Dual Effect of Carbonic Anhydrase (CA) Isoforms IX and XII on Non Small Cell Lung Carcinoma (NSCLC) Progression. A Clinico-Pathological Study from 555 Patients from a Single Institution (CHU of Nice, France)
MI Ilie, V Hofman, N Mazure, C Butori, S Lassalle, C Bonnetaud, J Mouroux, N Venissac, J Pouyssegur, P Hofman. CHU de Nice, Nice, France; University of Nice, Nice, France
Background: Adaptation of tumor cells to hypoxia is a critical driving force in tumor progression and metastasis. The expression of the membrane associated CAIX and CAXII is tightly controlled by oxygen levels in multiple epithelial tumor types, including lung cancer. Whereas tumor expression of CAIX in many tissues correlates with poor patient survival, the significance of CAXII has been poorly investigated.
Design: TMA-immunohistochemistry analysis was used to study CAIX and CAXII expression in 555 NSCLC, including 281 adenocarcinomas (AC), 184 squamous cell carcinomas (SCC), 43 large cell carcinomas (LCC), and 47 other tumor subtypes (NOS). Membrane immunoreactivity of each protein was assessed with a semi-automated tissue arrays image-analysis workstation (Spot Browser V7, Alphelys) in all tissue cores. An ELISA assay (R&D Systems) was performed to measure CAIX serum level in 208 of these patients and in 57 healthy individuals. Results were compared with clinicopathologic variables and clinical outcome.Statistical correlations were made with R software Windows version 2.8.1.
Results: CAIX overexpression was noted in 133/555 (24%) cases and correlated with tumor type [37% SCC vs 36% LCC vs 32% NOS vs 13% AC, p= 0.016] and shortened overall survival (p=0.022). The mean serum CAIX level in NSCLC patients was higher (45.4±4.81 pg/ml) than in healthy individuals (2.47±0.63 pg/ml). High CAIX serum level was related to tumor size (p=0.048), high rate of local recurrence (p=0.03), poor overall (p=0.017) and disease-free survival (p=0.047). CAXII overexpression was observed in 104/555 (18%) cases and correlated with tumor type [34% SCC vs 13% NOS vs 11% LCC vs 11% AC, p<0.001], pTNM staging [30% II stage vs 16% I stage vs 16% III stage vs 14% IV stage, p=0.011], and longer disease-free survival (p=0.0001). On multivariate analysis, CAIX and CAXII expression independently predicted patient survival.
Conclusions: These data indicate that CAIX is a strong predictor of recurrence, progression and poor overall survival of patients with NSCLC. Conversely, overexpression of CAXII is a favorable prognostic factor in NSCLC. Altogether, these results call for the development of new specific anti-CA drugs, taking into consideration the CA isoform profile of a given tumor subtype.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 233, Monday Morning