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REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 469-473

Proliferative verrucous leukoplakia: An update


1 Department of Oral Medicine and Radiology, Rural Dental College, Loni, Maharashtra, India
2 Department of Pathology, Rural Medical College, Pravara Institute of Medical Sciences, Loni, Maharashtra, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Anita Munde
Department of Oral Medicine and Radiology, Rural Dental College, Pravara Institute of Medical Sciences, Loni A/P-Loni, Tal-Rahata, Ahmednagar - 413736, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151443

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 > Abstract 


Proliferative verrucous leukoplakia (PVL) is a rare form of oral leukoplakia, which was first described in 1985 by Hansen et al. Since then, various published case series have presented PVL as a disease with aggressive biological behavior due to its high probability of recurrence and a high rate of malignant transformation, usually higher than 70%. PVL is a long-term progressive condition, which is observed more frequently in elderly women, over 60 years at the time of diagnosis. The buccal mucosa and tongue are the most frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features with a progressive deterioration of the lesions, making it more and more difficult to control. Tobacco use does not seem to have a significant influence on the appearance or progression of PVL and may occur both in smokers and nonsmokers. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa. At present, the etiology of PVL remains unclear as well as its management and diagnosis, which is still retrospective, late and poorly defined, lacking consensus criteria. This short review discusses the clinical and histopathological features, diagnosis, traditional treatment and the current management of the disease.

Keywords: Carcinoma, leukoplakia, malignant transformation, proliferative verrucous leukoplakia


How to cite this article:
Munde A, Karle R. Proliferative verrucous leukoplakia: An update. J Can Res Ther 2016;12:469-73

How to cite this URL:
Munde A, Karle R. Proliferative verrucous leukoplakia: An update. J Can Res Ther [serial online] 2016 [cited 2019 Jul 17];12:469-73. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/469/151443




 > Introduction Top


White lesions are relatively frequent in the oral cavity with a prevalence of approximately 24.8%.[1] Among them is oral leukoplakia with a prevalence rate of 0.2 to 3.6%.[2] Petti reported an estimated world leukoplakia prevalence of 2%[3] while for van der Waal a rate of 0.5% or lower is more realistic given the geographical variations.[4]

World Health Organization described Leukoplakia as a “Precancerous Lesion”.[5] However, more recently it has been suggested that the terms “premalignant “and “precancerous” should be substituted for “potentially malignant”, and that all precancerous lesions and conditions should be grouped under the common name of “potentially malignant disorders”.[6] Following the latest workshop on oral precancer organized in 2005 by the World Health Organization Collaborating Centre for Oral Cancer, oral leukoplakia should be defined as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer”.[4] Despite these modifications in its nomenclature and classification, oral leukoplakia remains the most frequent potentially malignant disorder in the oral cavity. According to the published data, its malignant transformation rate varies from 0.13 to 17.5%,[7] with a reported annual malignant transformation rate of approximately 1% for all types of oral leukoplakia.[8]

Proliferative verrucous leukoplakia (PVL), a rare form of oral leukoplakia was first reported in 1985 by Hansen et al. as a long-term progressive condition (sometimes more than 20 years), which develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features. The term that has been used before until the description of Hansen et al., was oral florid papillomatosis, which has now disappeared from the literature.[8]

PVL presents with specific characteristics, mainly a more aggressive biological behavior than other forms of leukoplakia expressed by: A tendency toward multifocality; a high probability of recurrence; and a high rate of malignant transformation, which can range between 40% and 100% in a follow-up period of 4.4 to 11.6 years.[9],[10],[11],[12] The lesions are slow-growing yet persistent, as well as irreversible and resistant to all forms of treatment with a high recurrence rate. Throughout its development, it is common to find erythematous and/or verrucous areas that occasionally progress to verrucous carcinoma or squamous cell carcinoma (SCC).[9] Many of the articles, in the literature, are case reports or case series and few review articles. It is not surprising therefore that there is little definitive knowledge on the causes or the best management of the disease. We summarize here the little that is known from the literature search.

Demographic features

PVL is more common in elderly women who have had lesions of leukoplakia for many years.[9] The mean age at the time of diagnosis is over 60 years. Silverman and Gorsky in 1997, studied 54 patients, and the mean age of their group was 62 years with a ratio of women: men of 4:1.[10] Most other authors reported similar patterns. Bagan et al., (2003) presented 30 cases with a mean age 70.9 yrs +/- 12.73 years, and of them 80% were women.[11] There is probably no racial preference.[13] Tobacco use does not seem to have a significant influence on the disease given that PVL occurs both in smokers as well as nonsmokers.[8]

