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Proliferative Verrucous Leukoplakia

Rahat S Azfar, MD, Staff Physician, Department of Dermatology, University of Pennsylvania Health System
William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

Updated: Apr 23, 2008

Introduction

Background

Proliferative verrucous leukoplakia (PVL) is an uncommon form of progressive multifocal leukoplakia with a high rate of malignant transformation to either squamous cell cancer or verrucous carcinoma and a high probability of recurrence. See Squamous Cell Carcinoma, Verrucous Carcinoma, and Leukoplakia, Oral for more information on these topics.

Pathophysiology

The etiology of PVL is unknown. An association with human papillomavirus (HPV) infection, particularly strains 16 and 18, has been implicated in some cases (see Human Papillomavirus and the Medscape HPV and Cervical Cancer Resource Center).1 Furthermore, because multiple cancers occur in PVL-afflicted patients (ie, field-cancerization phenomenon), this suggests an infectious agent is responsible for the tumors. However, this link is inconsistently present in investigated cases.2,3 Furthermore, a role for the P53 gene mutation or inactivation has not been found in the pathogenesis of PVL.4
 
Increased expression of immunoreactive tumor growth factor-α has been noted in lesions of both PVL and oral squamous cell cancer, but not in healthy oral mucosa.5 Tumor growth factor-α is a potent mitogenic polypeptide expressed by epithelial cells under physiologic conditions and by activated macrophages and eosinophils in certain pathologic conditions.

Flow cytometric analysis of archived lesions of PVL has shown evidence of aneuploid cell lines, with DNA indexes remaining constant throughout the course of disease in most cases. Thus, flow cytometry has been proposed as a tool to help identify lesions of PVL early in the course of the disease.6

Furthermore, unlike other forms of oral leukoplakia and oral squamous cell cancer, PVL lesions are not strongly associated with a history of alcohol or tobacco use or the presence of candidiasis, nor has evidence of immunodeficiency or vitamin deficiency been linked.7,8,9,10,11

Frequency

United States

PVL is an uncommon variant of oral leukoplakia, occurring in less than 1% of adults.

International

No data on worldwide incidence are reported.

Mortality/Morbidity

Nearly all cases of PVL develop into malignancy. PVL-associated cancer mortality rates reportedly are 39-43%.

Race

Although most studies of PVL have been reported from western populations in the United States, Great Britain, Spain, and Italy, cases of possible PVL have been reported in people of Indian and Chinese origin living in Malaysia.12

Sex

Most cases occur in females, with a female-to-male incidence ratio of approximately 4:1.

Age

PVL is usually seen in adults older than 40 years. The peak incidence occurs in women aged 60-70 years.

Clinical

History

Whereas approximately 5% of all oral leukoplakias become malignant over 5 years, 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. 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, PVL has a predilection for women older than their fifth decade of life. Only 30% of patients with PVL report a history of smoking, whereas the smoking incidence is much higher in the population of patients affected by conventional leukoplakia.

Lesions of PVL 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. 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 PVL patients.8,13 The tongue, however, has also been reported as a common site for malignancy in PVL patients. Verrucous carcinomas, on the other hand, occur most frequently on the buccal mucosa, alveolar ridge, or gingiva.

Physical

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. Individual lesions may progress from keratotic plaques to erosions, ulcerations, exophytic warty nodules, and plaques to clinical squamous or verrucous 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 disease, with a well-demarcated, crusted plaque on the skin of the lower lip contiguous with the vermillion and mandibular vestibule.14

Causes

See Pathophysiology.

Differential Diagnoses

Erythroleukoplakia
Squamous Cell Carcinoma
Keratoacanthoma
Squamous papilloma
Leukoplakia, Oral
Verrucous Carcinoma
Nodular leukoplakia
Verrucous hyperplasia
Oral Florid Papillomatosis

Other Problems to Be Considered

Verruca vulgaris
Condyloma acuminatum
Molluscum contagiosum
Other papillary lesions

Workup

Laboratory Studies

Although no definitive role has been identified for 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 PVL early in the course of disease.

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. Because of this variability, the diagnosis of PVL is based mainly on clinical findings.15,16

Treatment

Medical Care

Owing to the progressive nature of this disease, many forms of therapy used for the management of traditional leukoplakia have been disappointing. Carbon dioxide laser, radiation, topical bleomycin solution, oral retinoids, beta-carotene, and systemic chemotherapy have all failed at achieving permanent cure.  Although improvements have been noted with some of these modalities, recurrence rates after cessation of therapy are high, often within months of discontinuation of treatment.

