Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285–98.

    Article  CAS  Google Scholar 

  2. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. World Health Organization classification of head and neck tumors. 4th ed. Lyon: IARC; 2017.

    Google Scholar 

  3. Palefsky JM, Silverman S Jr, Abdel-Salaam M, Daniels TE, Greenspan JS. Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med. 1995;24:193–7.

    Article  CAS  Google Scholar 

  4. Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer. 1980;46:1855–62.

    Article  CAS  Google Scholar 

  5. Feller L, Wood NH, Raubenheimer EJ. Proliferative verrucous leukoplakia and field cancerization: report of a case. J Int Acad Periodontol. 2006;8:67–70.

    Google Scholar 

  6. Bagan JV, Murillo J, Poveda R, Gavalda C, Jimenez Y, Scully C. Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. Oral Oncol. 2004;40:440–3.

    Article  Google Scholar 

  7. Eversole LR. Papillary lesions of the oral cavity: relationship to human papillomaviruses. J Calif Dent Assoc. 2000;28:922–7.

    CAS  Google Scholar 

  8. Campisi G, Giovannelli L, Ammatuna P, Capra G, Colella G, Di Liberto C, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004;40:835–40.

    Article  CAS  Google Scholar 

  9. Fettig A, Pogrel MA, Silverman S Jr, Bramanti TE, Da Costa M, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723–30.

    Article  CAS  Google Scholar 

  10. Bagan JV, Jimenez Y, Murillo J, Gavalda C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007;65:46–9.

    Article  Google Scholar 

  11. Hay CM, Lachance JA, Lucas FL, Smith KA, Jones MA. Biomarkers p16, human papillomavirus and p53 predict recurrence and survival in early stage squamous cell carcinoma of the vulva. J Low Genit Tract Dis. 2016;20:252–6.

    Article  Google Scholar 

  12. Scheffner M, Munger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad USA. 1991;88:5523–7.

    Article  CAS  Google Scholar 

  13. Adegboyega PA, Boromound N, Freeman DH. Diagnostic utility of cell cycle and apoptosis regulatory proteins in verrucous squamous carcinoma. Appl Immunohistochem Mol Morphol. 2005;13:171–7.

    Article  CAS  Google Scholar 

  14. Gopalakrishnan R, Weghorst CM, Lehman TA, Calvert RJ, Bijur G, Sabourin CL, et al. Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:471–7.

    Article  CAS  Google Scholar 

  15. Lewis JS Jr, Chernock RD, Ma XJ, Flanagan JJ, Luo Y, Gao G, et al. Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlate with human papillomavirus RNA status. Mod Pathol. 2012;25:1212–20.

    Article  CAS  Google Scholar 

  16. Cerero-Lapiedra R, Balade-Martinez D, Moreno-Lopez LA, Esparza-Gomez G, Bagan JV. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:e839–45.

    Google Scholar 

  17. Carrard VC, Brouns ER, van der Waal I. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:e411–3.

    Google Scholar 

  18. Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999;35:354–9.

    Article  CAS  Google Scholar 

  19. Slootweg PJ, Muller H. Verrucous hyperplasia or verrucous carcinoma. An analysis of 27 patients. J Maxillofac Surg. 1983;11:13–9.

    Article  CAS  Google Scholar 

  20. Murrah VA, Batsakis JG. Proliferative verrucous leukoplakia and verrucous hyperplasia. Ann Otol Rhinol Laryngol. 1994;103:660–3.

    Article  CAS  Google Scholar 

  21. Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154–7.

    Article  Google Scholar 

  22. Bagan JV, Jimenez Y, Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379–82.

    Article  Google Scholar 

  23. Bagan JV, Jimenez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortes J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011;47:732–5.

    Article  Google Scholar 

  24. Reuschenbach M, Waterboer T, Wallin KL, Einenkel J, Dillner J, Hamsikova E, et al. Characterization of humoral immune responses against p16, p53, HPV16 E6 and HPV16 E7 in patients with HPV-associated cancers. Int J Cancer. 2008;123:2626–31.

    Article  CAS  Google Scholar 

  25. Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 1989;8:4099–105.

    Article  CAS  Google Scholar 

  26. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50:565–74.

    Article  Google Scholar 

  27. Akrish S, Ben-Izhak O, Sabo E, Rachmiel A. Oral squamous cell carcinoma associated with proliferative verrucous leukoplakia compared with conventional squamous cell carcinoma-a clinical, histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:318–25.

    Article  Google Scholar 

  28. Thennavan A, Byatnal AA, Solomon MC, Radhakrishnan RA. The role of Ki-67, p16, CD34, Bcl-2, cyclooxygenase-2 in the pathogenesis of proliferative verrucous leukoplakia. Indian J Cancer. 2015;52:498–502.

    Article  CAS  Google Scholar 

  29. Femiano F, Gombos F, Scully C. Oral proliferative verrucous leukoplakia (PVL); open trial of surgery compared with combined therapy using surgery and methisoprinol in papillomavirus-related PVL. Int J Oral Maxillofac Surg. 2001;30:318–22.

    Article  CAS  Google Scholar 

  30. Wang SS, Hildesheim A. Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr. 2003;2003(31):35–40.

    Article  Google Scholar 

  31. Santos M, Montagut C, Mellado B, Garcia A, Ramon y Cajal S, Cardesa A, et al. Immunohistochemical staining for p16 and p53 in premalignant and malignant epithelial lesions of the vulva. Int J Gynecol Pathol. 2004;23:206–14.

    Article  Google Scholar 

  32. Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res. 2000;6:1702–10.

    CAS  Google Scholar 

  33. Acin S, Li Z, Mejia O, Roop DR, El-Naggar AK, Caulin C. Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras. J Pathol. 2011;225:479–89.

    Article  CAS  Google Scholar 

  34. Shin DM, Lee JS, Lippman SM, Lee JJ, Tu ZN, Choi G, et al. p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. J Natl Cancer Inst. 1996;88:519–29.

    Article  CAS  Google Scholar 

  35. Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396–401.

    Article  CAS  Google Scholar 

  36. Poveda-Roda R, Bagan JV, Jimenez-Soriano Y, Diaz-Fernandez JM, Gavalda-Esteve C. Retinoids and proliferative verrucous leukoplakia (PVL). A preliminary study. Med Oral Patol Oral Cir Bucal. 2010;15:e3–9.

    Google Scholar 

Download references

Acknowledgements

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.

Funding

No funding was required for completion of this study.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, 1395 Center Drive, Gainesville, FL, 32610, USA

    Jasbir D. Upadhyaya, Sarah G. Fitzpatrick, Mohammed N. Islam, Indraneel Bhattacharyya & Donald M. Cohen

Authors
  1. Jasbir D. Upadhyaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah G. Fitzpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed N. Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Indraneel Bhattacharyya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald M. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jasbir D. Upadhyaya.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Upadhyaya, J.D., Fitzpatrick, S.G., Islam, M.N. et al. A Retrospective 20-Year Analysis of Proliferative Verrucous Leukoplakia and Its Progression to Malignancy and Association with High-risk Human Papillomavirus. Head and Neck Pathol 12, 500–510 (2018). https://doi.org/10.1007/s12105-018-0893-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-018-0893-7

Keywords

Search

Navigation