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125]

Review Article

Proliferative verrucous leukoplakia: An

update
ABSTRACT Anita Munde,
Proliferative verrucous leukoplakia(PVL) is a rare form of oral leukoplakia, which was first described in 1985 by Hansen etal. Since Ravindra Karle1
then, various published case series have presented PVL as a disease with aggressive biological behavior due to its high probability Department of
of recurrence and a high rate of malignant transformation, usually higher than 70%. PVL is a longterm progressive condition, which Oral Medicine and
is observed more frequently in elderly women, over60years at the time of diagnosis. The buccal mucosa and tongue are the most Radiology, Rural
frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with Dental College,
and 1Department of
confluent, exophytic and proliferative features with a progressive deterioration of the lesions, making it more and more difficult to
Pathology, Rural
control. Tobacco use does not seem to have a significant influence on the appearance or progression of PVL and may occur both Medical College,
in smokers and nonsmokers. Prognosis is poor for this seemingly harmlessappearing white lesion of the oral mucosa. At present, Pravara Institute of
the etiology of PVL remains unclear as well as its management and diagnosis, which is still retrospective, late and poorly defined, Medical Sciences,
lacking consensus criteria. This short review discusses the clinical and histopathological features, diagnosis, traditional treatment Loni, Maharashtra,
India
and the current management of the disease.
For correspondence:
Dr. Anita Munde,
KEY WORDS: Carcinoma, leukoplakia, malignant transformation, proliferative verrucous leukoplakia Department of
Oral Medicine and
Radiology,
Rural Dental College,
INTRODUCTION transformation rate of approximately 1% for all Pravara Institute of
types of oral leukoplakia.[8] Medical Sciences,
White lesions are relatively frequent in the oral Loni A/P-Loni,
cavity with a prevalence of approximately 24.8%.[1] Proliferative verrucous leukoplakia(PVL), a rare Tal-Rahata,
Among them is oral leukoplakia with a prevalence form of oral leukoplakia was first reported in Ahmednagar - 413736,
Maharashtra, India.
rate of 0.2 to 3.6%.[2] Petti reported an estimated 1985 by Hansen etal. as a longterm progressive E-mail: anitakarle7
world leukoplakia prevalence of 2%[3] while for van condition(sometimes more than 20years), @[Link]
der Waal a rate of 0.5% or lower is more realistic which develops initially as a white plaque
given the geographical variations.[4] of hyperkeratosis that eventually becomes a
multifocal disease with confluent, exophytic and
World Health Organization described Leukoplakia proliferative features. The term that has been
as a Precancerous Lesion. [5] However, more used before until the description of Hansen etal.,
recently it has been suggested that the terms was oral florid papillomatosis, which has now
premalignant and precancerous should be disappeared from the literature.[8]
substituted for potentially malignant, and that
all precancerous lesions and conditions should be PVL presents with specific characteristics,
grouped under the common name of potentially mainly a more aggressive biological behavior
malignant disorders. [6] Following the latest than other forms of leukoplakia expressed by: A
workshop on oral precancer organized in 2005 tendency toward multifocality; a high probability
by the World Health Organization Collaborating of recurrence; and a high rate of malignant
Centre for Oral Cancer, oral leukoplakia should transformation, which can range between Access this article online
be defined as a white plaque of questionable 40% and 100% in a followup period of 4.4 to Website: [Link]
risk having excluded(other) known diseases or 11.6years.[912] The lesions are slowgrowing yet DOI: 10.4103/0973-1482.151443
disorders that carry no increased risk for cancer.[4] persistent, as well as irreversible and resistant PMID: ***

Despite these modifications in its nomenclature to all forms of treatment with a high recurrence Quick Response Code:

and classification, oral leukoplakia remains the rate. Throughout its development, it is common
most frequent potentially malignant disorder in to find erythematous and/or verrucous areas that
the oral cavity. According to the published data, occasionally progress to verrucous carcinoma or
its malignant transformation rate varies from squamous cell carcinoma(SCC).[9] Many of the
0.13 to 17.5%,[7] with a reported annual malignant articles, in the literature, are case reports or case

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Munde and Karle: Proliferative verrucous leukoplakia