Laser ablation reportedly has been successful in a very small group of patients followed for 6-178 months.17 Topical photodynamic therapy also may prove useful; it causes relatively low morbidity and no scarring, and multiple mucosal sites can be treated simultaneously. However, multiple treatments over the course of the disease's progression may be required.

Methisoprinol (isoprinosine or inosine pranobex) is a synthetic agent capable of inhibiting viral RNA synthesis and replication and of stimulating antiviral cell–mediated reactions that has been shown to have some clinical efficacy in HPV-induced lesions. In an open-label trial of HPV-positive patients with PVL treated with surgery alone versus surgery with presurgical and postsurgical treatment with methisoprinol at 500 mg q4h for 3 days preoperatively, followed by 500 mg bid for 2 months postoperatively, 72% and 16% of patients in each respective treatment arm experienced relapse at 18-month postoperative follow-up; however, no longer-term follow-up or randomized controlled trial data are available.18

Surgical Care

Surgical resection is the current treatment of choice. However, given the high rate of recurrence, multiple surgical interventions may be necessary, including block resections in cases involving the gingiva.15

Consultations

Consultations with an oromaxillary pathologist, oral surgeon, and otorhinolaryngologist are suggested.

Follow-up

Further Outpatient Care

Given the high rate of malignant transformation in patients with PVL, a thorough intraoral examination should be performed every 6 months, with a low threshold for biopsy of suggestive lesions.

Deterrence/Prevention

Advise patients to avoid other known factors associated with development of oral carcinoma, such as tobacco, alcohol, and betel.

Prognosis

Nearly 100% of patients with PVL develop one or more oral malignancy over a lifetime, often resulting in death from disease.

Patient Education

Patients should avoid other known factors associated with development of oral squamous cell carcinoma, such as tobacco, alcohol, and betel.

Miscellaneous

Medicolegal Pitfalls

Misdiagnosis of dysplasia or cancer is possible if adequate biopsy specimens are not taken.

Multimedia

A leukokeratotic plaque is seen in on the upper l...

Media file 1: 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.

References

  1. 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. May 1995;24(5):193-7. [Medline].

  2. Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. Jan 2007;65(1):46-9. [Medline].

  3. 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. Sep 2004;40(8):835-40. [Medline].

  4. 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. Apr 1997;83(4):471-7. [Medline].

  5. Kannan R, Bijur GN, Mallery SR, Beck FM, Sabourin CL, Jewell SD, 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. Jul 1996;82(1):69-74. [Medline].

  6. Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. Oct 1994;78(4):469-75. [Medline].

  7. Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. Sep 1985;60(3):285-98. [Medline].

  8. Bagán JV, Murillo J, Poveda R, Gavaldá C, Jiménez 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. Apr 2004;40(4):440-3. [Medline].

  9. 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. Oct 1996;82(4):396-401. [Medline].

  10. Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Aug 1997;84(2):154-7. [Medline].

  11. Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. Jul 1999;35(4):354-9. [Medline].

  12. Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. Aug 2003;32(7):383-92. [Medline].

  13. 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. Aug 2003;32(7):379-82. [Medline].

  14. Haley JC, Hood AF, Mirowski GW. Proliferative verrucous leukoplakia with cutaneous involvement. J Am Acad Dermatol. Sep 1999;41(3 Pt 1):481-3. [Medline].

  15. Vigliante CE, Quinn PD, Alawi F. Proliferative verrucous leukoplakia: report of a case with characteristic long-term progression. J Oral Maxillofac Surg. May 2003;61(5):626-31. [Medline].

  16. Greer RO. Pathology of malignant and premalignant oral epithelial lesions. Otolaryngol Clin North Am. Apr 2006;39(2):249-75. [Medline].

  17. Schoelch ML, Sekandari N, Regezi JA, Silverman S Jr. Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope. Jun 1999;109(6):949-53. [Medline].

  18. 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. Aug 2001;30(4):318-22. [Medline].

Keywords

PVL, leukoplakia, oral squamous cell carcinoma, oral SCC, verrucous carcinoma, verrucous hyperplasia, oral cancer, mouth cancer

Contributor Information and Disclosures

Author

Rahat S Azfar, MD, Staff Physician, 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, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

Medical Editor

Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland
Disclosure: Stiefel Salary Employment

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Rosalie Elenitsas, MD, Associate 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 Society of Dermatopathology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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