ORIGINAL ARTICLE RISK OF THIRD AND FOURTH TUMORS IN PATIENTS WITH HEAD AND NECK CANCER Xavier Leo ´n, MD, PhD, 1 Vicenc ¸ Martı ´nez, MD, PhD, 2 Montserrat Lo ´ pez, MD, 1 Jacinto Garcı ´a, MD, 1 Miquel Quer, MD, PhD 1 1 Oto-rhino-laryngology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. E-mail: xleon@santpau.cat 2 Oto-rhino-laryngology Department, Hospital Nostra Senyora de Meritxell, Andorra Accepted 19 November 2009 Published online 4 February 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21348 Abstract: Background. The objective of our study was to analyze the incidence and location of second and subsequent tumors in patients after an index head and neck carcinoma. Methods. A retrospective study was made by reviewing clinical data prospectively collected from 3631 patients with head and neck cancer. Incidence, location, and histology of the second, third, and fourth tumors was evaluated. Results. During the follow-up, 839 second tumors, 147 third tumors, and 35 fourth tumors were diagnosed. The annual hazard ratio was 3.8% for second tumors, 5.1% for third tumors, and 7.8% for fourth tumors. The risk of second and subsequent neoplasms remained constant throughout the fol- low-up. There were significant differences in the risk of appear- ance between the second and third tumors (p < .0001), and between the third and fourth tumors (p ¼ .005). Conclusion. Patients with a second tumor after an index head and neck carcinoma have an increased risk for develop- ing subsequent tumors. V V C 2010 Wiley Periodicals, Inc. Head Neck 32: 1467–1472, 2010 Keywords: head and neck cancer; second primary neoplasm; aerodigestive tract carcinomas; subsequent neoplasms; carcinogenesis Numerous studies have demonstrated that patients with head and neck carcinoma have an increased risk of second malignant tumors, par- ticularly in the aerodigestive tract. 1–6 This risk seems to be constant throughout the follow-up period, with an incidence ranging between 2% and 4% per year. 3–6 The appearance of a second neoplasm is one of the main limiting factors in the survival of patients with head and neck carcinoma who achieve control of their index tumor. Little is known, however, about further malignant tumors after a second neoplasm in patients with head and neck carcinoma. Several authors have mentioned the possibility of third and fourth tumors, 2,6–8 but their incidence and effect on prognosis have not been approached systemati- cally to date. Such studies have likely been hampered by the need for a large series of patients with long follow-up periods. The most widely accepted explanation for the occurrence of second tumors was proposed by Slaughter et al 9 in 1953. Their theory of field cancerization assumes that long-term exposure to carcinogens, namely tobacco and alcohol, Correspondence to: X. Leo ´n V V C 2010 Wiley Periodicals, Inc. Third and Fourth Tumors in Patients with Head and Neck Cancer HEAD & NECK—DOI 10.1002/hed November 2010 1467