Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis

Our plain-English summary of Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis, by S. Thies, M. Friess, L. Frischknecht, et al (PloS One, 2015).

The study

• Authors: S. Thies, M. Friess, L. Frischknecht, D. Korol, E. Felley-Bosco, R. Stahel, B. Vrugt, W. Weder, I. Opitz, A. Soltermann
• Journal: PloS One
• Published: 2015;10(9):e0139312
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial-mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo-adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients.

Patients And Methods: Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naïve biopsies and -treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem).

Results: Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naïve biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naïve biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non-epithelioid histology was particularly/ dismal (all p-values <0.05).

Conclusions: The SC marker nestin and the EMT marker periostin allow for further prognostic stratification among histologic variants of MPM. Their expression level is influenced by neo-adjuvant chemotherapy.

In plain English

This Swiss laboratory study examined tumor tissue from 465 patients with malignant pleural mesothelioma. It asked whether the proteins nestin and periostin were linked to tumor type, chemotherapy and survival. Cohort 1 had 320 patients (1975 to 2004), mostly autopsy cases; cohort 2 had 145 patients (1999 to 2009) referred to University Hospital Zurich for chemotherapy and planned surgery. The study did not analyze asbestos exposure. In cohort 1, nestin rose from epithelioid to biphasic to sarcomatoid tumors. In pre-chemotherapy biopsies, median survival from diagnosis was 17 months (95% CI 9 to 24) for 33 nestin-positive patients and 22 months (17 to 27) for 64 nestin-negative patients. In surgical specimens taken after chemotherapy, median survival from surgery was 12 months (2 to 21) for 47 nestin-positive and 18 months (14 to 22) for 67 nestin-negative patients. After adjusting for tumor type, nestin remained linked to shorter survival in pre-chemotherapy biopsies but not post-chemotherapy specimens. Platinum/pemetrexed was linked to higher nestin than platinum/gemcitabine; periostin showed the opposite. The authors concluded that nestin is a prognosticator for survival. They noted few sarcomatoid tumors in cohort 2.

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 laboratory (immunohistochemistry) study of tumor tissue from two patient cohorts, analyzed on tissue microarrays and related to survival
• Who was studied: 465 malignant pleural mesothelioma patients in Zurich, Switzerland. Cohort 1: 320 patients, 1975 to 2004, whose tissue was sent to the Zurich Pneumoconiosis Research Group; mostly autopsy cases. Cohort 2: 145 patients, 1999 to 2009, referred to University Hospital Zurich for intended induction chemotherapy followed by extrapleural pneumonectomy. Paired before and after chemotherapy samples were available for 105 of 145.
• Exposure: No asbestos fiber or exposure data were analyzed. The study measured nestin and periostin protein in tumor tissue. It compared two neo-adjuvant chemotherapy regimens in cohort 2: platinum/gemcitabine (59 patients) and platinum/pemetrexed (85 patients).
• Main results:
  • Any nestin expression was found in 38 to 41% of mesotheliomas in both cohorts.
  • In cohort 1, nestin increased progressively from epithelioid (median 0, IQR 0 to 0) to biphasic (median 0, IQR 0 to 100) to sarcomatoid tumors (median 50, IQR 0 to 200), with all transitions significant. Calretinin and podoplanin showed the opposite pattern.
  • In cohort 2, periostin but not nestin rose significantly after neo-adjuvant chemotherapy (periostin median H-score 20 before vs 75 after, p 0.002).
  • Comparing regimens in cohort 2, periostin was higher after platinum/gemcitabine than platinum/pemetrexed (median 110 vs 33, p 0.027). Nestin was lower after platinum/gemcitabine (median 0 vs 3, p 0.024).
  • In pre-chemotherapy biopsies of cohort 2, median overall survival counted from diagnosis was 22 months (95% CI 17 to 27) with no nestin expression (n=64) vs 17 months (9 to 24) with nestin expression (n=33), p 0.017. In post-chemotherapy surgical specimens, survival counted from surgery was 18 months (14 to 22, n=67) vs 12 months (2 to 21, n=47), p 0.038. The two sets of times start at different points, so they are not directly comparable.
  • In pre-chemotherapy biopsies, high periostin (H-score above 20) was associated with shorter median survival (15 months, n=51) than low periostin (23 months, n=62), p 0.043. In post-chemotherapy specimens the periostin difference was not significant.
  • In pre-chemotherapy biopsies, patients with epithelioid tumors and no nestin had the longest median survival (24 months). Patients with non-epithelioid tumors and nestin expression had the shortest (10 months), p 0.002.
  • Patients with non-epithelioid tumors and high periostin in pre-chemotherapy samples had a median survival of 11 months, vs 22 to 25 months in the other three groups.
  • In the multivariate analysis of pre-chemotherapy biopsies (n=97), nestin expression was an independent predictor of survival (hazard ratio 1.6, 95% CI 1.0 to 2.5, p 0.035), alongside tumor type. In post-chemotherapy surgical specimens (n=114), only tumor type remained independent; for nestin the hazard ratio was 1.5 (1.0 to 2.2), not significant.
  • No significant association was found between response to induction chemotherapy and nestin or periostin levels before or after chemotherapy.
• The authors' conclusion: The authors concluded that nestin is a prognosticator for overall survival in malignant pleural mesothelioma patients and may allow further stratification together with the histologic variant.
• Limitations the authors state:
  • The statistics for cohort 2 were restricted by the low number of sarcomatoid tumors (4 each in the two chemotherapy groups).
  • Cohort 1 consisted mostly of autopsy cases with only limited clinical data.
  • Because mesothelioma is multifocal, linking marker levels to chemotherapy response would likely require precise mapping between imaging and tissue sections.

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: STEM, Pleural Mesothelioma, Prognosis, Epithelioid, Sarcomatoid, Biphasic Mesothelioma, Histology, Chemotherapy.

Related studies

• Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma — M. Meerang, K. Bérard, et al. (2016)
• PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy — B.K. Bitanihirwe, M. Meerang, et al. (2014)
• Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery — L. Frischknecht, M. Meerang, et al. (2015)
• Snail expression is associated with a poor prognosis in malignant pleural mesotheliomas — M. Kobayashi, C.L. Huang, et al. (2013)
• CD26-mediated regulation of periostin expression contributes to migration and invasion of malignant pleural mesothelioma cells — E. Komiya, K. Ohnuma, et al. (2014)
• Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival — K. Brenne, D.A. Nymoen, et al. (2012)

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