).
  • In epithelioid tumours, median survival was 20.5 months (95% CI 17 to 33 months) with 2+/3+ staining intensity, versus 8 months (95% CI 5 to 15 months) with 0 or 1+ intensity (P = 0.007).
  • In non-epithelioid tumours, no survival difference was found between tumours with no MSLN expression and MSLN-expressing tumours.
  • In the whole cohort, adjusted for age, sex and histology, MSLN positivity (at least 5% of tumour) was associated with a reduced hazard ratio, but this was not statistically significant (HR = 0.587, 95% CI 0.3025 to 1.139, P = 0.114).
  • In the same adjusted analysis, H-score as a continuous variable (HR = 0.994, 95% CI 0.989 to 0.999, P = 0.040) and an H-score of 33 or more (HR = 0.25, 95% CI 0.117 to 0.516, P less than 0.001) were independent markers of longer survival.
  • In the adjusted analysis, staining intensity of 2+ or 3+ was associated with a reduced hazard ratio (HR = 0.384, 95% CI 0.202 to 0.719, P = 0.003).
• The authors' conclusion: The authors concluded that MSLN expression in this cohort was lower and more uneven than reported elsewhere. They wrote that uneven expression and antigen-escape could be obstacles to anti-MSLN therapy, and advised that immunohistochemistry be used to stratify and select eligible patients for anti-MSLN therapies in future clinical trials.
• Limitations the authors state:
  • The authors recommended that the results be validated in a prospective trial and that the reliability of H-score testing be assessed.
  • No comprehensive disease-staging data were available, so survival and MSLN expression could not be analysed by disease stage.
  • More cases are needed to judge whether MSLN expression matters for survival in non-epithelioid subtypes.
  • The cohort had lower overall survival than recent publications. The samples pre-dated current standard chemotherapy, and the small numbers receiving palliative treatment did not allow a subgroup analysis.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Immunohistochemistry, Pleural Mesothelioma, Mesothelioma, Ovarian Cancer, Prognosis, Epithelioid, Multivariate Analysis.

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• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland — D. Vizcaya, B. Farahmand, et al. (2020)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)
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