High Stromal Carbonic Anhydrase IX Expression Is Associated With Decreased Survival in p16-Negative Head-and-Neck Tumors

• Published in: International journal of radiation oncology, biology, physics Vol. 80; no. 1; pp. 249 - 257
• Main Authors: Brockton, Nigel, Ph.D, Dort, Joseph, M.D, Lau, Harold, M.D, Hao, Desiree, M.D, Brar, Sony, M.Sc, Klimowicz, Alexander, Ph.D, Petrillo, Stephanie, M.Sc, Diaz, Roman, Ph.D, Doll, Corinne, M.D, Magliocco, Anthony, M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.05.2011; Elsevier
• Subjects: ANOXIA; Antigens, Neoplasm - metabolism; Biological and medical sciences; BIOLOGICAL MARKERS; Biomarkers - metabolism; BIOTECHNOLOGY; BODY; CARBON-OXYGEN LYASES; CARBONIC ANHYDRASE; Carbonic Anhydrase IX; Carbonic Anhydrases - metabolism; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; CARCINOMAS; Cell Hypoxia - genetics; CHEMOTHERAPY; Cyclin-Dependent Kinase Inhibitor p16; Dermatology; DISEASES; ENZYMES; Female; GENE AMPLIFICATION; GENETIC ENGINEERING; Glucose Transporter Type 1 - metabolism; HEAD; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - virology; Hematology, Oncology and Palliative Medicine; Human papilloma virus; Humans; HYDRO-LYASES; Hypoxia; Immunohistochemistry; IN-SITU HYBRIDIZATION; LYASES; Male; Medical sciences; MEDICINE; Middle Aged; NECK; Neoplasm Proteins - metabolism; NEOPLASMS; NUCLEAR MEDICINE; NUCLEIC ACID HYBRIDIZATION; ORGANIC COMPOUNDS; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Papillomavirus Infections - complications; POLYMERASE CHAIN REACTION; PROTEINS; RADIOLOGY; RADIOLOGY AND NUCLEAR MEDICINE; RADIOTHERAPY; Squamous cell carcinoma; Stroma; THERAPY; Tissue Array Analysis - methods; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Stroma; Hypoxia; Human papilloma virus; Squamous cell carcinoma; Carbonic anhydrase IX; Human; Skin disease; Oxygen; Basal cell carcinoma; Prognosis; Enzyme; Biological marker; Lyases; Malignant tumor; Head and neck; Papilloma; Carbonate dehydratase; Benign neoplasm; Predictive factor; Carbon-oxygen lyases; Cancer; Hydro-lyases; Tumor suppressor gene
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2010.11.059

Purpose 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 and Materials 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.