Laboratory Studies

Although no definitive role has been identified for human papillomavirus (HPV) infection, lesional polymerase chain reaction testing for HPV DNA may be performed. In addition, flow cytometric analysis of tissue may have a role in detecting lesions of proliferative verrucous leukoplakia (PVL) early in the course of disease. Furthermore, increased expression of Mcm-2 as detected by immunohistochemistry may be helpful in identifying areas of potential malignant transformation within lesions of proliferative verrucous leukoplakia.^{[24, 25]}A small 2016 study of salivary proteins has shown an association with low-expression levels of angiotensin and dipeptidyl peptidase 1 proteins in proliferative verrucous leukoplakia patients versus controls, suggesting that these could be used as potential biomarkers of disease in the future.^[26]

Procedures

Perform an oral biopsy using either a scalpel or a brush biopsy, and use computer-aided analytical techniques to detect dysplasia or carcinoma.

Histologic Findings

Histology findings can range from verrucous hyperplasia to verrucous carcinoma to less-differentiated carcinoma and can include any combination of these histologic features. Additionally, a lymphocytic lichenoid infiltrate without evidence of significant basilar vacuolization has been reported in some cases.^{[10, 20]}One or more of these histologic features may appear in a single biopsy specimen, multiple biopsies taken at the same time, or from serial biopsies over time.^[27]Because of this variability, the diagnosis of proliferative verrucous leukoplakia (PVL) is based mainly on clinical findings.^{[28, 29]}

Treatment & Management

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 May. 24(5):193-7. [Medline].
Bagan JV, Jimenez Y, Murillo J, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007 Jan. 65(1):46-9. [Medline].
Campisi G, Giovannelli L, Ammatuna P, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004 Sep. 40(8):835-40. [Medline].
Bagan JV, Jimenez Y, Murillo J, et al. Epstein-Barr virus in oral proliferative verrucous leukoplakia and squamous cell carcinoma: A preliminary study. Med Oral Patol Oral Cir Bucal. 2008 Feb 1. 13(2):E110-3. [Medline].
Aguirre-Urizar JM. Proliferative multifocal leukoplakia better name that proliferative verrucous leukoplakia. World J Surg Oncol. 2011 Oct 10. 9:122. [Medline]. [Full Text].
Kresty LA, Mallery SR, Knobloch TJ, et al. Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev. 2008 Nov. 17(11):3179-87. [Medline].
Gopalakrishnan R, Weghorst CM, Lehman TA, 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 Apr. 83(4):471-7. [Medline].
Kannan R, Bijur GN, Mallery SR, et al. Transforming growth factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Jul. 82(1):69-74. [Medline].
Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994 Oct. 78(4):469-75. [Medline].
Klanrit P, Sperandio M, Brown AL, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007 Mar. 43(3):310-6. [Medline].
Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985 Sep. 60(3):285-98. [Medline].
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 Apr. 40(4):440-3. [Medline].
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 Oct. 82(4):396-401. [Medline].
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 Aug. 84(2):154-7. [Medline].
Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999 Jul. 35(4):354-9. [Medline].
Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003 Aug. 32(7):383-92. [Medline].
Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés 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 Aug. 47(8):732-5. [Medline].
Gouvêa AF, Moreira AE, Reis RR, de Almeida OP, Lopes MA. Proliferative verrucous leukoplakia, squamous cell carcinoma and axillary metastasis. Med Oral Patol Oral Cir Bucal. 2010 Sep 1. 15(5):e704-8. [Medline].
Cerero-Lapiedra R, Baladé-Martínez D, Moreno-López LA, Esparza-Gómez G, Bagán JV. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010 Nov 1. 15(6):e839-45. [Medline].
Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007 May. 36(5):315-8. [Medline].
Bagan JV, Jimenez Y, Sanchis JM, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003 Aug. 32(7):379-82. [Medline].
Abadie WM, Partington EJ, Fowler CB, Schmalbach CE. Optimal Management of Proliferative Verrucous Leukoplakia: A Systematic Review of the Literature. Otolaryngol Head Neck Surg. 2015 Oct. 153 (4):504-11. [Medline].
Haley JC, Hood AF, Mirowski GW. Proliferative verrucous leukoplakia with cutaneous involvement. J Am Acad Dermatol. 1999 Sep. 41(3 Pt 1):481-3. [Medline].
Gouvêa AF, Vargas PA, Coletta RD, Jorge J, Lopes MA. Clinicopathological features and immunohistochemical expression of p53, Ki-67, Mcm-2 and Mcm-5 in proliferative verrucous leukoplakia. J Oral Pathol Med. 2010 Jul. 39(6):447-52. [Medline].
Gouvêa AF, Santos Silva AR, Speight PM, Hunter K, Carlos R, Vargas PA, et al. High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. Histopathology. 2013 Mar. 62 (4):551-62. [Medline].
Flores IL, Santos-Silva AR, Coletta RD, Leme AF, Lopes MA. Low expression of angiotensinogen and dipeptidyl peptidase 1 in saliva of patients with proliferative verrucous leukoplakia. World J Clin Cases. 2016 Nov 16. 4 (11):356-363. [Medline].
Cabay RJ, Morton TH Jr, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature. J Oral Pathol Med. 2007 May. 36(5):255-61. [Medline].
Vigliante CE, Quinn PD, Alawi F. Proliferative verrucous leukoplakia: report of a case with characteristic long-term progression. J Oral Maxillofac Surg. 2003 May. 61(5):626-31. [Medline].
Greer RO. Pathology of malignant and premalignant oral epithelial lesions. Otolaryngol Clin North Am. 2006 Apr. 39(2):249-75, v. [Medline].
Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Naranjo-Diaz MJ, Aneiros-Fernandez J, Ruiz-Villaverde R, et al. Successful treatment of proliferative verrucous leukoplakia with 5% topical imiquimod. Dermatol Ther. 2017 Mar. 30 (2):[Medline].
Schoelch ML, Sekandari N, Regezi JA, Silverman S Jr. Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope. 1999 Jun. 109(6):949-53. [Medline].
Bombeccari GP, Garagiola U, Candotto V, Pallotti F, Carinci F, Giannì AB, et al. Diode laser surgery in the treatment of oral proliferative verrucous leukoplakia associated with HPV-16 infection. Maxillofac Plast Reconstr Surg. 2018 Dec. 40 (1):16. [Medline].
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 Aug. 30(4):318-22. [Medline].

Media Gallery

A leukokeratotic plaque is seen in on the upper lip, along with an erythematous plaque on the left hard palate. The patient has a large right-palate defect from a prior surgical excision of a squamous cell carcinoma.

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Author

Rahat S Azfar, MD Clinical Instructor, Department of Dermatology, University of Pennsylvania Health System

Rahat S Azfar, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Fatima A Abdulla, MD Associated Staff Physician, Department of Dermatology, Cleveland Clinic Abu Dhabi, UAE

Fatima A Abdulla, MD is a member of the following medical societies: European Academy of Dermatology and Venereology, Jordan Medical Association, Jordanian Society of Dermatology and Venereology

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for MOHS Surgery, Association of Military Dermatologists, Phi Beta Kappa

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society of Dermatopathology, Pennsylvania Academy of Dermatology

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Jeff Burgess, DDS, MSD (Retired) Clinical Assistant Professor, Department of Oral Medicine, University of Washington School of Dental Medicine; (Retired) Attending in Pain Center, University of Washington Medical Center; (Retired) Private Practice in Hawaii and Washington; Director, Oral Care Research Associates

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

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