series and few review articles. It is not surprising therefore Clinical features
that there is little definitive knowledge on the causes or the PVL starts as one or more homogeneous leukoplakic areas
best management of the disease. We summarize here the little and, over time, the lesions enlarge and affect other locations,
that is known from the literature search. especially the gingivae. The buccal mucosa, gingiva, and
alveolar ridges were most commonly affected in the report
Demographic features by Reichart and Philipsen in 2003.[23] Others have found
PVL is more common in elderly women who have had lesions more frequently on the gingiva and tongue.[10,11]
lesions of leukoplakia for many years.[9] The mean age at the Baganetal.,(2003) in his series found 87% had lesions on the
time of diagnosis is over60years. Silverman and Gorsky in gingiva. Gandolfo etal. studied 47patients with PVL. Lesions
1997, studied 54patients, and the mean age of their group were most frequently observed on the alveolar crest(87.2%),
was 62years with a ratio of women: men of 4:1.[10] Most with gingival involvement in 46.8% cases.[12] It has been shown
other authors reported similar patterns. Bagan etal.,(2003) that almost all lesions occur bilaterally, mainly affecting
presented 30cases with a mean age 70.9 yrs +/12.73years, the lower alveolar ridge and buccal mucosa.[24]Clinically, it
and of them 80% were women.[11] There is probably no racial generally presents as a simple benign form, which tends to
preference.[13] Tobacco use does not seem to have a significant spread and become [Link] time, PVL develops exophytic,
influence on the disease given that PVL occurs both in smokers wartlike or erythroplakic areas that become oral carcinomas.[25]
as well as nonsmokers.[8]
Histopathological features
Etiopathogenesis The microscopic findings associated with PVL are dependent
Viral studies on the stage of the disease, the site and adequacy of
PVL is of uncertain etiology. An association with human the biopsy. Hansen etal. reported that PVL contained
papilloma virus(HPV) infection, particularly 16 and 18 has been areas that ranged from simple hyperkeratosis to less
suggested.[14] Palefsky etal.(1995) studied nine lesions from differentiated oral squamous cell carcinoma. Batsakis
seven patients with PVL and they found that eight lesions(89%) etal.(1999) similarly proposed four stages of development
were positive for HPV and out of these eight, seven contained of the [Link] histological stages
HPV16. They, therefore suggested that HPV16 infection in the continuum of PVL with intermediates[9] as follows
may play an important role in occurrence of these lesions.[15] Grade0:Normal mucosa Grade2: Hyperkeratosis(clinical
Gopalakrishnan etal.(1997) studied mucosal samples from 10 leukoplakia) Grade4: Verrucous hyperplasia Grade6: Verrucous
PVL patients, 10 oral squamous cell carcinomas(OSCC) and 10 carcinoma Grade8: Papillary squamous cell carcinoma
controls of normal mucosa, and found HPV16 and 18 in two of Grade10: Less welldifferentiated squamous cell carcinoma.
eight p53positive cases of PVL, and HPV16 in two out of seven
p53positive OSCC, and none in controls, again supporting an Batsakiset al. reduced the number of histological stages to
association of PVL with HPV.[16] Some authors have found HPV four with intermediates.[26] Grade0: Clinical flat leukoplakia
both in PVL and in other leukoplakias. Campisi etal.(2004) without dysplasia Grade2: Verrucous hyperplasia Grade4:
analyzed 58cases with PVL and 90 oral leukoplakia(OL) Verrucous carcinoma Grade6: Conventional squamous cell
cases, studying exfoliated lesional cells by nested PCR, and carcinoma with intermediates.
found HPV DNA in 24.1% of PVL and in 25.5% of OL, with
no statistical difference between both groups.[17] In contrast, Diagnosis
other authors did not find any association between PVL and Because of the lack of specific histological criteria, the
HPV. Using polymerase chain reaction(PCR), Fettig etal.(2000) diagnosis of PVL is based on combined clinical and
found that none of their 10 PVL cases was positive for HPV.[18] histopathologic evidence of [Link] previously
Bagan etal.,(2007) also did not find an association between published series, diagnosis of PVL was made according to
PVL and HPV.[19] PVL has also been reported in association with [Link] are few studies that apply a set of
EpsteinBarr virus(EBV) and Candida infection.[20,21] EBV was diagnostic criteria that are mentioned as follows:
examined by nested PCR in 10cases of PVL, five with OSCC,
and five normal mucosa samples. EBV was detected in 60% of Ghazaliet al.,established the following criteria:[13]
the PVL cases and in 40% of OSCC, but in none of the normal The lesion starts as homogenous leukoplakia without
mucosa samples.[20] More studies are required to confirm the evidence of dysplasia at the first visit
findings of these preliminary studies. With time, some areas of leukoplakia become verrucous
The disease progresses to the development of multiple
Genetic studies isolated or confluent lesions at the same or a different site
Aberrations in the cell cycle regulatory genes p16INK4a and with time
p14ARF, with homozygous deletion, loss of heterozygosity, and The disease progresses through the different
mutation appear to be frequent findings in 20 PVL cases.[21] histopathological stages reported by Hansenet al
Histopathology and DNA ploidy have been suggested as useful The appearance of new lesions after treatment
in predicting the site of malignant transformation in PVL.[22] Afollowup period of no less than one year.

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Munde and Karle: Proliferative verrucous leukoplakia

