title: Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis.
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.
  
  
  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.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Svenja
authors.initials: S
authors.lastname: Thies
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Friess
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Frischknecht
authors.affiliation: Cancer Registry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Korol
authors.affiliation: Clinic of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Felley-Bosco
authors.affiliation: Clinic of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahel
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Bart
authors.initials: B
authors.lastname: Vrugt
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D064231:Nestin / Q000378:metabolism*; D000068437:Pemetrexed / Q000627:therapeutic use; D010984:Platinum / Q000627:therapeutic use; D010997:Pleural Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D011013:Pneumonectomy / Q000379:methods; D011379:Prognosis; D012509:Sarcoma / Q000175:diagnosis* / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C577484:NES protein, human; D064231:Nestin; C512835:POSTN protein, human; D019089:Stem Cell Factor; D000068437:Pemetrexed; D003841:Deoxycytidine; D010984:Platinum; D000093542:Gemcitabine