History

Whereas approximately 5% of all oral leukoplakias become malignant over 5 years, proliferative verrucous leukoplakia (PVL) is a slow-growing, progressive, often multifocal condition of the oral mucosa that inevitably eventuates in squamous cell or verrucous carcinoma, often with multiple primaries and recurrences.^{[17, 18]}Malignant transformation tends to occur over an extended follow-up period. Unlike other types of leukoplakia, which tend to develop in men younger than 40 years, proliferative verrucous leukoplakia has a predilection for women older than their fifth decade of life. Only 30% of patients with proliferative verrucous leukoplakia report a history of smoking, whereas the smoking incidence is much higher in the population of patients affected by conventional leukoplakia.^[19]

Lesions of proliferative verrucous leukoplakia may manifest as a solitary asymptomatic or rough irregular white patch or plaque that recurs and slowly expands. Over time, multiple similar lesions occur and progress into warty masses. In advanced cases, the affected tissue may become deeply folded and infiltrate bone, forming pseudocysts that may be mistaken for odontogenic cysts.^[20]Only 15% of patients report discomfort.

While conventional oral squamous cell carcinomas tend to occur on the vermillion lower lip, tongue, or floor of the mouth, lesions on the palate and gingiva are at higher risk for cancer formation in proliferative verrucous leukoplakia patients.^{[12, 21, 22]} The tongue and buccal mucosa, however, have also been reported as a common site for malignancy in proliferative verrucous leukoplakia patients. Verrucous carcinomas, on the other hand, occur most frequently on the buccal mucosa, alveolar ridge, or gingiva.

Physical Examination

Proliferative verrucous leukoplakia (PVL) lesions commonly occur on the buccal mucosa, gingiva, tongue, floor of the mouth, and palate. Examination early in the disease process may reveal isolated areas of leukokeratosis, sometimes with adjacent erythematous mucosa, as demonstrated in the image below. Individual lesions may progress from keratotic plaques to erosions, ulcerations, exophytic warty nodules, and plaques to clinical squamous or verrucous carcinoma.

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.

While women are most commonly affected on the buccal mucosa, the preponderance of men have lesions on the tongue. One patient has been reported with cutaneous extension of proliferative verrucous leukoplakia, with a well-demarcated, crusted plaque on the skin of the lower lip contiguous with the vermillion and mandibular vestibule.^[23]

Differential Diagnoses

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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Aguirre-Urizar JM. Proliferative multifocal leukoplakia better name that proliferative verrucous leukoplakia. World J Surg Oncol. 2011 Oct 10. 9:122. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Klanrit P, Sperandio M, Brown AL, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007 Mar. 43(3):310-6. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999 Jul. 35(4):354-9. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Haley JC, Hood AF, Mirowski GW. Proliferative verrucous leukoplakia with cutaneous involvement. J Am Acad Dermatol. 1999 Sep. 41(3 Pt 1):481-3. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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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):[QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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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, The Scientific Research Honor Society

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<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

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, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

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; .

Sections Proliferative Verrucous Leukoplakia
Overview
Presentation
DDx
Workup
Treatment
Medication
References

Proliferative Verrucous Leukoplakia Clinical Presentation

History

Physical Examination

References

Tables

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