Gandolfo et al.,established the following criteria for GarcaChas etal., evaluated the ability of the diagnostic
diagnosis:[12] criteria proposed by CereroLapiedra etal. to perform an early
An initially innocuous lesion characterized by a diagnose in patients with PVL. The criteria were applied in
homogenous plaque that progresses over time to an 116patients, turning positive in 40cases. Out of these, 24(60%)
exophytic, diffuse, usually multifocal, lesion with a had been previously diagnosed with PVL. Most frequent
verrucous epithelial growth pattern criteria were major criteria A and E, concerning lesions site
Histopathologically, PVL changes gradually from a simple and histopathology, and minor criteria b and c, concerning sex
plaque of hyperkeratosis without dysplasia to verrucous and smoking habit. They concluded that diagnostic criteria
hyperplasia, verrucous carcinoma or OSCC. developed by CereroLapiedraet al. can be a useful tool for early
diagnoses of PVL, as in 60% of the cases, the criteria would have
CereroLapiedra et al.,established the following major and allowed making an early diagnose of the disease.[29]
minor criteria:[27]
Differential diagnosis
Major criteria The clinical differential diagnosis for PVL would include
(a) Leukoplakia lesion with more than two different oral sites, frictional keratosis, homogenous leukoplakia, squamous
which is most frequently found in the gingiva, alveolar papilloma, verrucous hyperplasia, verrucous carcinoma,
processes and palate squamous cell carcinoma and chronic hyperplastic candidiasis.
(b) The existence of a verrucous area
(c) That the lesions have spread or engrossed during Following are the differences between PVL and homogenous
development of the disease form of leukoplakia with regards to epidemiology, clinical
(d) That there has been a recurrence in a previously treated presentations, histopathology and biologic behavior.
area
(e) Histopathologically, there can be from simple epithelial Homogenous leukoplakia is more common, seen predominantly
hyperkeratosis to verrucous hyperplasia, Verrucous in males,(M: F ratio 2:1), has higher correlation with
carcinoma or OSCC, whetherin situor infiltrating. tobacco and alcohol use, has moderate rate of malignant
transformation (325%) and has a moderate mortality. In
Minor criteria contrast PVL is relatively uncommon, seen predominantly
(a) An OL lesion that occupies at least 3cm when adding all in women(M:F ratio 1:4), has lower correlation with
the affected areas tobacco and alcohol use, has high rate of malignant
(b) That the patient be female transformation(7080%) and has high mortality. PVL often
(c) That patient(male or female) be a nonsmoker begins as a focal lesion spreading laterally over time and can be
(d) Adisease evolution higher than 5years. multifocal. Early in its course, it is a flat hyperkeratotic lesion
that becomes progressively verrucous and histologically often
In order to make the diagnosis of PVL, it was suggested exhibits varying degrees of epithelial dysplasia.
that one of the two following combinations of the criteria
mentioned before were met. Three major criteria(E being As regards to other lesions mimicking PVL like frictional
among them) or Two major criteria(E being among them) keratosis will have a clinically identifiable cause, whereas
+ two minor criteria. Nevertheless, at present, there is other entities like squamous papilloma, verrucous carcinoma,
no criterion that will allow for the early diagnosis of the chronic hyperplastic candidiasis, etc., can be diagnosed by
disease. their different histological features.[30,31]

Carrard etal. suggested simplifying the diagnostic criteria of Treatment

PVL by omitting the distinction between major and minor There is a lack of randomized controlled studies on PVL.
criteria proposed by CereroLapiedraet al. Accordingly, they The published data are from series of retrospective cases or
modified diagnostic criteria as follows: case reports only. There is no reliably effective management
Leukoplakia showing the presence of verrucous or reported, and many of the lesions recur after treatment.
wartlike areas, involving more than two oral subsites Patients with PVL should be advised to avoid other known
When adding all involved sites, the minimum size should factors associated with development of oral carcinoma, such
be at least 3cm as tobacco, alcohol and betel.
A well documented period of disease evolution of at least
5years, being characterized by spreading And enlarging Because of the progressive nature of PVL, many forms of
and occurrence of one or more recurrences in a previously therapy used for the management of traditional leukoplakia
treated area have been disappointing. Carbon dioxide laser, radiation,
The availability of at least one biopsy in order to rule out topical bleomycin solution, oral retinoids, betacarotene and
the presence of verrucous carcinoma or squamous cell systemic chemotherapy have all failed at achieving permanent
carcinoma.[28] cure. Methisoprinol is a synthetic antiviral agent capable of

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Munde and Karle: Proliferative verrucous leukoplakia

inhibiting viral ribonucleic acid synthesis and replication and JOral Pathol Med 2007;36:57580.
of stimulating antiviral cellmediated reactions that has been 7. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant
transformation. Afollowup study of 257patients. Cancer
shown to have some clinical efficacy in HPVinduced lesions.
1984;53:5638.
Although improvements have been noted with some of these 8. Van der Waal I, Reichart PA. Oral proliferative verrucous leukoplakia
modalities, recurrence rates after cessation of therapy are high, revisited. Oral Oncol 2008;44:71921.
often within months of discontinuation of treatment.[32,33] Laser 9. Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous
ablation reportedly has been successful in a very small group leukoplakia. Alongterm study of thirty patients. Oral Surg Oral Med
Oral Pathol 1985;60:28598.
of patients followed for 6178months. Topical photodynamic
10. Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia:
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morbidity and no scarring and multiple mucosal sites can be Radiol Endod 1997;84:1547.
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12. GandolfoS, CastellaniR, PenteneroM. Proliferative verrucous
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13. GhazaliN, BakriMM, ZainRB. Aggressive, multifocal oral verrucous
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14. EversoleLR. Papillary lesions of the oral cavity: Relationship to human
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Source of Support: Nil, Conflict of Interest: None declared.
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