Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma

Second primary carcinoma is a peculiar feature of head and neck cancer and represents a form of treatment failure distinct from the recurrence of the primary tumor. Whether altered p53 expression in tumor-distant epithelia at the time of diagnosis is of clinical value as a biomarker for second prima ry carcinoma development has not been rigorously answered because of the la ck of long-term follow-up studies involving a sufficiently large patient co hort. In this prospective study, we have investigated p53 expression in tum or-distant epithelia and in the corresponding primary tumors of 105 head an d neck cancer patients by immunohistochemistry on frozen sections. After a median follow-up of 55 months, the clinical course of disease parameters, i .e., local recurrences, lymph node and distant metastasis, incidence of sec ond primary carcinoma, and survival, was evaluated. Overexpression of p53 i n tumor-distant epithelia was found in 49 patients (46.7%), and it was inde pendent of the p53 protein status of the primary tumor and of the tumor sit e, size, stage, and grading. Mucosal p53 overexpression was not associated with local primary recurrences, lymph node or distant metastases, or overal l survival. Importantly, mucosal p53 overexpression, but not overexpression in the primary tumors, was significantly associated with an increased inci dence of second primary carcinomas (P = 0.0001; Fisher's exact test), When the times to second primary tumor occurrence were analyzed by the Kaplan-Me ier method, the difference remained significant (P = 0.005; log rank test). We conclude that IHC staining for p53 overexpression in tumor-distant epit helia provides a simple and rapid tool to identify head and neck cancer pat ients at increased risk of developing second primary tumors. Because p53 ov erexpression in these epithelia in our patient cohort was specifically asso ciated with second primary cancer but not with recurrences, at least a frac tion of the second primary cancers appears to have resulted from genetic ev ents in the mucosa ("field cancerization").