IP typically occurs within a peak age range of 50 to 70 years, although it has been found in children as young as 8 years old.7 It has a male preponderance, as shown in one large series, in which 83% of patients were men. IP is typically unilateral, but it may be bilateral in less than 10% of cases.8 The etiology of IP is unknown; nonetheless, both human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been demonstrated in IP specimens.9'10 Squamous cell carcinoma occurs in association with IP in less than 2 to 56% of cases, although no study with more than 50 cases had a greater than 30% incidence of carcinoma, and most had less than 15%.8,11-17

Malignancy is often associated with aggressive growth, including intracranial, orbital, or mastoid invasion.18-20 Moreover, Cummings and Goodman4 noted a few cases in which transitional cell carcinomas were reclassified as IP. Clearly, the marked atypia found in aggressive IP can be misleading with regard to the true incidence of carcinoma, with a falsely higher incidence reported in the cases. In addition, most institutions that report these cases are tertiary care referral centers; thus, unusual cases are selected out, whereas less aggressive cases may never get into the literature.21 Lastly, histologic detection of a synchronous cancer during IP excision was reported at 4 to 11% in directed studies.16,22 It may be even less common to find metachronous carcinoma.21 Nonetheless, long-term follow-up in one study demonstrated a 16% (8/51) incidence, with cancer detected as late as 13 years after the diagnosis of IP.16 Myers et al.23 demonstrated a gradation in atypia from papilloma to malignancy in 4 of 6 synchronous carcinomas. This observation would support the theory that IP can undergo malignant transformation.23 Several molecular genetics studies have shown a convincing association between tumor pathogenesis and either HPV or p53 tumor suppressor gene interaction, or both.24-27

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