Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma

Our plain-English summary of Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma, by A. Schramm, I. Opitz, S. Thies, et al (European Journal of Cardio-thoracic Surgery, 2010).

The study

• Authors: A. Schramm, I. Opitz, S. Thies, B. Seifert, H. Moch, W. Weder, A. Soltermann
• Journal: European Journal of Cardio-thoracic Surgery
• Published: 2010;37(3):566-72
• Cited by: 74 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Epithelial-to-mesenchymal transition (EMT) is a morphologic transdifferentiation of carcinomas, conferring increased tumour invasiveness, but may also be applied to the epithelioid versus sarcomatoid histotype of malignant pleural mesothelioma (MPM). Herein, we correlated proteins of a putative MPM-EMT axis, including periostin, epidermal growth factor receptor (EGFR), integrin beta1, phosphatase and tensin homologue (PTEN), integrin-linked kinase (ILK), p21 and p27, with clinico-pathologic parameters, in particular overall survival (OS).

Patients And Methods: A retrospective cohort of 352 mostly untreated patients with MPM was investigated by immunohistochemistry of a tissue microarray. Protein expression intensities were semi-quantitatively scored from 0 to 3 in their respective compartments, including peritumoural stroma as well as tumour cell plasma membrane, cytoplasm or nucleus. Data were correlated with histotype and survival outcome.

Results: A total of 32% of the tumours were diagnosed as epithelioid, 13% as sarcomatoid and 55% as biphasic histotype. High expression of membranous EGFR and integrin beta1 as well as nuclear p27 correlated with the epithelioid and high expression of cytoplasmic tumoural and stromal periostin with the sarcomatoid histotype. The median survival time of the 128 patients with complete follow-up data was 11.7 months. Univariate survival analysis revealed age, epithelioid histotype and any therapy as prognosticators for better OS. High expression of cytoplasmic PTEN or ILK as well as high expression of nuclear p21 or p27 correlated with increased, whereas high expression of cytoplasmic periostin with decreased OS (all p values <0.05). Multivariate Cox regression revealed any treatment, low cytoplasmic periostin and high cytoplasmic PTEN as independent prognosticators for better OS.

Conclusion: Activation of periostin-triggered EMT is associated with the sarcomatoid histotype and has an impact on shorter survival of MPM patients. Finally, only the high expression of PTEN and the low expression of cytosolic periostin could be shown to be independent prognostic factors for longer OS.

Copyright (c) 2009. Published by Elsevier B.V.

In plain English

This retrospective study from Zürich, Switzerland, examined tumour tissue from 352 patients with malignant pleural mesothelioma diagnosed between 1975 and 2004. Most patients were untreated; 77% of samples came from autopsies. The tissue had been sent to a pneumoconiosis research group to assess dust exposure, especially asbestos. The authors measured seven proteins linked to epithelial-mesenchymal transition, in which tumour cells lose adhesion and become more mobile. They compared the results with tumour type and survival. Asbestos exposure was known for 97 of the 206 patients with clinical data; no protein was associated with asbestos exposure. Median survival of 128 patients with complete follow-up was 11.7 months (95% confidence interval 10.0 to 13.6). High periostin in surrounding tissue and tumour cells was associated with the sarcomatoid type, and high periostin inside tumour cells with shorter survival. In combined analysis, treatment, low cytoplasmic periostin and high cytoplasmic PTEN remained independent predictors of better survival. The authors concluded these two proteins were independent factors for longer survival. They noted that retrospective clinical data limited analysis of tumour stage and therapy.

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 cohort study using immunohistochemistry (protein staining) on tissue microarrays
• Who was studied: 352 patients with malignant pleural mesothelioma diagnosed between 1975 and 2004, whose tissue was sent to the Zürich Pneumoconiosis research group: 114 epithelioid, 192 biphasic and 46 sarcomatoid. 77% of specimens came from autopsy. Clinical data were available for 206 patients (59%), who were mainly male (94%), with a median age of 62 years. 128 patients had complete follow-up data.
• Exposure: The study examined tumour protein expression (periostin, EGFR, integrin beta-1, PTEN, ILK, p21 and p27), not asbestos dose. Asbestos exposure was known for 97 of the 206 patients with clinical data (47%). Fiber types were not reported.
• Main results:
  • No association was found between expression of any of the markers and asbestos exposure in this retrospectively collected data.
  • Median overall survival of the 128 patients with complete follow-up data was 11.7 months (95% confidence interval 10.0 to 13.6).
  • High stromal and cytoplasmic periostin were associated with the sarcomatoid type. High membranous EGFR, high membranous integrin beta-1 and high nuclear p27 were associated with the epithelioid type.
  • In univariate analysis of the 128 patients, age, histotype and therapy were survival predictors. High cytoplasmic (tumour-cell) periostin was associated with shorter survival. Stromal periostin was not significantly associated with survival in Table 1 (p = 0.171). High cytoplasmic PTEN and ILK and high nuclear p21 and p27 were associated with better survival. EGFR at the tumour cell membrane had no significant survival impact.
  • In multivariate Cox analysis, three factors were retained as independent predictors of better overall survival: treatment (hazard ratio 0.644; 95% CI 0.433 to 0.957; p = 0.029), low cytoplasmic periostin (reported hazard ratio 1.824; 95% CI 1.249 to 2.665; p = 0.002) and high cytoplasmic PTEN (hazard ratio 0.560; 95% CI 0.367 to 0.854; p = 0.007).
• The authors' conclusion: The authors concluded that low cytoplasmic periostin and high cytoplasmic PTEN in tumour cells were independent factors for better overall survival. They suggested that patients with high cytoplasmic periostin combined with decreased cytoplasmic PTEN may be a high-risk group for poor prognosis.
• Limitations the authors state:
  • The clinical data were retrospective, so correlation of marker expression with tumour stage and therapy was limited.
  • Tumour stage was not documentable in most cases. Retrospective staging was performed for 102 patients.
  • There was no standardised therapy during the study period.
  • Staining for Akt was not reproducible and was omitted from the 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: Pleural Mesothelioma, Carcinoma, Epithelioid, Sarcomatoid, EGFR, Overall Survival, Immunohistochemistry, Biphasic Mesothelioma.

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