title: Cancer stem cell enrichment marker CD98: a prognostic factor for survival in patients with human papillomavirus-positive oropharyngeal cancer.
abstract: OBJECTIVE
  Several hypotheses have been proposed to explain the relatively good prognosis of patients with a human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and one of these is a higher sensitivity to (chemo)radiation. Previous studies have suggested that treatment failure in OPSCC patients is caused by resistance of cancer stem cells (CSCs). The purpose of this study was to evaluate the association between the number of CSCs and prognosis in HPV-positive OPSCC patients.
  
  
  METHODS
  All OPSCC patients (n=711) treated between 2000 and 2006 in two Dutch university hospitals were included. Presence of HPV in a tumour tissue specimen was tested by p16-immunostaining followed by HPV DNA GP5+/6+polymerase chain reaction (PCR). The presence and intensity of tumour CSC markers CD44 and CD98 were determined by immunohistochemistry and semiquantitative scoring was performed. Overall survival (OS) and progression-free survival (PFS) rates were compared between patients with low and high CD44/CD98 expression in relation to HPV status.
  
  
  RESULTS
  HPV-positive tumours showed a lower percentage of cells with CD44 and CD98 expression than HPV-negative tumours (p<0.001, χ(2)-test). Within the group of patients with HPV-positive OPSCC, a high percentage of CD98-positive tumour cells was associated with a significantly worse 5-year OS and PFS (OS: 36.4% and PFS: 27.3%) compared to patients with a low percentage of CD98-positive cells (OS: 71.9% and PFS: 70.5%, respectively) (p<0.001).
  
  
  CONCLUSIONS
  HPV-positive OPSCCs harbour fewer cells expressing the CSC enrichment markers CD44 and CD98. Furthermore, OS and PFS were significantly worse for patients with HPV-positive OPSCC with a high percentage of CD98-positive cells.
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Michelle M
authors: MM
authors: Rietbergen
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Sanne R
authors: SR
authors: Martens-de Kemp
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Department of Maxillofacial Surgery/Oral Pathology, VU University Medical Center/Academic Centre for Dentistry, Amsterdam, The Netherlands.
authors: Elisabeth
authors: E
authors: Bloemena
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Birgit I
authors: BI
authors: Witte
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Arjen
authors: A
authors: Brink
authors: Department of Otolaryngology/Head and Neck Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Robert J
authors: RJ
authors: Baatenburg de Jong
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: C René
authors: CR
authors: Leemans
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors: Boudewijn J M
authors: BJ
authors: Braakhuis
authors: Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: rh.brakenhoff@vumc.nl.
authors: Ruud H
authors: RH
authors: Brakenhoff
mesh_terms: D052685:Alphapapillomavirus / Q000302:isolation & purification; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000401:mortality*; D005260:Female; D027261:Fusion Regulatory Protein-1 / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000401:mortality*; D030361:Papillomavirus Infections / Q000150:complications / Q000401:mortality*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D027261:Fusion Regulatory Protein-1; D018960:Hyaluronan Receptors
keywords: CD98; Cancer stem cell; Human papillomavirus (HPV); Oropharyngeal cancer; Survival; p16