Proliferative Verrucous Leukoplakia

Updated: Feb 20, 2019
Author: Rahat S Azfar, MD; Chief Editor: Jeff Burgess, DDS, MSD 



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.


The etiology of proliferative verrucous leukoplakia (PVL) is unknown. An association with human papillomavirus (HPV) infection, particularly strains 16 and 18, has been implicated in some cases.[1] Furthermore, because multiple cancers occur in proliferative verrucous leukoplakia–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, 4, 5]

Furthermore, the cell cycle regulatory genes p16INK4aand p14ARFare noted to be altered in lesions of proliferative verrucous leukoplakia.[6] However, a role for the TP53 gene mutation or inactivation has not been found in the pathogenesis of proliferative verrucous leukoplakia.[7]

Increased expression of immunoreactive tumor growth factor-alpha has been noted in lesions of both proliferative verrucous leukoplakia and oral squamous cell cancer, but not in healthy oral mucosa.[8] Tumor growth factor-alpha 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 proliferative verrucous leukoplakia 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 proliferative verrucous leukoplakia early in the course of the disease.[9] More recently, it has been suggested that a combination of image-based DNA ploidy analysis and evidence of dysplasia on histology may be useful in predicting which lesions are likely to undergo malignant transformation.[10]

Furthermore, unlike other forms of oral leukoplakia and oral squamous cell cancer, proliferative verrucous leukoplakia 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.[11, 12, 13, 14, 15]



United States

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


No data on the worldwide incidence of proliferative verrucous leukoplakia are reported.


Although most studies of proliferative verrucous leukoplakia have been reported from western populations in the United States, Great Britain, Spain, and Italy, cases of possible proliferative verrucous leukoplakia have been reported in people of Indian and Chinese origin living in Malaysia.[16]


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


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


Nearly all cases of proliferative verrucous leukoplakia (PVL) develop into malignancy. Proliferative verrucous leukoplakia–associated cancer mortality rates reportedly are 39-43%.

Patient Education

Patients with proliferative verrucous leukoplakia (PVL) should avoid other known factors associated with development of oral squamous cell carcinoma, such as tobacco, alcohol, and betel.




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 li 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



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]


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]



Medical Care

Owing to the progressive nature of proliferative verrucous leukoplakia (PVL), 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. Topical imiquimod therapy has been suggested to be successful.[30]

Laser ablation reportedly has been successful in a very small group of patients followed for 6-178 months.[31] Diode laser based excision has been reported to achieve a good clinical response over a 2-year period in one case report of HPV-16–associated proliferative verrucous leukoplakia.[32]

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 proliferative verrucous leukoplakia 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.[33]

Surgical Care

Surgical resection is the current treatment of choice for proliferative verrucous leukoplakia (PVL). However, given the high rate of recurrence, multiple surgical interventions may be necessary, including block resections in cases involving the gingiva.[28]


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


Advise patients with proliferative verrucous leukoplakia (PVL) to avoid other known factors associated with development of oral carcinoma, such as tobacco, alcohol, and betel.

Long-Term Monitoring

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



Antineoplastic Agent, Antibiotic

Bleomycin (Blenoxane)

This agent consists of a 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. The planar end intercalates with DNA, while the 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.

It is not absorbed when given orally; peak levels are reached in approximately 30-60 min when given intramuscularly and are only one third of the levels obtained after intravenous administration; approximately 50% of the drug is absorbed systemically after intrapleural or intraperitoneal administration; systemic absorption after intracavitary administration for craniopharyngioma not negligible.

The volume of distribution is 20-30 L, both in intracellular and extracellular fluid. Less than 10% is bound to plasma proteins.

Bleomycin has plasma half-life of more than 1 hour and a terminal half-life of 2-4 hours, but it could be as long as 22 hours in patients with renal dysfunction or those previously treated with cisplatin.

Approximately 50% is eliminated in the urine within 24 hours. Most tissues (known exceptions—skin and lungs) contain an enzyme, bleomycin hydrolase (most active tissues are liver and kidney), which readily inactivates the drug; therefore, toxicity is tissue specific, occurring in tissues lacking this enzyme. Bleomycin is mostly used systemically in combination with other drugs (mostly with cisplatin and vincristine).

The principal mechanisms of resistance include high levels of bleomycin hydrolase, cell mutations altering DNA sequences to prevent intercalation, poor cell accumulation of the drug, and rapid plasma removal. None of these factors plays an important role when bleomycin is administered locally in a 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.

The maximum recommended total cumulative dose for systemic use is 400 U. Unit measurement is based on toxicity to bacteria; 1 U equals approximately 1.7 mg.

Administered systemically, bleomycin does not produce significant bone marrow toxicity. Toxicity with local administration is due to both systemic contamination (when anaphylactoid reactions, transient fever, nausea, and vomiting could occur) and leakage into surrounding neural tissue. Fatal outcomes have been reported with leakage, owing 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.