Malignant Transformation of Recurrent Respiratory Papillomatosis Associated With Integrated Human Papillomavirus Type 11 DNA and Mutation of p53

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Abstract
Recurrent respiratory papillomatosis (RRP), usually confined to the nasopharynx, trachea, and larynx, occasionally can progress to extensive bronchopulmonary disease. Most cases of bronchopulmonary and laryngeal papillomatosis are cytologically benign and do not undergo malignant transformation; however, squamous cell carcinoma (SCC) can arise in RRP 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 metastasis was extracted. The physical state of the human papillomavirus type 11 (HPV‐11) DNA was investigated by two‐dimensional gel electrophoresis. Molecular genetic alterations of the host genome were studied by direct sequencing of polymerase chain reaction‐amplified gene fragments and restriction fragment length polymorphism (RFLP) analysis. Episomal and integrated forms of HPV‐11 sequences were detected in histologically benign tumors, but only the integrated form of the viral DNA could be found in malignant tissue samples. Molecular genetic studies revealed that an allelic loss of the interferon‐β gene (IFNβ‐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 associated with integration of HPV‐11 in histologically malignant lesions. This association may promote a progressive genetic instability that can lead to the development and clonal expansion of malignant lesions in RRP.