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Carbonic Anhydrase IX Expression, Hypoxia, and Prognosis in Patients with Uterine Cervical Carcinomas

¹ Division of Experimental Therapeutics and Departments of
² Radiation Oncology,
³ Biostatistics, and
⁴ Medical Oncology and Hematology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, and
⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Purpose: Hypoxia is associated with adverse outcome for a number of solid tumors, including cervical carcinomas. Direct pO₂ measurement requires specialized equipment and expertise that is not generally available. Immunohistochemical measurement of intrinsic tissue markers of hypoxia is an alternative approach. Recent studies suggest that carbonic anhydrase IX (CA IX), which is regulated via hypoxia-inducible factor 1, is a useful intrinsic marker of tumor hypoxia.

Experimental Design: Biopsies were obtained from 110 patients with locally advanced cervical carcinoma treated with radiotherapy or chemoradiotherapy. Tissue sections were labeled using an immunofluorescence technique and CA IX expression in the viable tumor area measured using a semiautomated fluorescence image analysis technique. Results were compared with direct pO₂ values obtained using an Eppendorf probe and to patient outcome. Intratumoral heterogeneity of CA IX expression was examined in a subgroup of patient who underwent multiple biopsies.

Results: The median percentage of tumor area staining for CA IX was 3.56 (range, 0.01–58.85). CA IX staining did not correlate with the Eppendorf pO₂ measurements. Whereas the latter values were predictive of patient outcome, the CA IX levels were not. Measurement of CA IX in multiple biopsies indicated that intratumoral heterogeneity accounted for 41% of the total variance in the data set.

Conclusions: In contrast to some recent studies, we did not find significant associations between CA IX expression and tumor pO₂ levels or patient outcome in locally advanced carcinomas of the cervix. Probable explanations relate to the problems of sampling error using single biopsies and the existence of biological factors other than hypoxia that influence CA IX levels.

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