P63 expression in lung carcinoma: a tissue microarray study of 408 cases

p63 is a recently discovered member of the p53 family that has been shown to be important in the development of epithelial tissues. p63 may also play a role in squamous cell carcinomas of the lung, head and neck, and cervix, and its expression is increased in these tumors. The purpose of this study was to investigate the expression of p63 in a broad spectrum of histologic types of lung tumors. A total of 441 cases of primary lung tumors with follow-up data were identified, and the paraffin-embedded tissue blocks were used to construct a duplicate core tissue microarray. After review of the tissue cores, 408 cases, consisting of 123 squamous cell carcinomas, 93 adenocarcinomas, 68 large cell carcinomas, 68 classic carcinoids, 31 atypical carcinoids, 11 large cell neuroendocrine carcinomas, and 14 small cell carcinomas, were adequate for analysis. Immunohistochemistry was performed at 2 different laboratories using monoclonal antibody 4A4 to detect the expression of p63, using different staining protocols. p53 expression was also studied with immunohistochemistry using monoclonal antibody DO-7. Kaplan-Meier curves were plotted to compare the survival of p63-expressing versus nonexpressing tumors. A large proportion of squamous cell carcinomas expressed p63 (96.9%), most showing strong positive nuclear immunoreactivity. Expression in other nonsmall cell lung cancers was also present. Thirty percent of adenocarcinomas and 37% of large cell carcinomas showed p63 expression. In the neuroendocrine tumors, an increasing proportion of tumors stained for p63 as tumor grade increased; 1.9% of classic carcinoids, 30.8% of atypical carcinoids, 50% of large cell neuroendocrine carcinomas, and 76.9% of small cell carcinomas were positive. Approximately half of the positively staining neuroendocrine cases showed strong staining. Expression of p63 was of prognostic significance in neuroendocrine tumors (P < 0.0001), with higher-grade tumors more likely to express p63. Correlation between p63 and p53 expression was not observed (P = 0.18) in nonsmall cell lung cancer; however, a significant correlation between the 2 markers was found in neuroendocrine tumors (P < 0.0001). p63 staining was repeated with a different staining protocol, yielding similar results overall but a lower percentage of positive cases (34.2% vs. 48.4% of tumors positive). In conclusion, p63 expression is consistently expressed in squamous cell carcinoma in the lung, but is also expressed in a subset of adenocarcinomas and large cell carcinomas. Pulmonary neuroendocrine tumors also show p63 staining in some instances, particularly in higher-grade tumors, and the majority of small cell carcinomas are p63-positive. These results suggest that p63 may be involved in oncogenesis in a broader range of tumors than was previously thought.