High-Risk Human Papillomavirus-Positive Lung Cancer Molecular Evidence for a Pattern of Pulmonary Metastasis

Introduction: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital, and oropharyngeal cancers. Since a causal contribution of hrHPV infection to lung cancer (LC) is still a matter of debate, a comprehensive study was performed to delineate hrHPV involvement in LC, using a Dutch study population. Methods: Archival tissue specimens from 223 patients (145 men, 78 women, median age 65 years, range 27-87 years), who presented with cancer in the lungs, were subjected to GP5+/6+ polymerase chain reaction and p16(INK4A) immunohistochemistry. The series included primary lung carcinomas of patients without a history of cancer (n = 175), primary lung carcinomas of patients with an unrelated cancer in the past (n = 36), and carcinomas with primary presentation in the lungs of which the origin (i.e., primary or metastasis) was equivocal at the time of diagnosis (n = 12). GP5+/6+ polymerase chain reaction/p16(INK4A) double-positive carcinomas were subjected to HPV genotyping, HPVE7 transcript analysis, loss of heterozygosity analysis, and array-comparative genomic hybridization. Results: Whereas all primary lung carcinomas were hrHPV-negative (211 of 211, 100%), three hrHPV-positive equivocal carcinomas (3 of 12, 25%) were identified. These patients (1 male, 2 females) had a history of hrHPV-associated disease; one tonsillar and two cervical carcinomas. A clonal relationship between individual tumor pairs was supported by identical hrHPV genotype, pattern of p16(INK4A) expression, HPVE7 mRNA expression, and genomic aberrations. Conclusions: hrHPV presence in a tumor with primary presentation in the lungs signifies pulmonary metastasis from a primary hrHPV-positive cancer elsewhere in the body. No support was found for an attribution of hrHPV infection to the development of primary LC.