title: High levels of phosphatase and tensin homolog expression are associated with tumor progression, tumor recurrence, and systemic metastases in pT1 urothelial carcinoma of the bladder: a tissue microarray study of 156 patients treated by transurethral resection.
abstract: OBJECTIVE
  To evaluate immunohistochemical expression of phosphatase and tensin homolog (PTEN) and mammalian target of rapamycin (mTOR) pathway members in pT1 urothelial carcinomas treated by transurethral resection and to determine if immunohistochemistry can be used to predict prognosis.
  
  
  METHODS
  Formalin-fixed, paraffin-embedded tissue samples from 156 patients with pT1 urothelial carcinoma treated by transurethral resection were used to build 5 tissue microarrays. Tissue microarray sections were stained for PTEN, phosphorylated (phos)-AKT, phos-mTOR, phos-S6, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), and phos-4EBP1. Patients were monitored after initial treatment (mean, 22.5; median, 16; range, 3-108 months) to detect tumor recurrence, tumor progression, or systemic metastases.
  
  
  RESULTS
  During follow-up, 101 patients (65%) showed tumor recurrence, 57 showed tumor progression (37%), and 18 showed systemic metastases (12%). Patients with ≥2 lesions at the initial workup had higher proportions and higher hazard ratios of tumor recurrence, tumor progression, and systemic metastases. Complete loss of PTEN expression was observed in 6 patients (4%), and >80% of the mTOR pathway members showed at least focal positivity. Proportions of tumors with higher levels of PTEN immunohistochemical expression were higher in patients with tumor recurrence (P=.001), tumor progression (P=.05), and systemic metastases (P=.001). Proportions of tumors with lower phos-S6 and low phos-4EBP1 levels were higher in patients with tumor recurrence (P≤.05). Proportions were similar for the remaining biomarkers.
  
  
  CONCLUSIONS
  Higher levels of PTEN immunohistochemical expression were associated with higher rates of tumor recurrence, tumor progression, and systemic metastases in patients with pT1 urothelial carcinomas treated by transurethral resection.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
authors.forename: Alcides
authors.initials: A
authors.lastname: Chaux
authors.forename: Eva
authors.initials: E
authors.lastname: Compérat
authors.forename: Justine
authors.initials: J
authors.lastname: Varinot
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Kristen
authors.initials: K
authors.lastname: Lecksell
authors.forename: Jason
authors.initials: J
authors.lastname: Solus
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000201:enzymology* / Q000556:secondary* / Q000601:surgery; D018797:Cell Cycle Proteins; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000601:surgery; D019459:Urothelium / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase