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Dermatology > DISEASES OF THE ORAL MUCOSA
Proliferative Verrucous Leukoplakia
Article Last Updated: Apr 23, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Rahat S Azfar, MD, Staff Physician, Department of Dermatology, University of Pennsylvania Health System
Rahat S Azfar is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Sigma Xi
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
Editors: Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland; 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; 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; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
PVL, leukoplakia, oral squamous cell carcinoma, oral SCC, verrucous carcinoma, verrucous hyperplasia, oral cancer, mouth cancer
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.
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.
Other Problems to Be Considered
Verruca vulgaris
Condyloma acuminatum
Molluscum contagiosum
Other papillary lesions
Lab 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
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.
Drug Category: Antineoplastic Agent, Antibiotic
| Drug Name | Bleomycin (Blenoxane) |
|---|
| Description | Group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. Planar end intercalates with DNA, while amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.
Not absorbed when given PO; peak levels reached in approximately 30-60 min when given IM and are only one third of levels obtained after IV administration; approximately 50% of drug absorbed systemically after intrapleural or intraperitoneal administration; systemic absorption after intracavitary administration for craniopharyngioma not negligible.
Volume of distribution is 20-30 L both in intracellular and extracellular fluid. Less than 10% is bound to plasma proteins.
Has plasma half-life of >1 h and terminal half-life of 2-4 h, but it could be as long as 22 h in patients with renal dysfunction or those previously treated with cisplatin.
Approximately 50% eliminated in urine within 24 h. Most tissues (known exceptions—skin and lungs) contain an enzyme, bleomycin hydrolase (most active tissues are liver and kidney), which readily inactivates drug; therefore, toxicity is tissue specific, occurring in tissues lacking this enzyme. Bleomycin mostly used systemically in combination with other drugs (mostly with cisplatin and vincristine).
Principal mechanisms of resistance include high levels of bleomycin hydrolase, cell mutations altering DNA sequences to prevent intercalation, poor cell accumulation of drug, and rapid plasma removal. None of these factors plays important role when bleomycin administered locally in residual cyst.
Toxicity is age dependent and cumulative-dose related; systemic administration mostly causes pulmonary toxicity. This consists of pneumonitis, which can progress to fatal pulmonary fibrosis.
Maximum recommended total cumulative dose for systemic use is 400 U. Unit measurement based on toxicity to bacteria; 1 U equals approximately 1.7 mg.
Administered systemically, does not produce significant bone marrow toxicity. Toxicity with local administration due to both systemic contamination (when anaphylactoid reactions, transient fever, nausea, and vomiting could occur) and leakage into surrounding neural tissue. Fatal outcome has been reported with leakage, due to subsequent diffuse diencephalon and brainstem edema.
Contrast CT cystography is required prior to intracavitary administration to ensure cyst wall integrity; when inconclusive, MR cystography with gadopentetate dimeglumine has been advocated.
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| Adult Dose | 0.5-1% topical solution daily for 15 d |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; significant renal function impairment; compromised pulmonary function |
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| Interactions | May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically |
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| Pregnancy | D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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| Precautions | Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis may occur (1%); monitor for adverse effects during and after treatment; vasoocclusive phenomenon with distal necrosis of digit; permanent damage to nail matrix may occur |
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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.
Medical/Legal Pitfalls
Misdiagnosis of dysplasia or cancer is possible if adequate biopsy specimens are not taken.
| 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. |
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Media type: Photo
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- 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].
- 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].
- 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].
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- 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].
- 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].
Proliferative Verrucous Leukoplakia excerpt Article Last Updated: Apr 23, 2008
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