Carbonic anhydrase IX expression, hypoxia, and prognosis in patients with uterine cervical carcinomas.
OBJECTIVE
Hypoxia is associated with adverse outcome for a number of solid tumors, including cervical carcinomas. Direct pO(2) 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.


METHODS
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 pO(2) 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 pO(2) 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 pO(2) 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.
Hedley
David
D
Division of Experimental Therapeutics and Department of Radiation Oncology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada. david.hedley@ubn.on.ca
Pintilie
Melania
M
Woo
Jennifer
J
Morrison
Andrew
A
Birle
Diana
D
Fyles
Anthony
A
Milosevic
Michael
M
Hill
Richard
R
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases