A Retrospective 20-Year Analysis of Proliferative Verrucous Leukoplakia and Its Progression to Malignancy and Association with High-risk Human Papillomavirus

  • Jasbir D. Upadhyaya
  • Sarah G. Fitzpatrick
  • Mohammed N. Islam
  • Indraneel Bhattacharyya
  • Donald M. Cohen
Original Paper


Proliferative verrucous leukoplakia (PVL) is defined as an aggressive, relentless and recalcitrant form of leukoplakia that has a high propensity for malignant transformation. The aim of this study was to evaluate the malignant potential of PVL and determine its possible association with high-risk human papillomavirus (HPV). Twenty cases with a clinical and biopsy proven diagnosis of PVL were collected from the University of Florida Oral Medicine clinic database. Immunohistochemistry was performed to evaluate the expression of p16INK4A and p53 genes in the PVL lesions. The lesions were also tested for high-risk HPV by DNA in-situ hybridization. The average age of the patients at the time of first biopsy was 62.7 years. Most patients had multiple sites of involvement, gingiva being the most common location. The lesions progressed to malignancy in approximately 50% of patients. The expression of p16INK4A gene was considered negative, with at least a 50–65% immunoreactivity observed in only three cases that progressed to malignancy. No expression of high-risk HPV was detected, whereas p53 staining was positive in less than 25% of the cells demonstrating gene expression. No definite association between PVL and high-risk HPV infection could be established. Due to the high transformation potential of PVL, early recognition with aggressive treatment, including multiple biopsies, and continued close clinical follow-up, remain the mainstay of favorable management of this condition.


Proliferative verrucous leukoplakia Verrucous hyperplasia Verrucous carcinoma Squamous cell carcinoma P16INK4A Human papillomavirus 



The authors thank Dr. Elizabeth Bilodeau, Associate Professor, Oral & Maxillofacial Pathology, University of Pittsburgh, for providing assistance with p53 immunohistochemistry and high-risk HPV in-situ hybridization techniques.


No funding was required for completion of this study.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest or other disclosures.

Ethical Approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

The study was conducted after obtaining an approval from the University of Florida Institutional Review Board.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jasbir D. Upadhyaya
    • 1
  • Sarah G. Fitzpatrick
    • 1
  • Mohammed N. Islam
    • 1
  • Indraneel Bhattacharyya
    • 1
  • Donald M. Cohen
    • 1
  1. 1.Department of Oral and Maxillofacial Diagnostic SciencesUniversity of Florida College of DentistryGainesvilleUSA

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