MALIGNANT TRANSFORMATION OF RECURRENT RESPIRATORY PAPILLOMATOSIS ASSOCIATED WITH INTEGRATED HUMAN-PAPILLOMAVIRUS TYPE-11 DNA AND MUTATION OF P53

Recurrent respiratory papillomatosis (RRP), usually confined to the na sopharynx, trachea, and larynx, occasionally can progress to extensive bronchopulmonary disease. Most cases of bronchopulmonary and laryngea l papillomatosis are cytologically benign and do not undergo malignant transformation; however, squamous cell carcinoma (SCC) can arise in R RP in the absence of known risk factors such as radiation and smoking. In this study, the authors investigated molecular genetic alterations occurring in a case of metastasizing SCC that arose in long-standing bronchopulmonary papillomatosis. Genomic DNA from tracheal papillomata , tracheobronchial papillomata, SCC of the lung, and a lymph node meta stasis was extracted. The physical state of the human papillomavirus t ype 11 (HPV-11) DNA was investigated by two-dimensional gel electropho resis. Molecular genetic alterations of the host genome were studied b y direct sequencing of polymerase chain reaction-amplified gene fragme nts and restriction fragment length polymorphism (RFLP) analysis. Epis omal and integrated forms of HPV-11 sequences were detected in histolo gically benign tumors, but only the integrated form of the viral DNA c ould be found in malignant tissue samples. Molecular genetic studies r evealed that an allelic loss of the interferon-beta gene (IFN beta-1) and an endogenous type of mutation of the p53 antioncogene were found only in the malignant lesions. Mutations were not observed in the ras, neu, or multiple tumor suppressor (MTS1/p16) genes in any specimens. The authors' data indicated that the p53 genetic mutation was associat ed with integration of HPV-11 in histologically malignant lesions. Thi s association may promote a progressive genetic instability that can l ead to the development and clonal expansion of malignant lesions in RR P.