High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma

Our plain-English summary of High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma, by H. Ollila, J. Paajanen, H. Wolff, et al (The Journal of Pathology. Clinical Research, 2021).

The study

• Authors: H. Ollila, J. Paajanen, H. Wolff, I. Ilonen, E. Sutinen, K. Välimäki, A. Östman, S. Anttila, E. Kettunen, J. Räsänen, O. Kallioniemi, M. Myllärniemi, M.I. Mäyränpää, T. Pellinen
• Journal: The Journal of Pathology. Clinical Research
• Published: 2021;7(5):482-494
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p < 0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00-1.03 and HR = 1.05, 95% CI = 1.00-1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence-based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.

© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.

In plain English

This Finnish study examined stored tumor tissue from 74 patients with malignant pleural mesothelioma diagnosed in 2000–2012. Sixteen of them survived more than 60 months. Using multi-color fluorescent staining and computer image analysis, the authors measured seven fibroblast markers in tumor cells and in the surrounding tissue (stroma) and compared these levels with survival. Higher PDGFRB in tumor cells was linked to shorter survival (hazard ratio 1.02, p less than 0.001). It was the only marker still statistically significant after correction for multiple comparisons. After adjustment for age, sex, side of disease, stage and histology, tumor-cell PDGFRB (HR 1.01, 95% CI 1.00 to 1.03) and stromal SPARC (HR 1.05, 95% CI 1.00 to 1.11) remained associated with shorter survival. An artificial-intelligence analysis gave a similar result. In a separate group of 117 Finnish patients, high PDGFRB was linked to shorter survival before adjustment, but not after. In epithelioid cases alone it was not clearly linked (HR 2.13, 95% CI 0.84 to 5.40). Recorded asbestos exposure (52 of 74 patients) was not associated with survival. The authors concluded that PDGFRB is a negative prognostic marker, especially in epithelioid disease.

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 archived tumor tissue samples, with survival analysis (Cox regression) in a primary patient group and a separate external validation group
• Who was studied: Primary group: 74 Finnish patients with malignant pleural mesothelioma diagnosed 2000–2012 (69 epithelioid, 5 biphasic; 62 men, 12 women; median age 65), including 16 who survived more than 60 months. Validation group: 117 Finnish patients diagnosed 1990–2006 (76 epithelioid, 19 biphasic, 22 sarcomatoid)
• Exposure: The study measured tissue levels of seven fibroblast markers (PDGFRA, PDGFRB, alpha smooth muscle actin, FAP, SPARC, periostin and collagen I) in tumor cells and stroma. Asbestos exposure status was recorded from the occupational disease register and medical records: 52 of 74 patients (70%) were exposed. It was not the main focus of the study.
• Main results:
  • Primary group, unadjusted analysis: higher PDGFRB in tumor cells was associated with shorter survival (HR = 1.02, p less than 0.001, corrected p = 0.04). It was the only marker that stayed statistically significant after correction for multiple comparisons.
  • Primary group, unadjusted analysis: higher stromal FAP (HR = 1.01, p = 0.03, corrected p = 1.00) and higher stromal SPARC (HR = 1.07, p = 0.006, corrected p = 0.21) were associated with shorter survival, but neither was significant after correction.
  • Primary group, model combining all three markers and adjusted for clinical factors (n = 69): tumor-cell PDGFRB HR = 1.01 (95% CI 1.00 to 1.03; p = 0.005) and stromal SPARC HR = 1.05 (95% CI 1.00 to 1.11; p = 0.045) remained independently associated with survival.
  • Primary group, epithelioid cases only (n = 64): high tumor-cell PDGFRB was associated with increased risk of death (HR = 1.01, 95% CI 1.00 to 1.03, p = 0.006).
  • Primary group, artificial-intelligence analysis: PDGFRB-positive tumor cells were detected in 33 of 74 patients (45%). Higher PDGFRB was associated with shorter survival (HR 4.48, 95% CI 1.34 to 14.99; p = 0.015), and after adjustment the HR was 6.19 (95% CI 1.77 to 21.63; p = 0.004).
  • Validation group of 117 patients: high PDGFRB area was associated with shorter survival in unadjusted analysis (HR = 2.10, p = 0.010, corrected p = 0.041). It was not associated after adjustment for age, sex and histology (HR = 1.25, 95% CI 0.66 to 2.35; p = 0.489). In epithelioid cases only, there was no clear association (HR = 2.13, 95% CI 0.84 to 5.40; p = 0.112).
  • Primary group: none of the baseline factors examined, including asbestos exposure (median 16.6 months to death in exposed vs 22.0 months in unexposed, log-rank p = 0.149), showed an association with overall survival.
  • Primary group, epithelioid cases: high tumor-cell PDGFRB was associated with unfavorable tumor architecture (predominantly solid or micropapillary growth pattern) (p = 0.020).
• The authors' conclusion: The authors concluded that high PDGFRB in mesothelioma tumor cells is a negative prognostic marker, especially in epithelioid histology. They suggested it is a potential marker for risk stratification and a target for therapy, and that further studies are warranted.
• Limitations the authors state:
  • The patients came from a fairly genetically homogeneous single-nation population, which may limit generalizability to other countries.
  • Some patients were diagnosed nearly 20 years ago, and diagnosis and treatment have changed since.
  • Patients were a selected subgroup fit enough for biopsy or surgery. Patients diagnosed at autopsy were not included, and the primary group included a selected subgroup of long-term survivors.
  • The difference between the primary and validation results could reflect differences between the patient groups or lack of statistical power. The validation group included only one patient who survived longer than 60 months.
  • Most patients, especially in the primary group, had the epithelial subtype, so the results may not apply to other subtypes.

Topics

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

Medical terms in this study, explained in our Lexicon: Platelet-Derived Growth Factor (PDGF), Epithelioid, Mesothelioma, Pleural Mesothelioma, Fibroblast, Immunohistochemistry, Hazard Ratio, confidence interval.

Related studies

• Immunoreactivity for the beta chain of the platelet-derived growth factor receptor in malignant mesothelioma and non-neoplastic mesothelium — M. Ramael, C. Buysse, et al. (1992)
• Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts — J.C. Bonner, A.L. Goodell, et al. (1993)
• Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression — A.W. Langerak, K.A. Williamson, et al. (1995)
• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort — S. Brosseau, C. Danel, et al. (2019)
• Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity — A. Syrokou, G.N. Tzanakakis, et al. (1999)
• Glycosaminoglycans from two human malignant mesothelioma cell lines: determination, distribution, and effect of platelet-derived growth factor on their synthesis — G.N. Tzanakakis, N.K. Karamanos, et al. (1995)

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