Etiopathogenesis

Viral studies

PVL is of uncertain etiology. An association with human papilloma virus (HPV) infection, particularly 16 and 18 has been suggested.[14] Palefsky et al. (1995) studied nine lesions from seven patients with PVL and they found that eight lesions (89%) were positive for HPV and out of these eight, seven contained HPV-16. They, therefore suggested that HPV-16 infection may play an important role in occurrence of these lesions.[15] Gopalakrishnan et al. (1997) studied mucosal samples from 10 PVL patients, 10 oral squamous cell carcinomas (OSCC) and 10 controls of normal mucosa, and found HPV-16 and 18 in two of eight p53-positive cases of PVL, and HPV-16 in two out of seven p53-positive OSCC, and none in controls, again supporting an association of PVL with HPV.[16] Some authors have found HPV both in PVL and in other leukoplakias. Campisi et al. (2004) analyzed 58 cases with PVL and 90 oral leukoplakia (OL) cases, studying exfoliated lesional cells by nested PCR, and found HPV DNA in 24.1% of PVL and in 25.5% of OL, with no statistical difference between both groups.[17] In contrast, other authors did not find any association between PVL and HPV. Using polymerase chain reaction (PCR), Fettig et al. (2000) found that none of their 10 PVL cases was positive for HPV.[18] Bagan et al., (2007) also did not find an association between PVL and HPV.[19] PVL has also been reported in association with Epstein–Barr virus (EBV) and Candida infection.[20],[21] EBV was examined by nested PCR in 10 cases of PVL, five with OSCC, and five normal mucosa samples. EBV was detected in 60% of the PVL cases and in 40% of OSCC, but in none of the normal mucosa samples.[20] More studies are required to confirm the findings of these preliminary studies.

Genetic studies

Aberrations in the cell cycle regulatory genes p16INK4a and p14ARF, with homozygous deletion, loss of heterozygosity, and mutation appear to be frequent findings in 20 PVL cases.[21] Histopathology and DNA ploidy have been suggested as useful in predicting the site of malignant transformation in PVL.[22]

Clinical features

PVL starts as one or more homogeneous leukoplakic areas and, over time, the lesions enlarge and affect other locations, especially the gingivae. The buccal mucosa, gingiva, and alveolar ridges were most commonly affected in the report by Reichart and Philipsen in 2003.[23] Others have found lesions more frequently on the gingiva and tongue.[10],[11] Bagan et al., (2003) in his series found 87% had lesions on the gingiva. Gandolfo et al. studied 47 patients with PVL. Lesions were most frequently observed on the alveolar crest (87.2%), with gingival involvement in 46.8% cases.[12] It has been shown that almost all lesions occur bilaterally, mainly affecting the lower alveolar ridge and buccal mucosa.[24] Clinically, it generally presents as a simple benign form, which tends to spread and become diffuse. In time, PVL develops exophytic, wart-like or erythroplakic areas that become oral carcinomas.[25]

Histopathological features

The microscopic findings associated with PVL are dependent on the stage of the disease, the site and adequacy of the biopsy. Hansen et al. reported that PVL contained areas that ranged from simple hyperkeratosis to less differentiated oral squamous cell carcinoma. Batsakis et al. (1999) similarly proposed four stages of development of the disease. Hansen et al. suggested histological stages in the continuum of PVL with intermediates [9] as follows Grade 0: Normal mucosa Grade 2: Hyperkeratosis (clinical leukoplakia) Grade 4: Verrucous hyperplasia Grade 6: Verrucous carcinoma Grade 8: Papillary squamous cell carcinoma Grade10: Less well-differentiated squamous cell carcinoma.

Batsakis et al. reduced the number of histological stages to four with intermediates.[26] Grade 0: Clinical flat leukoplakia without dysplasia Grade 2: Verrucous hyperplasia Grade 4: Verrucous carcinoma Grade 6: Conventional squamous cell carcinoma with intermediates.

Diagnosis

Because of the lack of specific histological criteria, the diagnosis of PVL is based on combined clinical and histopathologic evidence of progression. In previously published series, diagnosis of PVL was made according to Hansen's definition. There are few studies that apply a set of diagnostic criteria that are mentioned as follows:

Ghazali et al., established the following criteria:[13]

  • The lesion starts as homogenous leukoplakia without evidence of dysplasia at the first visit
  • With time, some areas of leukoplakia become verrucous
  • The disease progresses to the development of multiple isolated or confluent lesions at the same or a different site with time
  • The disease progresses through the different histopathological stages reported by Hansen et al
  • The appearance of new lesions after treatment
  • A follow-up period of no less than one year.


Gandolfo et al., established the following criteria for diagnosis:[12]

  • An initially innocuous lesion characterized by a homogenous plaque that progresses over time to an exophytic, diffuse, usually multifocal, lesion with a verrucous epithelial growth pattern
  • Histopathologically, PVL changes gradually from a simple plaque of hyperkeratosis without dysplasia to verrucous hyperplasia, verrucous carcinoma or OSCC.


Cerero-Lapiedra et al., established the following major and minor criteria:[27]

Major criteria

  1. Leukoplakia lesion with more than two different oral sites, which is most frequently found in the gingiva, alveolar processes and palate
  2. The existence of a verrucous area
  3. That the lesions have spread or engrossed during development of the disease
  4. That there has been a recurrence in a previously treated area
  5. Histopathologically, there can be from simple epithelial hyperkeratosis to verrucous hyperplasia, Verrucous carcinoma or OSCC, whether in situ or infiltrating.


