Immunohistochemically, p63 (a member of the p53 family) has been used as a highly sensitive marker of squamous cell differentiation. However, it lacks specificity and is frequently positive in large cell neuroendocrine carcinomas and small cell carcinomas of lung as well as in large cell lymphomas. The problem of lack of specificity of p63 has been resolved by the use of p40, an antibody that recognizes a p63 isoform. It is equivalent to p63 in sensitivity for squamous cell carcinoma but has much higher specificity. It is rarely positive in large cell neuroendocrine carcinomas or large cell lymphomas. The image shows p40 immunoreactivity in the nuclei of squamous cell carcinoma of lung. Image courtesy of: Jian-Hua Qiao, MD, FCAP, Los Angeles, CA.