Human Papillomavirus Type 18: Association With Poor Prognosis in Early Stage Cervical Cancer

• Published in: JNCI : Journal of the National Cancer Institute 1996-10, Vol.88 (19), p.1361-1368
• Main Authors: Burger, Robert A., Monk, Bradley J., Kurosaki, Tom, Anton-Culver, Hoda, Vasilev, Steven A., Berman, Michael L., Wilczynski, Sharon P.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cervical cancer; Cohort Studies; Deoxyribonucleic acid; DNA; DNA, Viral - isolation & purification; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical research; Medical sciences; Middle Aged; Neoplasm Staging; Papillomaviridae; Papillomavirus Infections - complications; Polymerase Chain Reaction; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk; Survival Analysis; Treatment Outcome; Tumor Virus Infections - complications; Tumors; Uterine Cervical Neoplasms - mortality; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Viruses
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/88.19.1361

Background: Cervical carcinoma is a leading cause of mortality from cancer among women worldwide, accounting for approximately 160 000 deaths annually. Prognosis in patients with this disease is dependent on several well-established clinical features (stage of disease and age of patient) and pathologic features (lymph node status, grade of tumor, and depth of invasion). Although the features associated with poor clinical outcome have been well studied, molecular markers such as human papillomavirus (HPV) type that may reflect the underlying biologic basis for clinical behavior are poorly understood. Purpose: To test the hypothesis that differences in survival among patients with cervical carcinoma are associated with HPV DNA type, we conducted a historical cohort study of patients treated at our institutions over a 10-year period. Methods: Fresh primary tumor tissue samples from 291 women with all stages of cervical carcinoma diagnosed from April 1983 through August 1993 were rapidly frozen and stored at −70 °C until analysis. High-molecular-weight DNA was extracted and purified by homogenization, proteinase K digestion, phenol extraction, ammonium acetate salt displacement, ethanol precipitation, and ribonuclease treatment. HPV nucleotide sequences were amplified from tumor DNA samples by polymerase chain reaction with the use of both consensus L1 (MY09/MY11) primers that recognize more than 25 HPV types and modifications of type-specific primers developed for HPV types 16, 18, and 6. Clinical data were abstracted from hospital, office, and tumor registry records. Univariate analysis was conducted using Student's t test and chi-squared tests. Survival curves were estimated by use of the Kaplan-Meier method; differences between groups were examined by the logrank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Results: HPV DNA was detected in 247 (85%) of 291 tumors: HPV16 in 52%, HPV18 in 20%, other HPV types in 13%, and no HPV DNA in 15%. Eighty-eight percent of squamous tumors contained HPV DNA compared with 79% of adenocarcinomas, the latter harboring predominantly HPV18. Women 45 years old or younger with a history of cigarette smoking tended to have HPV DNA in their tumors, but the HPV type was not associated with established prognostic factors such as stage, grade, lymph node metastasis, or depth of stromal invasion. After a median follow-up of 38.9 months, among potential prognostic factors of pat