Minor criteria

  1. An OL lesion that occupies at least 3 cm when adding all the affected areas
  2. That the patient be female
  3. That patient (male or female) be a non-smoker
  4. A disease evolution higher than 5 years.
In order to make the diagnosis of PVL, it was suggested that one of the two following combinations of the criteria mentioned before were met. Three major criteria (E being among them) or Two major criteria (E being among them) + two minor criteria. Nevertheless, at present, there is no criterion that will allow for the early diagnosis of the disease.

Carrard et al. suggested simplifying the diagnostic criteria of PVL by omitting the distinction between major and minor criteria proposed by Cerero-Lapiedra et al. Accordingly, they modified diagnostic criteria as follows:

  • Leukoplakia showing the presence of verrucous or wart-like areas, involving more than two oral subsites
  • When adding all involved sites, the minimum size should be at least 3 cm
  • A well documented period of disease evolution of at least 5 years, being characterized by spreading And enlarging and occurrence of one or more recurrences in a previously treated area
  • The availability of at least one biopsy in order to rule out the presence of verrucous carcinoma or squamous cell carcinoma.[28]


García-Chías et al., evaluated the ability of the diagnostic criteria proposed by Cerero-Lapiedra et al. to perform an early diagnose in patients with PVL. The criteria were applied in 116 patients, turning positive in 40 cases. Out of these, 24 (60%) had been previously diagnosed with PVL. Most frequent criteria were major criteria A and E, concerning lesion's site and histopathology, and minor criteria b and c, concerning sex and smoking habit. They concluded that diagnostic criteria developed by Cerero-Lapiedra et al. can be a useful tool for early diagnoses of PVL, as in 60% of the cases, the criteria would have allowed making an early diagnose of the disease.[29]

Differential diagnosis

The clinical differential diagnosis for PVL would include frictional keratosis, homogenous leukoplakia, squamous papilloma, verrucous hyperplasia, verrucous carcinoma, squamous cell carcinoma and chronic hyperplastic candidiasis.

Following are the differences between PVL and homogenous form of leukoplakia with regards to epidemiology, clinical presentations, histopathology and biologic behavior.

Homogenous leukoplakia is more common, seen predominantly in males, (M: F ratio 2:1), has higher correlation with tobacco and alcohol use, has moderate rate of malignant transformation (3−25%) and has a moderate mortality. In contrast PVL is relatively uncommon, seen predominantly in women (M:F ratio 1:4), has lower correlation with tobacco and alcohol use, has high rate of malignant transformation (70−80%) and has high mortality. PVL often begins as a focal lesion spreading laterally over time and can be multifocal. Early in its course, it is a flat hyperkeratotic lesion that becomes progressively verrucous and histologically often exhibits varying degrees of epithelial dysplasia.

As regards to other lesions mimicking PVL like frictional keratosis will have a clinically identifiable cause, whereas other entities like squamous papilloma, verrucous carcinoma, chronic hyperplastic candidiasis, etc., can be diagnosed by their different histological features.[30],[31]

Treatment

There is a lack of randomized controlled studies on PVL. The published data are from series of retrospective cases or case reports only. There is no reliably effective management reported, and many of the lesions recur after treatment. Patients with PVL should be advised to avoid other known factors associated with development of oral carcinoma, such as tobacco, alcohol and betel.

Because of the progressive nature of 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. Methisoprinol is a synthetic antiviral agent capable of inhibiting viral ribonucleic acid synthesis and replication and of stimulating antiviral cell-mediated reactions that has been shown to have some clinical efficacy in HPV-induced lesions. 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.[32],[33] Laser ablation reportedly has been successful in a very small group of patients followed for 6-178 months. 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 diseases progression may be required.[32] This lesion is resistant to the presently available treatment modalities; therefore, total excision with free surgical margins is critical combined with a lifelong follow-up.

Malignant transformation and recurrences

PVL is characterized not only by a high rate of recurrences after treatment but also by malignant transformation in nearly 74% of cases, with a tendency for several oral cancers to appear.[34] PVL is known for its aggressive pathology, given its multifocal involvement, high malignant transformation rates (60−100%), frequent recurrences (87−100%) and high mortality rates (30−50%).[11],[21] The gingiva and palate represented the areas with the highest frequency of these multiple malignant tumors. Given the high tendency for OSCCs to appear in these patients, they should be checked for life at least once every 6 months.[35]


 > Conclusion Top


PVL is a rare but persistent and highly progressive oral lesion that requires early and aggressive treatment to increase the chances of favorable outcome. Therefore, early diagnosis is recommended as well as consensus on diagnostic criteria, which improves therapeutic approaches. The care should be taken to follow up these cases for a long time even after surgical management as they have higher recurrence rate and are also known to undergo malignant transformation.

 
 > References Top

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