Molecular Events in the Progression of Recurrent Respiratory Papillomatosis to Carcinoma

Abstract

Abstract Context.—Identification of the type of human papillomavirus (HPV) by polymerase chain reaction and sequencing to determine coinfection or superinfection (by more than 1 HPV type) and other molecular events have not been reported in a series of patients exhibiting the morphologic spectrum of recurrent respiratory papillomatosis progressing to carcinoma. Design.—Four cases of juvenile-onset recurrent respiratory papillomatosis progressing to carcinoma (no history of smoking or irradiation in 2 cases) were studied. Morphologically distinct foci (squamous papilloma, pulmonary papillomatosis, squamous dysplasia subjacent to carcinoma, and squamous carcinoma) were subjected to laser capture microdissection and polymerase chain reaction amplification using general primers in addition to type-specific primers for HPV types 16 and 18. Direct sequencing of polymerase chain reaction products identified the type of HPV. The tissue sections were immunostained using antibodies to p53, pRb, p21WAF1, and p16 proteins with a semiquantitative assessment. Results.—Human papillomavirus 11 was the only type of HPV identified in all lesions of all cases associated with recurrent respiratory papillomatosis. There was a marked increase in p53 protein expression in foci of dysplasia and carcinoma as compared to squamous papilloma and pulmonary papillomatosis. An inverse correlation between p53 and p21WAF1 protein expression was noted in all lesions. pRb protein expression increased from the benign to the malignant end of the spectrum. p16 protein was expressed in all lesions. Conclusions.—Infection by HPV-11 may be an early event associated with progression of recurrent respiratory papillomatosis to carcinoma. Increased expression of p53 and pRb proteins and a reduced expression of p21WAF1 protein appear to be significant subsequent events.