Reduced expression of CD44v3 variant isoform is associated with unfavorable outcome in non–small cell lung carcinoma☆

Abstract The expression of CD44 standard form (CD44s) and variant isoforms v3 and v6 was analyzed in 233 resected non–small cell lung carcinoma (NSCLC) specimens by immunohistochemistry (IHC), and the mRNA status of CD44v3 and CD44v6 in a cohort of samples was determined by in situ hybridization (ISH) and further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of CD44s, CD44v3, and CD44v6 was correlated with clinicopathologic variables and survival. The expression of CD44v3 and v6 was reduced in 97% and 90% of the adenocarcinomas and in 86% and 74% of the large cell/anaplastic carcinomas, respectively, as compared with squamous cell carcinomas, where they were reduced in 53% and 51% of the cases ( P = .0001 and P = .004 for v3 and v6). The corresponding values for CD44s were 92%, 70%, and 51%, respectively ( P = .011). The reduced CD44s and CD44v6 expression was associated with lymph node metastases ( P = .03 and P = .005, respectively) and the reduced expression of CD44s also with advanced stage ( P = .04). Recurrences during the follow-up were more often found within the tumors showing reduced expression of CD44v3 ( P = .04). Combining ISH and IHC results showed that CD44v3 and v6 mRNA were not always processed into protein, suggesting a regulation disturbance posttranscriptionally since malignant transformation of cells has occurred. In survival analyses, the reduced expression of CD44s and CD44v3 was associated with a shortened disease-free survival ( P = .04 and P = .01, respectively). In multivariate analysis, CD44v3 retained its independent prognostic value ( P = .03). These results emphasize the value of CD44, and especially the v3 variant isoform in the behavior of NSCLC. H UM P ATHOL 31:1088-1095.