title: High stromal carbonic anhydrase IX expression is associated with decreased survival in P16-negative head-and-neck tumors.
abstract: OBJECTIVE
  Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide. Alcohol use and tobacco use are the most established risk factors; however, human papilloma virus (HPV) infection is a major risk factor for a subset of HNSCCs. Although HPV-positive tumors typically present at a more advanced stage at diagnosis, they are associated with a better prognosis. Tumor hypoxia confers poor prognosis and treatment failure, but direct tumor oxygen measurement is challenging. Endogenous markers of hypoxia (EMHs) have been proposed but have not replicated the prognostic utility of direct oxygen measurement. The expression of endogenous markers of hypoxia may be influenced by oxygen-independent factors, such as the HPV status of the tumor.
  
  
  METHODS
  Consecutive cases of locally advanced HNSCC, treated with a uniform regimen of combined radiotherapy and chemotherapy, were identified. Tissue microarrays were assembled from triplicate 0.6-mm cores of archived tumor tissue. HPV status was inferred from semiquantitative p16 immunostaining and directly measured by use of HPV-specific chromogenic in situ hybridization and polymerase chain reaction. Automated quantitative fluorescent immunohistochemistry was conducted to measure epithelial and stromal expression of carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1).
  
  
  RESULTS
  High stromal CAIX expression was associated with significantly reduced overall survival (p = 0.03) in patients with p16-negative tumors.
  
  
  CONCLUSIONS
  This is the first study to use quantitative immunohistochemistry to examine endogenous markers of hypoxia stratified by tumor p16/HPV status. Assessment of CAIX expression in p16-negative HNSCC could identify patients with the least favorable prognosis and inform therapeutic strategies.
authors.affiliation: Department of Population Health Research, Alberta Health Services-Cancer Care, Calgary, Alberta, Canada. nigel.brockton@albertahealthservices.ca
authors.forename: Nigel
authors.initials: N
authors.lastname: Brockton
authors.forename: Joseph
authors.initials: J
authors.lastname: Dort
authors.forename: Harold
authors.initials: H
authors.lastname: Lau
authors.forename: Desiree
authors.initials: D
authors.lastname: Hao
authors.forename: Sony
authors.initials: S
authors.lastname: Brar
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimowicz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Petrillo
authors.forename: Roman
authors.initials: R
authors.lastname: Diaz
authors.forename: Corinne
authors.initials: C
authors.lastname: Doll
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000821:virology; D015687:Cell Hypoxia / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000150:complications; D046888:Tissue Array Analysis / Q000379:methods
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051272:Glucose Transporter Type 1; D009363:Neoplasm Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases