Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta-analysis, 1982-1997

Craig S. Miller, Bryan M. Johnstone

Research output: Contribution to journalArticlepeer-review

388 Scopus citations


Objective. Human papillomavirus (HPV) infection is a significant risk factor for uterine cervical carcinoma. However, the role of HPV infection in oral squamous cell carcinoma (OSCC) is less well defined. To determine the significance of the relationship of this virus in the progressive development of oral cancer, we estimated the risk of HPV detection in normal oral mucosa, precancerous oral tissue, and oral carcinoma using meta-analysis. Study design. Case reports and clinical series published in English-language journals were retrieved by searching MEDLINE (January 1980-August 1998). Review articles were also examined to identify additional studies. Studies that used biochemical, immunologiC, microscopic, or molecular analyses to detect HPV in tissue or cells derived from normal oral mucosa (n = 25), benign leukoplakia (n = 21), intraepithelial neoplasia (ie, dysplasia and carcinoma in situ; n = 27), and oral cancer (n = 94) were included in the meta-analysis. Information on sample size, age, sex, method of tissue preservation (ie, fresh, frozen, paraffin-embedded), assay, primer amplification region (early, late), high-risk versus low-risk genotype, and use of tobacco or alcohol was abstracted by one author (C.S.M.). Results. Data from 94 reports that analyzed 4680 samples were included in the meta-analysis. Analyses made by means of a random-effects model with and without adjustments for assay sensitivity showed increased probability of HPV detection in tissue with precancerous and cancerous features compared with normal mucosa. The likelihood of detecting HPV in normal oral mucosa (10.0%; 95% confidence interval [Cl], 6.1%-14.6%) was significantly less than of detecting benign leukoplakia (22.2%; 95% Cl, 15.7%-29.9%), intraepithelial neoplasia (26.2%; 95% Cl, 19.6%-33.6%), verrucous carcinoma (29.5%; 95% Cl, 23%-36.8%), and OSCC (46.5%; 95% Cl, 37.6%-55.5%). Adjustment of findings for differences in assay sensitivity indicated that these estimates may be conservative. Overall, HPV was between 2 and 3 times more likely to be detected in precancerous oral mucosa and 4.7 times more likely to be detected in oral carcinoma than in normal mucosa. The pooled odds ratio for the subset of studies directly comparing the prevalence of HPV in normal mucosa and OSCC was 5.37, confirming the trend observed in the overall sample. The probability of detecting high-risk HPVs in OSCCs was 2.8 times greater than that of low-risk HPVs. Conclusion. This meta-analysis indicates that HPV is detected with increased frequency in oral dysplastic and carcinomatous epithelium in comparison with normal oral mucosa. The findings provide further quantitative evidence that oral infection with HPV, particularly with high-risk genotypes, is a significant independent risk factor for OSCC.

Original languageEnglish
Pages (from-to)622-635
Number of pages14
JournalOral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics
Issue number6
StatePublished - Jun 2001

ASJC Scopus subject areas

  • Surgery
  • Oral Surgery
  • Otorhinolaryngology
  • General Dentistry


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